Skip to main content
Download PDF

Critical signaling pathways governing hepatocellular carcinoma behavior; small molecule-based approaches

Cancer Cell International volume 21, Article number: 208 (2021) Cite this article

Abstract

Hepatocellular carcinoma (HCC) is the second leading cause of death due to cancer. Although there are different treatment options, these strategies are not efficient in terms of restricting the tumor cell’s proliferation and metastasis. The liver tumor microenvironment contains the non-parenchymal cells with supportive or inhibitory effects on the cancerous phenotype of HCC. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of liver carcinoma cells. Recent studies have established new approaches for the prevention and treatment of HCC using small molecules. Small molecules are compounds with a low molecular weight that usually inhibit the specific targets in signal transduction pathways. These components can induce cell cycle arrest, apoptosis, block metastasis, and tumor growth. Devising strategies for simultaneously targeting HCC and the non-parenchymal population of the tumor could lead to more relevant research outcomes. These strategies may open new avenues for the treatment of HCC with minimal cytotoxic effects on healthy cells. This study provides the latest findings on critical signaling pathways governing HCC behavior and using small molecules in the control of HCC both in vitro and in vivo models.

Background

Hepatocellular carcinoma (HCC) or hepatoma is the most type of cancer in the tissues of the liver and the second leading cause of cancer-related death around the world [1, 2]. Hepatitis B/C virus and alcohol consumption are two important and independent risk factors that increase the risk of HCC [3,4,5]. Liver transplantation or surgical liver resection are two main options for the treatment of HCC [6, 7]. In addition to other surgical treatment options, some non-surgical methods such as chemotherapy or radiotherapy are effective treatments for HCC [8, 9]. However, these methods are not able to restrict the growth, progression, and metastasis of HCC [10]. On the other hand, these treatments cause side effects on the surrounding healthy cells [11]. Several signaling pathways are dis-regulated in HCC and lead to uncontrolled cell division and metastasis [12, 13]. Targeting specific signaling pathways that are involved in HCC phenotypes such as non-stopped cell proliferation, migration, and metastasis may control the progress of the disease [14, 15]. Recent studies have established a new approach for the prevention and treatment of HCC using small molecules [16]. Small molecules are compounds with a low molecular weight that usually inhibit the specific targets in signal transduction pathways [14, 17]. Targeting cancer-specific signaling pathways using small molecules can be novel therapeutic strategies against HCC (Table 1). Inhibition of these signaling pathways or common downstream effectors by different anti-cancer agents leads to increase apoptosis and autophagy along with a decrease in the survival, metastasis, EMT, proliferation, and colony formation of HCC cell lines and animal models [18, 19]. This study provides the latest findings on using small molecules in the control of HCC both in vitro and in vivo models.

Table 1 The effects of small molecules on signaling pathways related to HCC
Full size table

Characterization of HCC

Hepatocytes as the most functionally liver cells have been reported to participate in HCC [20, 21].

Disruption of intracellular regulators or extracellular signals in the tumor microenvironment (TME) leads to inappropriate activation of certain signaling pathways [22,23,24]. Thus, aberrant molecular signaling increases levels of abnormal epigenetic modification and gene expression in the cancerous hepatocytes [25]. The outcome of these events is the loss of mature or differentiated hepatocytes (a phenomenon termed cellular dedifferentiation) [26, 27]. Under these conditions, the expression of E-cadherin (an epithelial marker) is downregulated and the cytoskeleton is reorganized [28]. The expression of Snail, Twist, and ZEB as the major transcription factors associated with mesenchymal cellular phenotype are up-regulated and induce an epithelial-to-mesenchymal transition (EMT) state in HCC [29]. Matrix metalloproteinases (MMPs) are also expressed at a high level in HCC and promote cellular migration and angiogenesis [30]. In HCC, the telomerase activity increases by up to 90%, checkpoints of the cell cycle are inactivated, and apoptosis is suppressed [31, 32]. All of these events cause uncontrolled cell proliferation, prolonged cell viability, and metastasis in HCC [33]. In HCC, several growth factors are released from non-parenchymal cells around the hepatocytes [14]. This event triggers cancerous phenotypes include EMT, metastasis, checkpoints aberration, uncontrolled proliferation, immortalization, and neovascularization in hepatocytes [34]. Other stimulators of hepatocyte malignancy come from microenvironmental cues such as hypoxia [35].

Critical signaling pathways in HCC

Several signaling pathways, including TGF-β, Wnt/B-catenin, Hh, Notch, EGF, HGF, VEFG, JAK/STAT, Hippo, and HIF are dis-regulated in HCC and lead to uncontrolled cell division and metastasis (Fig. 1).

Fig. 1
figure 1

Critical signaling pathways governing HCC behavior and using small molecules in the control of HCC

Full size image

Transforming growth factor-β (TGF-β) signaling

Cancer-associated fibroblast (CAF), derived from either stromal cells or hepatocytes is the main source of TGF-β secretion in the liver tumor [36]. TGF-β binds to the heterodimer of receptors, TβRII and TβRI, phosphorylates and activates Smad2/3 that further translocate to the nucleus in association with Smad4 [37]. TGF-β upregulates the expression of Snail, downregulates E-cadherin in the polarized hepatocytes, and promotes EMT and metastasis [38]. The role of the TGF-β signaling pathway is also the preservation of CSC subpopulation and the promotion of HCC proliferation [39]. This pathway has been shown to induce VEGF expression in HCC and recruit endothelial cells at the tumor site [40]. TGF-β with the EGF, Wnt, and SHH pathways can promote the mesenchymal features of HCC cell lines [41]. TGF-β converts tumor-associated macrophages (TAM) to M2-like macrophages and improves proliferation, metastasis, and neoangiogenesis of HCC [38], suppresses MHC-I and II expression on HCC and modulates the immune cell defense in HCC [39]. Accumulating evidence shows that HCC cell lines represent different levels of TGF-β activity (Sk-Hep1 cells with low expression and HepG2 cells with high expression of TGF-β) [42]. Suppression of TGF-β receptors by LY2109761 or SB431542 increases E-cadherin expression, decreases migration, and invasion of HCC [43]. Recently, LY2157299 (Galunisertib) was shown to decrease both the canonical and non-canonical TGF-β pathway in HCC [42]. Galunisertib with Sorafenib has entered into the phase II clinical trial [44]. FGFR or MAPK/ERK inhibitors (such as PD98059) can also be used for inhibition of TGF-β and metastasis in HCC [45]. A combination of TGF-β inhibitor and atezolizumab (a programmed cell death ligand 1 (PD-L1) inhibitor) can overcome the immune escape of HCC [46].

Wnt/B-catenin signaling

In the liver tumor, HCC cells, and macrophages are emerging sources of Wnt ligand [47]. Besides, some of the environmental risk factors cause mutations in different components of the Wnt pathway, leading to overactivation of Wnt signaling in HCC [48, 49]. Binding of Wnt ligand to the Frizzled (Fzd) and low-density lipoprotein receptor-related protein (LRP) receptors causes phosphorylation of the Disheveled [50]. Activated receptors and Disheveled inhibit the destruction of complex proteins (glycogen synthase kinase 3β (GSK3β), axis inhibition protein (Axin), and adenomatous polyposis coli (APC)), thereby causing the release of β-catenin [51, 52]. Activated β-catenin further translocates to the nucleus, binds with other co-activators (like lymphoid enhancer factor (LEF)/ T-cell factor (TCF) proteins or histone acetyltransferase CREB-binding protein (CBP)/p300), and activates the transcription of several target genes [53]. These genes are involved in CSC maintenance (CD44, EpCAM), proliferation (cyclin D1, c-Myc), and EMT [54]. Leucine-rich repeat-containing G (LGR5) is a receptor related to the Wnt/B-catenin pathway and metastasis of HCC [55, 56]. High expression of LGR5 has been found in the PLC and HepG2 lines [57]. Wnt/β-catenin also regulates angiogenesis in the liver tumor [58]. TGF-β, HGF, and environmental cues (such as hypoxia condition) can activate β-catenin [59, 60]. Targeting this pathway at the receptors-ligand level or downstream effectors modulate its activation in HCC [61, 62]. It has been reported that CGP049090 and PKF115-854 can block TCF/LEF/β-catenin interactions [58]. A recent study reported that IC-2 can decrease CSC subpopulation by sphere formation assay [63]. Some of the inhibitors of β-catenin-CBP interaction can induce the differentiation of CSCs [58].

Hedgehog (Hh) signaling

In the liver, hepatocytes and kupffer cells are able to secrete SHH ligands after injury [64, 65]. Hepatitis B virus also activates the SHH pathway [66]. SHH interacts with Patched (Ptch) receptor and triggers Smoothened (Smo) receptor, initiates the signaling cascade, and subsequent nuclear translocation of the transcription factor, and the glioma protein (Gli) [67, 68]. SHH causes the expression of cell cycle-related genes (cyclin D, c-Myc), invasion-related genes (especially MMPs), and CSC-specific genes (like CD133) in HCC [65]. Gli enhances the expression of VEGF in HCC and tumor angiogenesis [69]. SHH can bind to the TGF-β, Wnt, or Notch pathways to promote EMT and metastasis in HCC [65]. Smo and Gli can be increased in several HCC cell lines such as Hep3B, Huh7, Sk-Hep1, and HepG2 [70]. Cyclopamine is a small molecule that inhibits SMO and GANT61 [70,71,72].

Notch signaling

Activation of the Notch pathway is regulated via the interaction of two receptors on adjacent cells, wherein one of them acts as a ligand (majorly from macrophages) and the other as a receptor, known as the Notch receptor (on hepatocytes) [73, 74]. The intracellular domain (NICD) of the Notch receptor is then cleaved by γ-secretase, which further translocates to the nucleus and binds to the DNA binding transcription factors [75]. The main target genes of the Notch pathway such as Hes1, P53, cyclin-D, and c-Myc control the expression of cancer cell proliferation, invasion, and apoptosis markers [76, 77]. However, it is notable that the Notch pathway has controversial effects on HCC [75]. This pathway crosstalks with the Wnt and SHH pathways for CSC maintenance, the PI3K and mTOR pathways for HCC proliferation, and the VEGF pathway for angiogenesis [78]. The level of the Notch pathway activity in various HCC cell lines depends on their invasion character [79]. For instance, activation of Notch signaling in an invasive MHCC97 cell line is more than the HepG2 cell line [79]. Small molecules like GSI or PF-03084014 (4014) are known to suppress γ-secretase activity [80, 81]. Brivanib is a tyrosine kinase and a Notch3 inhibitor that promotes the intracellular accumulation of P53 protein and enhances HCC apoptosis [82].

Epidermal growth factor (EGF) signaling

The EGF pathway can be abnormally activated in HCC via autocrine or paracrine secretion, which promotes cell proliferation and migration [83]. EGF binds to the EGF receptors and activates PI3K/Akt, MAPK/ERK, P38/MAPK, or NF-kB proteins via a series of downstream signal transduction events [84, 85]. Overexpression and overactivation of EGFR are often observed in HCC [86]. EGF pathway is involved in the recruitment of the inflammatory cells for the secretion of interleukins (IL-1, 6, 8) and tumor progression [87]. U0126 is a small molecule inhibitor of ERK; while BEZ-235 and SHBM1009 are the antagonists of PI3K [87]. EGCG can suppress the EGFR, PI3K/Akt, and MAPK/ERK pathways [88].

Hepatocyte growth factor (HGF) signaling

HGF was found to regulate HCC proliferation, survival, and metastasis [89, 90]. HGF binds to the c-met receptor and activates PI3K, ERK, and Jnk/Stat3 pathways [91]. c-Met inhibitors such as capmatinib and tepotinib have been assessed in liver tumor clinical trials [89, 92]. c-Met is overexpressed in the MHCC97 and HCCLM3 cell lines [89]. It has been confirmed that 3-(1H-benzimidazole-2-methylene)-5-(2-methylphenylaminosulfo)-2-indolone (Indo5), PHA665752, and AMG 337 as selective c-MET inhibitors decrease HCC proliferation, migration, and tumor growth [93,94,95,96].

Vascular endothelial growth factor (VEGF) signaling

In order to ensure efficient nutrient and oxygen supply in the solid tumors, the liver tumor cells secrete growth factors that promote angiogenesis [97]. Angiogenic signals can be triggered via several pathways like HGF, PDGF, FGF, and VEGF [98]. VEGF, as the main angiogenic factor, not only induces angiogenesis, but also interacts with RTK in an autocrine manner, and activates PI3K/Akt pathway in HCC [99, 100]. Sorafenib is known to inhibit the VEGF, PDGF, and FGF pathways, thereby suppressing neovasculogeneis in HCC [101, 102]. LY2109761 (TGF-β inhibitor) can suppress VEGF secretion and neovascularization in HCC [103].

Targeting common downstream proteins in HCC

Several growth factors or environmental signaling pathways can activate the common targets in HCC [104, 105]. Signal transducer and activator of transcription 3 (Stat3), Hippo, and HIF are the main downstream proteins that are activated in HCC [106]. Inhibition of these proteins can suppress or weaken the activated signal pathway, thereby modulating the tumorigenicity of HCC [107, 108].

Janus kinases (Jak)/Stat3 signaling

The Jak/Stat3 pathway can be stimulated by inflammatory cytokines (such as interleukins, tumor necrosis factor (TNF), HGF, TGF-β, and EGF) [109, 110]. Stat3 as a transcription factor can promote HCC proliferation, metastasis, tumor survival, and angiogenesis [111]. The Jak inhibitors such as Jaki and S3i-201, or Stat3 inhibitor-related small molecules such as C188-9, ursolic acid (UA), and 2-Ethoxystypandrone can induce apoptosis, cell cycle arrest, and block CSC self-renewal in HCC [112,113,114,115].

Hippo signaling

Several growth factors such as Wnt, Notch, EGF, and SHH can activate the YAP (Yes-associated protein) pathway [116, 117]. Activated YAP translocates to the nucleus and interacts with a transcriptional coactivator, PDZ-binding motif (TAZ), and transcriptional enhanced associate domain (TEAD) to promote proliferation, metastasis, and inhibition of apoptosis and autophagy in HCC [118]. YAP or TAZ are highly expressed in HCC cell lines such as HLF and HepG2 and also primary liver tumor samples [119, 120]. Hippo protein activates several kinases and negatively regulates the expression of oncoprotein YAP [121]. Inhibition of YAP/TAZ/TEAD transcriptional activity is often used for anti-cancer treatment [122,123,124]. Verteporfin is a small molecule that inhibits YAP/TEAD complex interaction [125].

Hypoxia signaling

It has been confirmed that HCC cells rapidly use environmental oxygen [126]. In the center of the liver tumor, hypoxic conditions activate major transcription factors and inducing factors such as HIF-1A, HIF-2A [127]. HIF induces the expression of TGF-β and Snail and enhances EMT in tumor cells [126]. HIF via MMP expression helps in ECM remodeling and tumor cell invasion [128]. It also increases c-Myc expression, HCC proliferation, and escape of HCC from the immune destruction [129]. HIF also inhibits P53 (a tumor suppressor gene), enhances the activity of anti-apoptotic proteins (like Bcl-2, caspases), and prevents HCC apoptosis [126]. HIF-1A promotes CSCs maintenance in liver tumors [130]. HSP90, a general oncogene protein, stabilizes HIF-1A and positively modulates the survival, growth, and metastasis of the tumor cells [131]. Under hypoxia conditions, the cells transition from aerobic to anaerobic metabolism [132]. HIF-1A promotes glycolysis metabolism and increases lactate production in HCC [133]. The components of this pathway also interact with other pathways to promote tumorigenicity [134]. HIF-1A impacts on downstream signal transduction and increases VEGF expression and angiogenesis in HCC [98]. HIF-1A also stimulates TGF-β interaction with its receptors, enhances HCC survival, and proliferation [128]. Hypoxia activates the expression of Notch downstream genes and recruits HIF-1A for HCC metastasis [130]. Recent studies have suggested that hypoxia can regulate the Hh pathway [130]. The Wnt pathway also increases the expression of HIF-1A in HCC [130]. YAP interacts and stabilizes HIF-1A in HCC [135]. HIF-1A regulates the metabolism of HCC, increases the expression of glycolysis enzymes and glucose uptake receptors for adaptation to the hypoxic condition [130]. Besides, HIF-1A changes the activity of the macrophages and hepatic stellate cells (HSC) to promote HCC survival, growth, and angiogenesis [130]. PT2385 as a small molecule can suppress HIF-activated proteins such as Stat3, VEGF, PDGF, and ERK [136].

Cell division signaling

Uncontrolled cell cycle program and telomerase activity in the hepatocytes increase carcinogenesis [137]. The cell cycle is regulated by cyclin-dependent kinases (CDK)/Cyclin complex at different stages [138]. Downstream of signaling pathways such as EGF, TGF-β, TNF, and IL6 can stimulate CDK/CyclinD complex and phosphorylated retinoblastoma (pRb) to promote HCC proliferation [139]. P53, an anti-proliferation protein, activates P16, P21, and P27 tumor suppressor proteins at the G1 phase, thereby hindering the pRb and CDK/Cyclin proteins [140]. Notably, P21 via inhibition of procaspase 3 has contradictory effects in cancers [141]. Normal hepatocytes have a cell cycle arrest in the G0 phase; however, in the case of HCC, P21, and P27 are usually degraded [142]. Mutations of β-catenin or P53 lead to sustain expression of c-Myc, misregulation of PI3K and ERK pathways, and uncontrolled cell cycle progression in HCC [138].

In this regard, Dinaciclib and Ribociclib are CDK/pRb inhibitors that upregulate P53 to control HCC proliferation [143, 144].

Apoptosis signaling

Targeted activation of the apoptosis pathway in cancer cells is another crucial way in cancer therapy [145, 146]. In normal cells, apoptosis may initiate via the extrinsic (owing to the attachment of external ligands to the receptors) or intrinsic (owing to mitochondrial factors) pathways [147]. Cellular FlICE/caspase-8-inhibitory protein (cFLIP) and Bcl-2 are negative regulators of the apoptosis pathway, while PPARγ acts as an apoptosis inducer [148, 149].

The extrinsic pathway is activated when immune cells secrete TNF-related apoptosis-inducing ligand (TRAIL) that binds to death receptors (DR) on the cell surface [150]. This cascade causes the recruitment of a complex of FAAD-procaspase 8 (DISC complex), and subsequent activation of caspase 8 (an endonuclease and protease), leading to apoptosis [148]. The proteasome complex causes the degradation of tumor suppressor proteins and activation of NF-kB and c-FLIP, thereby promoting the survival and proliferation of HCC [148]. Additionally, NF-kB regulates MMP9 expression and HCC metastasis [151]. On the other hand, in the intrinsic apoptosis pathway, DNA damage in the cells activates P53 protein, triggers the activation of Bax, and mitochondria-mediated caspase activity [152]. P53 is crucial for cell cycle arrest, cell senescence, and cell autophagy [153, 154]. In HCC, mutations or deletion in the P53 gene or increase of its inhibitors such as a ubiquitin ligase DM2 (Double Minute 2) obligate the apoptosis pathway [155]. Snail inhibits the TRAIL pathway and P53 in cancer cells [156] HCC cell lines express P53 at different levels. For instance, Hep3B, HepG2, and Huh7 have no, normal, and high levels of P53, respectively [157]. PPARγ also positively modulates the components of these pathways and inhibits HCC survival [158]. The strategies that upregulate TRAIL receptors or ligands (via recombinant protein or agonist receptor antibodies) were shown to cause selective apoptosis in HCC cell lines [159, 160]. Co-treatment of HCC cell lines with recombinant TRAIL and Bortezomib (as proteasome inhibitors) increased the apoptosis induction in the Huh7 cells, compared to the primary hepatocytes [159]. Nutlin, an inhibitor of DM, was reported to stabilize P53 and decrease Bcl-2 expression [161]. Rubone can downregulate the expression of Notch, cyclin D1, Bcl-2, while increase P53 level in HCC [162].

Autophagy signaling

Autophagy, a type II cell death, is lysosome-dependent and initiated by surrounding the intracellular organelle with a double membrane (autophagosome) and self-degradation of cells [163]. ATG7, LC3, and beclin are the major proteins involved in this process [164]. Depends on the stage of cancer, autophagy either negatively or positively regulates cancer progression [165, 166]. In HCC late stages, autophagy promotes survival, metastasis, and EMT via activation of the TGFβ pathway, P53 degradation, and chemotherapy resistance of HCC [167]. Inhibitors of main signaling pathways such as PI3K/Akt, MAPK/ERK, and JAK/Stat3 can induce autophagy and cell death in HCC [168, 169]. Small molecules like rapamycin, Mitoxantrone (PI3K/mTOR inhibitors), and Erlotinib/Cetuximab (EGFR inhibitors) are thought to activate cellular autophagy and apoptosis in various HCC cell lines [167, 170]. Tumstatin was previously shown to increase the expression of Bax, Fas, and Fasl to induce apoptosis and autophagy in HCC [171]. However, some studies have found that the suppression of autophagy via 3-MA leads to inhibit HCC growth [167, 172]. Verteporfin, mitoxantrone, and NVP-BGT226 are small molecules that trigger autophagy in HCC [170, 173, 174].

Oxidative stress signaling

Both the intrinsic and extrinsic apoptotic pathways affect the mitochondrial respiratory chain and cause the generation of reactive oxygen species (ROS) in the cells [152, 175]. In cancer cells, ROS may play as a double-edged sword in the induction or suppression of tumor growth in a concentration-dependent manner [176]. A low level of ROS is normal in all the cell types, while its moderate level leads to promote cancer development [176]. ROS, via activation of the TGF-β pathway along with an increase in MMP expression, causes EMT, metastasis, and invasion of cancer cells [176]. ROS can stimulate VEGF or the hypoxia pathway to promote angiogenesis in HCC [177, 178] and mediates cell cycle activation and CSC maintenance in cancer [179]. ROS-mediated signaling events mediate chemoresistance to the cancer cells [180]. Though, excessive ROS can disrupt the proteins in mitochondria and promote the DNA mutations, causing the release of pro-apoptotic factors into the cytoplasm of the cancer cells [178]. Accordingly, agents that restore the intracellular REDOX balance or elevate the ROS content cannot be useful in cancer treatment [181, 182]. In this regard, vitamin C as a natural antioxidant can increase ROS production in HCC and stimulate apoptosis, cell cycle arrest, and suppress CSC self-renewal [183]. Auranofin, a thioredoxin reductase (TXNRD) inhibitor, increases ROS in HCC and suppresses both the extrinsic and intrinsic apoptotic pathways [184]. Morin, a flavonoid from Ficus carica, in combination with Auranofin caused apoptosis in HCC [185]. Propyl gallate (PG), a synthetic antioxidant, activates superoxidase and ROS formation in HCC, thereby causing autophagy and apoptosis [186]. N-acetylcysteine (NAC) acts as a potent ROS inhibitor [187]. ART, a YAP inhibitor, promotes ROS formation in HCC [188].

Conclusion and perspective

Several important signaling pathways such as TGF-β, Wnt, SHH, Notch, and RTK are misregulated in HCC, compared to the normal hepatocytes. These pathways initiate differential networks that consequently result in HCC cell cycle promotion, EMT, metastasis, vasculogenesis, and anti-apoptotic mechanisms. Suppression of these pathways with small molecules, herbal drugs, and miRNA stimulates cell cycle arrest, apoptosis, and inhibits the invasion of HCC [189, 190]. Simultaneously targeting different signaling pathways or common downstream proteins would facilitate control over malignant HCC. Induction of differentiation in transformed mesenchymal HCC to the epithelial state would also help in regulating the tumorigenesis of HCC. Smart delivery of anti-cancer agents to the liver tumor could facilitate the targeted therapy in this solid tumor.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

APC:

Adenomatous polyposis coli

CAF:

Cancer-associated fibroblast

CBP:

CREB-binding protein

CDK:

Cyclin-dependent kinases

Cflip:

Cellular FlICE/caspase-8-inhibitory protein

DM2:

Double Minute 2

DR:

Death receptors

HSC:

Hepatic stellate cells

ROS:

Reactive oxygen species

EGF:

Epidermal growth factor

EMT:

Epithelial-to-mesenchymal transition

Fzd:

Frizzled

Gli:

Glioma protein

GSK3β:

Glycogen synthase kinase 3β

HGF:

Hepatocyte growth factor

HCC:

Hepatocellular carcinoma

Hh:

Hedgehog

Indo5:

3-(1H-benzimidazole-2-methylene)-5 (2methylphenylaminosulfo)-2-indolone

Jak:

Janus kinases

LEF:

Lymphoid enhancer factor

LGR5:

Leucine-rich repeat-containing G

LRP:

Lipoprotein receptor-related protein

MMPs:

Matrix metalloproteinases

PD-L1:

Programmed cell death ligand 1

PRb:

Phosphorylated retinoblastoma

Ptch:

Patched

Smo:

Smoothened

TAM:

Tumor-associated macrophages

TCF:

T-cell factor

TEAD:

Transcriptional enhanced associate domain

TGF-β:

Transforming growth factor-β

TME:

Tumor microenvironment

TRAIL:

TNF-related apoptosis-inducing ligand

TXNRD:

Thioredoxin reductase

UA:

Ursolic acid

VEGF:

Vascular endothelial growth factor

YAP:

Yes-associated protein

References

  1. Chen S, Cao Q, Wen W, Wang H. Targeted therapy for hepatocellular carcinoma: Challenges and opportunities. Cancer Lett. 2019;460:1–9.

    Article  CAS  PubMed  Google Scholar 

  2. Balogh J, Victor D 3rd, Asham EH, Burroughs SG, Boktour M, Saharia A, Li X, Ghobrial RM, Monsour HP Jr. Hepatocellular carcinoma: a review. J Hepatocell Carcinoma. 2016;3:41–53.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Iida-Ueno A, Enomoto M, Tamori A, Kawada N. Hepatitis B virus infection and alcohol consumption. World J Gastroenterol. 2017;23:2651–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Midorikawa Y, Takayama T, Nakayama H, Higaki T, Moriguchi M, Moriya K, Kanda T, Matsuoka S, Moriyama M. Prior hepatitis B virus infection as a co-factor of chronic hepatitis C patient survival after resection of hepatocellular carcinoma. BMC Gastroenterol. 2019;19:147.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Li W, Deng R, Liu S, Wang K, Sun J. Hepatitis B virus-related hepatocellular carcinoma in the era of antiviral therapy: The emerging role of non-viral risk factors. Liver Int. 2020;40:2316–25.

    Article  CAS  PubMed  Google Scholar 

  6. Kumari R, Sahu MK, Tripathy A, Uthansingh K, Behera M. Hepatocellular carcinoma treatment: hurdles, advances and prospects. Hepat Oncol. 2018;5:HEP08.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Raza A, Sood GK. Hepatocellular carcinoma review: current treatment, and evidence-based medicine. World J Gastroenterol. 2014;20:4115–27.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Chen CP. Role of radiotherapy in the treatment of hepatocellular carcinoma. J Clin Transl Hepatol. 2019;7:183–90.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Gallicchio R, Nardelli A, Mainenti P, Nappi A, Capacchione D, Simeon V, Sirignano C, Abbruzzi F, Barbato F, Landriscina M, Storto G. Therapeutic strategies in HCC: radiation modalities. Biomed Res Int. 2016;2016:1295329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Lin Y-L, Li Y. Study on the hepatocellular carcinoma model with metastasis. Genes Dis. 2020;7:336–50.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Daher S, Massarwa M, Benson AA, Khoury T. Current and future treatment of hepatocellular carcinoma: an updated comprehensive review. J Clin Transl Hepatol. 2018;6:69–78.

    Article  PubMed  Google Scholar 

  12. Swamy SG, Kameshwar VH, Shubha PB, Looi CY, Shanmugam MK, Arfuso F, Dharmarajan A, Sethi G, Shivananju NS, Bishayee A. Targeting multiple oncogenic pathways for the treatment of hepatocellular carcinoma. Target Oncol. 2017;12:1–10.

    Article  PubMed  Google Scholar 

  13. Alqahtani A, Khan Z, Alloghbi A, Said Ahmed TS, Ashraf M, Hammouda DM. Hepatocellular carcinoma: molecular mechanisms and targeted therapies. Medicina (Kaunas). 2019;55:526.

    Article  Google Scholar 

  14. Lachenmayer A, Alsinet C, Chang CY, Llovet JM. Molecular approaches to treatment of hepatocellular carcinoma. Dig Liver Dis. 2010;42(Suppl 3):S264-272.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Dimri M, Satyanarayana A. Molecular signaling pathways and therapeutic targets in hepatocellular carcinoma. Cancers (Basel). 2020;12:491.

    Article  CAS  Google Scholar 

  16. Ma Y-S, Liu J-B, Wu T-M, Fu D. New therapeutic options for advanced hepatocellular carcinoma. Cancer Control. 2020;27:1073274820945975.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Xie J, Zhang A, Wang X. Metabolomic applications in hepatocellular carcinoma: toward the exploration of therapeutics and diagnosis through small molecules. RSC Adv. 2017;7:17217–26.

    Article  CAS  Google Scholar 

  18. Wei Q, Qian Y, Yu J, Wong CC. Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications. Oncogene. 2020;39:6139–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ren T, Zhu L, Cheng M. CXCL10 accelerates EMT and metastasis by MMP-2 in hepatocellular carcinoma. Am J Transl Res. 2017;9(6):2824–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Tummala KS, Brandt M, Teijeiro A, Graña O, Schwabe RF, Perna C, Djouder N. Hepatocellular carcinomas originate predominantly from hepatocytes and benign lesions from hepatic progenitor cells. Cell Rep. 2017;19:584–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Mu X, Español-Suñer R, Mederacke I, Affò S, Manco R, Sempoux C, Lemaigre FP, Adili A, Yuan D, Weber A, Unger K, Heikenwälder M, Leclercq IA, Schwabe RF. Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment. J Clin Invest. 2015;125:3891–903.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis. 2007;27:55–76.

    Article  CAS  PubMed  Google Scholar 

  23. Yu L-X, Ling Y, Wang H-Y. Role of nonresolving inflammation in hepatocellular carcinoma development and progression. NPJ Precis Oncol. 2018;2(1):1–10.

    CAS  Google Scholar 

  24. Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 2013;144:512–27.

    Article  PubMed  Google Scholar 

  25. Toh TB, Lim JJ, Chow EK-H. Epigenetics of hepatocellular carcinoma. Clin Transl Med. 2019;8:13–13.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Chao J, Zhao S, Sun H. Dedifferentiation of hepatocellular carcinoma: molecular mechanisms and therapeutic implications. Am J Transl Res. 2020;12:2099–109.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Agarwal T, Subramanian B, Maiti TK. Liver tissue engineering: challenges and opportunities. ACS Biomater Sci Eng. 2019;5:4167–82.

    Article  CAS  PubMed  Google Scholar 

  28. Loh C-Y, Chai JY, Tang TF, Wong WF, Sethi G, Shanmugam MK, Chong PP, Looi CY. The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition: signaling, therapeutic implications, and challenges. Cells. 2019;8:1118.

    Article  CAS  PubMed Central  Google Scholar 

  29. Giannelli G, Koudelkova P, Dituri F, Mikulits W. Role of epithelial to mesenchymal transition in hepatocellular carcinoma. J Hepatol. 2016;65:798–808.

    Article  CAS  PubMed  Google Scholar 

  30. Scheau C, Badarau IA, Costache R, Caruntu C, Mihai GL, Didilescu AC, Constantin C, Neagu M. The role of matrix metalloproteinases in the epithelial-mesenchymal transition of hepatocellular carcinoma. Anal Cell Pathol (Amst). 2019;2019:9423907.

    Google Scholar 

  31. Nault J-C, Ningarhari M, Rebouissou S, Zucman-Rossi J. The role of telomeres and telomerase in cirrhosis and liver cancer. Nat Rev Gastroenterol Hepatol. 2019;16:544–58.

    Article  PubMed  Google Scholar 

  32. Hong M, Almutairi MM, Li S, Li J. Wogonin inhibits cell cycle progression by activating the glycogen synthase kinase-3 beta in hepatocellular carcinoma. Phytomedicine. 2020;68:153174.

    Article  CAS  PubMed  Google Scholar 

  33. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008;48:1312–27.

    Article  CAS  PubMed  Google Scholar 

  34. Cicchini C, Amicone L, Alonzi T, Marchetti A, Mancone C, Tripodi M. Molecular mechanisms controlling the phenotype and the EMT/MET dynamics of hepatocyte. Liver Int. 2015;35:302–10.

    Article  PubMed  Google Scholar 

  35. Gonzalez DM, Medici D. Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014;7:re8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Zhang J, Gu C, Song Q, Zhu M, Xu Y, Xiao M, Zheng W. Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma. Cell Biosci. 2020;10:127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hata A, Chen Y-G. TGF-β signaling from receptors to Smads. Cold Spring Harb Perspect Biol. 2016;8:a022061.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Fabregat I, Caballero-Diaz D. Transforming growth factor-beta-induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Front Oncol. 2018;8:357.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Krstic J, Trivanovic D, Mojsilovic S, Santibanez JF. Transforming growth factor-beta and oxidative stress interplay: implications in tumorigenesis and cancer progression. Oxid Med Cell Longev. 2015;2015:654594.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Mancarella S, Krol S, Crovace A, Leporatti S, Dituri F, Frusciante M, Giannelli G. Validation of hepatocellular carcinoma experimental models for TGF-β promoting tumor progression. Cancers (Basel). 2019;11:1510.

    Article  CAS  Google Scholar 

  41. Steinway SN, Zanudo JG, Ding W, Rountree CB, Feith DJ, Loughran Albert TPR Jr. Network modeling of TGFbeta signaling in hepatocellular carcinoma epithelial-to-mesenchymal transition reveals joint sonic hedgehog and Wnt pathway activation. Cancer Res. 2014;74:5963–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Serova M, Tijeras-Raballand A, Dos Santos C, Albuquerque M, Paradis V, Neuzillet C, Benhadji KA, Raymond E, Faivre S, de Gramont A. Effects of TGF-beta signalling inhibition with galunisertib (LY2157299) in hepatocellular carcinoma models and in ex vivo whole tumor tissue samples from patients. Oncotarget. 2015;6:21614–27.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Fransvea E, Angelotti U, Antonaci S, Giannelli G. Blocking transforming growth factor-beta up-regulates E-cadherin and reduces migration and invasion of hepatocellular carcinoma cells. Hepatology. 2008;47:1557–66.

    Article  CAS  PubMed  Google Scholar 

  44. Kelley RK, Gane E, Assenat E, Siebler J, Galle PR, Merle P, Hourmand IO, Cleverly A, Zhao Y, Gueorguieva I, Lahn M, Faivre S, Benhadji KA, Giannelli G. A phase 2 study of galunisertib (TGF-beta1 receptor type I inhibitor) and sorafenib in patients with advanced hepatocellular carcinoma. Clin Transl Gastroenterol. 2019;10:e00056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Huang J, Qiu M, Wan L, Wang G, Huang T, Chen Z, Jiang S, Li X, Xie L, Cai L. TGF-beta1 promotes hepatocellular carcinoma invasion and metastasis via ERK pathway-mediated FGFR4 expression. Cell Physiol Biochem. 2018;45:1690–9.

    Article  CAS  PubMed  Google Scholar 

  46. Chen J, Gingold JA, Su X. Immunomodulatory TGF-beta signaling in hepatocellular carcinoma. Trends Mol Med. 2019;25:1010–23.

    Article  CAS  PubMed  Google Scholar 

  47. Yang Y, Ye Y-C, Chen Y, Zhao J-L, Gao C-C, Han H, Liu W-C, Qin H-Y. Crosstalk between hepatic tumor cells and macrophages via Wnt/β-catenin signaling promotes M2-like macrophage polarization and reinforces tumor malignant behaviors. Cell Death Dis. 2018;9:793–793.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Wang W, Smits R, Hao H, He C. Wnt/beta-catenin signaling in liver cancers. Cancers (Basel). 2019;11:926.

    Article  Google Scholar 

  49. Xu W, Zhou W, Cheng M, Wang J, Liu Z, He S, Luo X, Huang W, Chen T, Yan W, Xiao J. Hypoxia activates Wnt/beta-catenin signaling by regulating the expression of BCL9 in human hepatocellular carcinoma. Sci Rep. 2017;7:40446.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jung Y-S, Park J-I. Wnt signaling in cancer: therapeutic targeting of Wnt signaling beyond β-catenin and the destruction complex. Exp Mol Med. 2020;52(2):183–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Stamos JL, Weis WI. The β-catenin destruction complex. Cold Spring Harb Perspect Biol. 2013;5:a007898–a007898.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Liu C, Takada K, Zhu D. Targeting Wnt/β-catenin pathway for drug therapy. Med Drug Discov. 2020;8:100066.

    Article  Google Scholar 

  53. Wang W, Smits R, Hao H, He C. Wnt/β-catenin signaling in liver cancers. Cancers. 2019;11:926.

    Article  PubMed Central  Google Scholar 

  54. Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36:1461–73.

    Article  CAS  PubMed  Google Scholar 

  55. Ma Z, Guo D, Wang Q, Liu P, Xiao Y, Wu P, Wang Y, Chen B, Liu Z, Liu Q. Lgr5-mediated p53 Repression through PDCD5 leads to doxorubicin resistance in Hepatocellular Carcinoma. Theranostics. 2019;9:2967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Koni M, Pinnarò V, Brizzi MF. The Wnt signalling pathway: a tailored target in cancer. Int J Mol Sci. 2020;21:7697.

    Article  CAS  PubMed Central  Google Scholar 

  57. Effendi K, Yamazaki K, Fukuma M, Sakamoto M. Overexpression of leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5) represents a typical Wnt/beta-catenin pathway-activated hepatocellular carcinoma. Liver Cancer. 2014;3:451–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Vilchez V, Turcios L, Marti F, Gedaly R. Targeting Wnt/beta-catenin pathway in hepatocellular carcinoma treatment. World J Gastroenterol. 2016;22:823–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zheng J-J, Que Q-Y, Xu H-T. Hypoxia activates SOX5/Wnt/β-catenin signaling by suppressing MiR-338–3p in gastric cancer. Technol Cancer Res Treat. 2020;19:1533033820905825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Han Z, Li Y, Yang B, Tan R, Wang M, Zhang B, Dai C, Wei L, Chen D, Chen Z. Agmatine attenuates liver ischemia reperfusion injury by activating Wnt/β-catenin signaling in mice. Transplantation. 2020;104(9):1906–16.

    Article  CAS  PubMed  Google Scholar 

  61. Yuan K, Xie K, Lan T, Xu L, Chen X, Li X, Liao M, Li J, Huang J, Zeng Y. TXNDC12 promotes EMT and metastasis of hepatocellular carcinoma cells via activation of β-catenin. Cell Death Differ. 2020;27:1355–68.

    Article  CAS  PubMed  Google Scholar 

  62. Hou J, Zhao N, Zhu P, Chang J, Du Y, Shen W. Irradiated mesenchymal stem cells support stemness maintenance of hepatocellular carcinoma stem cells through Wnt/β-catenin signaling pathway. Cell Biosci. 2020;10:1–7.

    Article  CAS  Google Scholar 

  63. Seto K, Sakabe T, Itaba N, Azumi J, Oka H, Morimoto M, Umekita Y, Shiota G. A novel small-molecule WNT inhibitor, IC-2, has the potential to suppress liver cancer stem cells. Anticancer Res. 2017;37:3569–79.

    CAS  PubMed  Google Scholar 

  64. Shen X, Peng Y, Li H. The injury-related activation of hedgehog signaling pathway modulates the repair-associated inflammation in liver fibrosis. Front Immunol. 2017;8:1450–1450.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Jeng KS, Jeng CJ, Jeng WJ, Sheen I, Li SY, Leu CM, Tsay YG, Chang CF. Sonic Hedgehog signaling pathway as a potential target to inhibit the progression of hepatocellular carcinoma. Oncol Lett. 2019;18:4377–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Li Y, Jiang M, Li M, Chen Y, Wei C, Peng L, Liu X, Liu Z, Tong G, Zhou D, He J. Compound phyllanthus urinaria L inhibits HBV-related HCC through HBx-SHH pathway axis inactivation. Evid Based Complement Alternat Med. 2019;2019:1635837.

    PubMed  PubMed Central  Google Scholar 

  67. Skoda AM, Simovic D, Karin V, Kardum V, Vranic S, Serman L. The role of the Hedgehog signaling pathway in cancer: a comprehensive review. Bosn J Basic Med Sci. 2018;18:8–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Quijada L, Callejo A, Torroja C, Guerrero I. The patched receptor: Switching on/off the Hedgehog signaling pathway. Hedgehog-Gli signaling in human disease. 2013;23:12–33.

  69. Pinter M, Sieghart W, Schmid M, Dauser B, Prager G, Dienes HP, Trauner M, Peck-Radosavljevic M. Hedgehog inhibition reduces angiogenesis by downregulation of tumoral VEGF-A expression in hepatocellular carcinoma. United European Gastroenterol J. 2013;1:265–75.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Patil MA, Zhang J, Ho C, Cheung ST, Fan ST, Chen X. Hedgehog signaling in human hepatocellular carcinoma. Cancer Biol Ther. 2006;5:111–7.

    Article  CAS  PubMed  Google Scholar 

  71. Wang Y, Han C, Lu L, Magliato S, Wu T. Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells. Hepatology. 2013;58:995–1010.

    Article  CAS  PubMed  Google Scholar 

  72. Chen XL, Cheng QY, She MR, Wang Q, Huang XH, Cao LQ, Fu XH, Chen JS. Expression of sonic hedgehog signaling components in hepatocellular carcinoma and cyclopamine-induced apoptosis through Bcl-2 downregulation in vitro. Arch Med Res. 2010;41:315–23.

    Article  CAS  PubMed  Google Scholar 

  73. Steinbuck MP, Winandy S. A review of notch processing with new insights into ligand-independent notch signaling in T-cells. Front Immunol. 2018;9:1230–1230.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Anna B, Lluis E. Notch Signaling in Cell-Cell Communication Pathways. Current Stem Cell Reports. 2016;2:349–55.

    Article  Google Scholar 

  75. Huang Q, Li J, Zheng J, Wei A. The carcinogenic role of the notch signaling pathway in the development of hepatocellular carcinoma. J Cancer. 2019;10:1570–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Dotto GP. Crosstalk of notch with p53 and p63 in cancer growth control. Nat Rev Cancer. 2009;9:587–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Dai M-Y, Fang F, Zou Y, Yi X, Ding Y-J, Chen C, Tao Z-Z, Chen S-M. Downregulation of Notch1 induces apoptosis and inhibits cell proliferation and metastasis in laryngeal squamous cell carcinoma. Oncol Rep. 2015;34:3111–9.

    Article  CAS  PubMed  Google Scholar 

  78. Giovannini C, Bolondi L, Gramantieri L. Targeting notch3 in hepatocellular carcinoma: molecular mechanisms and therapeutic perspectives. Int J Mol Sci. 2016;18:56.

    Article  PubMed Central  CAS  Google Scholar 

  79. Zhou L, Wang DS, Li QJ, Sun W, Zhang Y, Dou KF. Downregulation of the Notch signaling pathway inhibits hepatocellular carcinoma cell invasion by inactivation of matrix metalloproteinase-2 and -9 and vascular endothelial growth factor. Oncol Rep. 2012;28:874–82.

    Article  CAS  PubMed  Google Scholar 

  80. Wu CX, Xu A, Zhang CC, Olson P, Chen L, Lee TK, Cheung TT, Lo CM, Wang XQ. Notch inhibitor PF-03084014 inhibits hepatocellular carcinoma growth and metastasis via suppression of cancer stemness due to reduced activation of Notch1-Stat3. Mol Cancer Ther. 2017;16:1531–43.

    Article  CAS  PubMed  Google Scholar 

  81. Shen Y, Yin Y, Peng Y, Lv D, Miao F, Dou F, Zhang J. Modulation of the gamma-secretase activity as a therapy against human hepatocellular carcinoma. J Cancer Res Ther. 2018;14:S473–9.

    Article  CAS  PubMed  Google Scholar 

  82. Giovannini C, Salzano AM, Baglioni M, Vitale M, Scaloni A, Zambrano N, Giannone FA, Vasuri F, D’Errico A, Svegliati Baroni G, Bolondi L, Gramantieri L. Brivanib in combination with Notch3 silencing shows potent activity in tumour models. Br J Cancer. 2019;120:601–11.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Liu Z, Chen D, Ning F, Du J, Wang H. EGF is highly expressed in hepatocellular carcinoma (HCC) and promotes motility of HCC cells via fibronectin. J Cell Biochem. 2018;119:4170–83.

    Article  CAS  PubMed  Google Scholar 

  84. Peng Q, Deng Z, Pan H, Gu L, Liu O, Tang Z. Mitogen-activated protein kinase signaling pathway in oral cancer. Oncol Lett. 2018;15:1379–88.

    PubMed  Google Scholar 

  85. Cargnello M, Roux PP. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol Mol Biol Rev. 2011;75:50–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Komposch K, Sibilia M. EGFR signaling in liver diseases. Int J Mol Sci. 2015;17:30.

    Article  PubMed Central  CAS  Google Scholar 

  87. Huang P, Xu X, Wang L, Zhu B, Wang X, Xia J. The role of EGF-EGFR signalling pathway in hepatocellular carcinoma inflammatory microenvironment. J Cell Mol Med. 2014;18:218–30.

    Article  CAS  PubMed  Google Scholar 

  88. Chen J, Chen L, Lu T, Xie Y, Li C, Jia Z, Cao J. ERalpha36 is an effective target of epigallocatechin-3-gallate in hepatocellular carcinoma. Int J Clin Exp Pathol. 2019;12:3222–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Wang H, Rao B, Lou J, Li J, Liu Z, Li A, Cui G, Ren Z, Yu Z. The Function of the HGF/c-met axis in hepatocellular carcinoma. Front Cell Dev Biol. 2020;8:55–55.

    Article  PubMed  PubMed Central  Google Scholar 

  90. García-Vilas JA, Medina MÁ. Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications. World J Gastroenterol. 2018;24:3695–708.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Zhang Y, Xia M, Jin K, Wang S, Wei H, Fan C, Wu Y, Li X, Li X, Li G, Zeng Z, Xiong W. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities. Mol Cancer. 2018;17:45–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Bouattour M, Raymond E, Qin S, Cheng AL, Stammberger U, Locatelli G, Faivre S. Recent developments of c-Met as a therapeutic target in hepatocellular carcinoma. Hepatology. 2018;67:1132–49.

    Article  PubMed  Google Scholar 

  93. You H, Ding W, Dang H, Jiang Y, Rountree CB. c-Met represents a potential therapeutic target for personalized treatment in hepatocellular carcinoma. Hepatology. 2011;54:879–89.

    Article  CAS  PubMed  Google Scholar 

  94. Luo T, Zhang SG, Zhu LF, Zhang FX, Li W, Zhao K, Wen XX, Yu M, Zhan YQ, Chen H, Ge CH, Gao HY, Wang L, Yang XM, Li CY. A selective c-Met and Trks inhibitor Indo5 suppresses hepatocellular carcinoma growth. J Exp Clin Cancer Res. 2019;38:130.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Du Z, Caenepeel S, Shen Y, Rex K, Zhang Y, He Y, Tang ET, Wang O, Zhong W, Zhou H, Huang J, Huang E, Hu L, Coxon A, Zhang M. Preclinical Evaluation of AMG 337, a highly selective small molecule MET inhibitor, in hepatocellular carcinoma. Mol Cancer Ther. 2016;15:1227–37.

    Article  CAS  PubMed  Google Scholar 

  96. Korhan P, Erdal E, Atabey N. miR-181a-5p is downregulated in hepatocellular carcinoma and suppresses motility, invasion and branching-morphogenesis by directly targeting c-Me. Biochem Biophys Res Commun. 2014;450:1304–12.

    Article  CAS  PubMed  Google Scholar 

  97. Lugano R, Ramachandran M, Dimberg A. Tumor angiogenesis: causes, consequences, challenges and opportunities. Cell Mol Life Sci. 2020;77:1745–70.

    Article  CAS  PubMed  Google Scholar 

  98. Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. J Hepatol. 2004;41:864–80.

    Article  PubMed  Google Scholar 

  99. Mathonnet M, Descottes B, Valleix D, Labrousse F, Denizot Y. VEGF in hepatocellular carcinoma and surrounding cirrhotic liver tissues. World J Gastroenterol. 2006;12:830–1.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Hamdy M, Shaheen K, Awad MA, Barakat EM, Shalaby S, Gupta N, Gupta V. Vascular endothelial growth factor (VEGF) as a biochemical marker for the diagnosis of hepatocellular carcinoma (HCC). Clin Pract. 2020;17:1441–53.

    Google Scholar 

  101. Morse MA, Sun W, Kim R, He AR, Abada PB, Mynderse M, Finn RS. The role of angiogenesis in hepatocellular carcinoma. Clin Cancer Res. 2019;25:912–20.

    Article  CAS  PubMed  Google Scholar 

  102. Tang W, Chen Z, Zhang W, Cheng Y, Zhang B, Wu F, Wang Q, Wang S, Rong D, Reiter FP, De Toni EN, Wang X. The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther. 2020;5:87–87.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Mazzocca A, Fransvea E, Lavezzari G, Antonaci S, Giannelli G. Inhibition of transforming growth factor beta receptor I kinase blocks hepatocellular carcinoma growth through neo-angiogenesis regulation. Hepatology. 2009;50:1140–51.

    Article  CAS  PubMed  Google Scholar 

  104. Kudo M. Signaling pathway/molecular targets and new targeted agents under development in hepatocellular carcinoma. World J Gastroenterol. 2012;18:6005–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Moeini A, Cornellà H, Villanueva A. Emerging signaling pathways in hepatocellular carcinoma. Liver Cancer. 2012;1:83–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Liu Y, Wang X, Yang Y. Hepatic Hippo signaling inhibits development of hepatocellular carcinoma. Clin Mol Hepatol. 2020;26(4):742–50.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Luo D, Wang Z, Wu J, Jiang C, Wu J. The role of hypoxia inducible factor-1 in hepatocellular carcinoma. Biomed Res Int. 2014;2014:409272.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Jia J, Qiao Y, Pilo MG, Cigliano A, Liu X, Shao Z, Calvisi DF, Chen X. Tankyrase inhibitors suppress hepatocellular carcinoma cell growth via modulating the Hippo cascade. PLoS ONE. 2017;12:e0184068.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Seif F, Khoshmirsafa M, Aazami H, Mohsenzadegan M, Sedighi G, Bahar M. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal. 2017;15:23–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. JAK-STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects. Drugs. 2017;77:521–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Svinka J, Mikulits W, Eferl R. STAT3 in hepatocellular carcinoma: new perspectives. Hepat Oncol. 2014;1:107–20.

    Article  PubMed  Google Scholar 

  112. Xie L, Zeng Y, Dai Z, He W, Ke H, Lin Q, Chen Y, Bu J, Lin D, Zheng M. Chemical and genetic inhibition of STAT3 sensitizes hepatocellular carcinoma cells to sorafenib induced cell death. Int J Biol Sci. 2018;14:577–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Jung KH, Yoo W, Stevenson HL, Deshpande D, Shen H, Gagea M, Yoo SY, Wang J, Eckols TK, Bharadwaj U, Tweardy DJ, Beretta L. Multifunctional effects of a small-molecule STAT3 inhibitor on NASH and hepatocellular carcinoma in mice. Clin Cancer Res. 2017;23:5537–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Liu T, Ma H, Shi W, Duan J, Wang Y, Zhang C, Li C, Lin J, Li S, Lv J, Lin L. Inhibition of STAT3 signaling pathway by ursolic acid suppresses growth of hepatocellular carcinoma. Int J Oncol. 2017;51:555–62.

    Article  CAS  PubMed  Google Scholar 

  115. Li W, Zhang Q, Chen K, Sima Z, Liu J, Yu Q. 2-Ethoxystypandrone, a novel small-molecule STAT3 signaling inhibitor from Polygonum cuspidatum, inhibits cell growth and induces apoptosis of HCC cells and HCC Cancer stem cells. BMC Complement Altern Med. 2019;19:38.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Shan L, Jiang H, Ma L, Yu Y. Yes-associated protein: a novel molecular target for the diagnosis, treatment and prognosis of hepatocellular carcinoma. Oncol Lett. 2017;14:3291–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Xia H, Dai X, Yu H, Zhou S, Fan Z, Wei G, Tang Q, Gong Q, Bi F. EGFR-PI3K-PDK1 pathway regulates YAP signaling in hepatocellular carcinoma: the mechanism and its implications in targeted therapy. Cell Death Dis. 2018;9:269.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Valero V 3rd, Pawlik TM, Anders RA. Emerging role of Hpo signaling and YAP in hepatocellular carcinoma. J Hepatocell Carcinoma. 2015;2:69–78.

    PubMed  PubMed Central  Google Scholar 

  119. Shan L, Li Y, Jiang H, Tao Y, Qian Z, Li L, Cai F, Ma L, Yu Y. Huaier restrains proliferative and migratory potential of hepatocellular carcinoma cells partially through decreased yes-associated protein 1. J Cancer. 2017;8:4087–97.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Hayashi H, Higashi T, Yokoyama N, Kaida T, Sakamoto K, Fukushima Y, Ishimoto T, Kuroki H, Nitta H, Hashimoto D, Chikamoto A, Oki E, Beppu T, Baba H. An imbalance in TAZ and YAP expression in hepatocellular carcinoma confers cancer stem cell–like behaviors contributing to disease progression. Can Res. 2015;75:4985–97.

    Article  CAS  Google Scholar 

  121. Shi J, Farzaneh M, Khoshnam SE. Yes-associated protein and PDZ binding motif: a critical signaling pathway in the control of human pluripotent stem cells self-renewal and differentiation. Cell Reprogram. 2020;22:55–61.

    Article  CAS  PubMed  Google Scholar 

  122. Warren JSA, Xiao Y, Lamar JM. YAP/TAZ Activation as a Target for Treating Metastatic Cancer. Cancers (Basel). 2018;10:115.

    Article  CAS  Google Scholar 

  123. Pobbati AV, Hong W. A combat with the YAP/TAZ-TEAD oncoproteins for cancer therapy. Theranostics. 2020;10:3622–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Liu Y, Wang X, Yang Y. Hepatic Hippo signaling inhibits development of hepatocellular carcinoma. Clin Mol Hepatol. 2020;26:742–50.

    Article  PubMed  PubMed Central  Google Scholar 

  125. Perra A, Kowalik MA, Ghiso E, Ledda-Columbano GM, Di Tommaso L, Angioni MM, Raschioni C, Testore E, Roncalli M, Giordano S, Columbano A. YAP activation is an early event and a potential therapeutic target in liver cancer development. J Hepatol. 2014;61:1088–96.

    Article  CAS  PubMed  Google Scholar 

  126. Chen C, Lou T. Hypoxia inducible factors in hepatocellular carcinoma. Oncotarget. 2017;8:46691–703.

    Article  PubMed  PubMed Central  Google Scholar 

  127. Lee JW, Ko J, Ju C, Eltzschig HK. Hypoxia signaling in human diseases and therapeutic targets. Exp Mol Med. 2019;51:1–13.

    Article  PubMed  PubMed Central  Google Scholar 

  128. Lin D, Wu J. Hypoxia inducible factor in hepatocellular carcinoma: a therapeutic target. World J Gastroenterol. 2015;21:12171–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Mu H, Yu G, Li H, Wang M, Cui Y, Zhang T, Song T, Liu C. Mild chronic hypoxia-induced HIF-2α interacts with c-MYC through competition with HIF-1α in hepatocellular carcinoma proliferation. 2020;33:1–13.

  130. Guo Y, Xiao Z, Yang L, Gao Y, Zhu Q, Hu L, Huang D, Xu Q. Hypoxiainducible factors in hepatocellular carcinoma (Review). Oncol Rep. 2019;8(28):46691.

    Google Scholar 

  131. Liu X, Chen S, Tu J, Cai W, Xu Q. HSP90 inhibits apoptosis and promotes growth by regulating HIF-1alpha abundance in hepatocellular carcinoma. Int J Mol Med. 2016;37:825–35.

    Article  CAS  PubMed  Google Scholar 

  132. Koziel A, Jarmuszkiewicz W. Hypoxia and aerobic metabolism adaptations of human endothelial cells. Pflugers Arch. 2017;469:815–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Jia YY, Zhao JY, Li BL, Gao K, Song Y, Liu MY, Yang XJ, Xue Y, Wen AD, Shi L. miR-592/WSB1/HIF-1alpha axis inhibits glycolytic metabolism to decrease hepatocellular carcinoma growth. Oncotarget. 2016;7:35257–69.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Masoud GN, Li W. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B. 2015;5:378–89.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Zhang X, Li Y, Ma Y, Yang L, Wang T, Meng X, Zong Z, Sun X, Hua X, Li H. Yes-associated protein (YAP) binds to HIF-1alpha and sustains HIF-1alpha protein stability to promote hepatocellular carcinoma cell glycolysis under hypoxic stress. J Exp Clin Cancer Res. 2018;37:216.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Xu J, Zheng L, Chen J, Sun Y, Lin H, Jin RA, Tang M, Liang X, Cai X. Increasing AR by HIF-2alpha inhibitor (PT-2385) overcomes the side-effects of sorafenib by suppressing hepatocellular carcinoma invasion via alteration of pSTAT3, pAKT and pERK signals. Cell Death Dis. 2017;8:e3095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Nault J-C, Ningarhari M, Rebouissou S, Zucman-Rossi J. The role of telomeres and telomerase in cirrhosis and liver cancer. Nat Rev Gastroenterol Hepatol. 2019;16(9):544–58.

    Article  PubMed  Google Scholar 

  138. Bisteau X, Caldez MJ, Kaldis P. The complex relationship between liver cancer and the cell cycle: a story of multiple regulations. Cancers (Basel). 2014;6:79–111.

    Article  CAS  Google Scholar 

  139. Sonntag R, Giebeler N, Nevzorova YA, Bangen J-M, Fahrenkamp D, Lambertz D, Haas U, Hu W, Gassler N, Cubero FJ, Müller-Newen G, Abdallah AT, Weiskirchen R, Ticconi F, Costa IG, Barbacid M, Trautwein C, Liedtke C. Cyclin E1 and cyclin-dependent kinase 2 are critical for initiation, but not for progression of hepatocellular carcinoma. Proc Natl Acad Sci U S A. 2018;115:9282–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Wang TJ, Huang MS, Hong CY, Tse V, Silverberg GD, Hsiao M. Comparisons of tumor suppressor p53, p21, and p16 gene therapy effects on glioblastoma tumorigenicity in situ. Biochem Biophys Res Commun. 2001;287:173–80.

    Article  CAS  PubMed  Google Scholar 

  141. Shamloo B, Usluer S. p21 in cancer research. Cancers (Basel). 2019;11(8):1178.

    Article  CAS  Google Scholar 

  142. Yang Z, Zhang J, Lin X, Wu D, Li G, Zhong C, Fang L, Jiang P, Yin L, Zhang L. Inhibition of neddylation modification by MLN4924 sensitizes hepatocellular carcinoma cells to sorafenib. Oncol Rep. 2019;41:3257–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Shao YY, Li YS, Hsu HW, Lin H, Wang HY, Wo RR, Cheng AL, Hsu CH. Potent activity of composite cyclin dependent kinase inhibition against hepatocellular carcinoma. Cancers (Basel). 2019;11:1433.

    Article  CAS  Google Scholar 

  144. Reiter FP, Denk G, Ziesch A, Ofner A, Wimmer R, Hohenester S, Schiergens TS, Spampatti M, Ye L, Itzel T, Munker S, Teufel A, Gerbes AL, Mayerle J, De Toni EN. Predictors of ribociclib-mediated antitumour effects in native and sorafenib-resistant human hepatocellular carcinoma cells. Cell Oncol (Dordr). 2019;42:705–15.

    Article  CAS  Google Scholar 

  145. Pfeffer CM, Singh ATK. Apoptosis: a target for anticancer therapy. Int J Mol Sci. 2018;19:448.

    Article  PubMed Central  CAS  Google Scholar 

  146. Zhu X, Qiu J, Zhang T, Yang Y, Guo S, Li T, Jiang K, Zahoor A, Deng G, Qiu C. MicroRNA-188-5p promotes apoptosis and inhibits cell proliferation of breast cancer cells via the MAPK signaling pathway by targeting Rap2c. J Cell Physiol. 2020;235:2389–402.

    Article  CAS  PubMed  Google Scholar 

  147. Jan R, Chaudhry G-ES. Understanding apoptosis and apoptotic pathways targeted cancer therapeutics. Adv Pharm Bull. 2019;9:205–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Fayyaz S, Yaylim I, Turan S, Kanwal S, Farooqi AA. Hepatocellular carcinoma: targeting of oncogenic signaling networks in TRAIL resistant cancer cells. Mol Biol Rep. 2014;41:6909–17.

    Article  CAS  PubMed  Google Scholar 

  149. Bai J, Gao Y, Du Y, Yang X, Zhang X. MicroRNA-300 inhibits the growth of hepatocellular carcinoma cells by downregulating CREPT/Wnt/beta-catenin signaling. Oncol Lett. 2019;18:3743–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Dai X, Zhang J, Arfuso F, Chinnathambi A, Zayed ME, Alharbi SA, Kumar AP, Ahn KS, Sethi G. Targeting TNF-related apoptosis-inducing ligand (TRAIL) receptor by natural products as a potential therapeutic approach for cancer therapy. Exp Biol Med (Maywood). 2015;240:760–73.

    Article  CAS  Google Scholar 

  151. Wang H, Ma D, Wang C, Zhao S, Liu C. triptolide inhibits invasion and tumorigenesis of hepatocellular carcinoma MHCC-97H cells through NF-kappaB signaling. Med Sci Monit. 2016;22:1827–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Redza-Dutordoir M, Averill-Bates DA. Activation of apoptosis signalling pathways by reactive oxygen species. Biochim et Biophys Acta (BBA) Mol Cell Res 2016; 1863: 2977–2992.

  153. Gupta S, Silveira DA, Mombach JCM. Towards DNA-damage induced autophagy: a Boolean model of p53-induced cell fate mechanisms. DNA Repair. 2020;96:102971.

    Article  CAS  PubMed  Google Scholar 

  154. Mijit M, Caracciolo V, Melillo A, Amicarelli F, Giordano A. Role of p53 in the regulation of cellular senescence. Biomolecules. 2020;10:420.

    Article  CAS  PubMed Central  Google Scholar 

  155. Azer SA. MDM2-p53 interactions in human hepatocellular carcinoma: what is the role of nutlins and new therapeutic options? J Clin Med. 2018;7(4):64.

    Article  PubMed Central  CAS  Google Scholar 

  156. Wan Z, Pan H, Liu S, Zhu J, Qi W, Fu K, Zhao T, Liang J. Downregulation of SNAIL sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis by regulating the NF-kappaB pathway. Oncol Rep. 2015;33:1560–6.

    Article  CAS  PubMed  Google Scholar 

  157. Gomes AR, Abrantes AM, Brito AF, Laranjo M, Casalta-Lopes JE, Goncalves AC, Sarmento-Ribeiro AB, Botelho MF, Tralhao JG. Influence of P53 on the radiotherapy response of hepatocellular carcinoma. Clin Mol Hepatol. 2015;21:257–67.

    Article  PubMed  PubMed Central  Google Scholar 

  158. Hsu HT, Chi CW. Emerging role of the peroxisome proliferator-activated receptor-gamma in hepatocellular carcinoma. J Hepatocell Carcinoma. 2014;1:127–35.

    PubMed  PubMed Central  Google Scholar 

  159. Wahl K, Siegemund M, Lehner F, Vondran F, Nussler A, Langer F, Krech T, Kontermann R, Manns MP, Schulze-Osthoff K, Pfizenmaier K, Bantel H. Increased apoptosis induction in hepatocellular carcinoma by a novel tumor-targeted TRAIL fusion protein combined with bortezomib. Hepatology. 2013;57:625–36.

    Article  CAS  PubMed  Google Scholar 

  160. Yuan X, Gajan A, Chu Q, Xiong H, Wu K, Wu GS. Developing TRAIL/TRAIL death receptor-based cancer therapies. Cancer Metastasis Rev. 2018;37:733–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Shi X, Liu J, Ren L, Mao N, Tan F, Ding N, Yang J, Li M. Nutlin-3 downregulates p53 phosphorylation on serine392 and induces apoptosis in hepatocellular carcinoma cells. BMB Rep. 2014;47:221–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Xiao Z, Li CH, Chan SL, Xu F, Feng L, Wang Y, Jiang JD, Sung JJ, Cheng CH, Chen Y. A small-molecule modulator of the tumor-suppressor miR34a inhibits the growth of hepatocellular carcinoma. Cancer Res. 2014;74:6236–47.

    Article  CAS  PubMed  Google Scholar 

  163. Yu L, Chen Y, Tooze SA. Autophagy pathway: cellular and molecular mechanisms. Autophagy. 2018;14:207–15.

    Article  CAS  PubMed  Google Scholar 

  164. Li X, He S, Ma B. Autophagy and autophagy-related proteins in cancer. Mol Cancer. 2020;19:12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Yun CW, Lee SH. The roles of autophagy in cancer. Int J Mol Sci. 2018;19:3466.

    Article  PubMed Central  CAS  Google Scholar 

  166. Wang B-S, Liu Y-Z, Yang Y, Zhang Y, Hao J-J, Yang H, Wang X-M, Zhang Z-Q, Zhan Q-M, Wang M-R. Autophagy negatively regulates cancer cell proliferation via selectively targeting VPRBP. Clin Sci. 2013;124:203–14.

    Article  CAS  Google Scholar 

  167. Yazdani HO, Huang H, Tsung A. Autophagy: dual response in the development of hepatocellular carcinoma. Cells. 2019;8(2):91.

    Article  CAS  PubMed Central  Google Scholar 

  168. Duan Y, Li J, Jing X, Ding X, Yu Y, Zhao Q. Fucoidan induces apoptosis and inhibits proliferation of hepatocellular carcinoma via the p38 MAPK/ERK and PI3K/Akt signal pathways. Cancer Manag Res. 2020;12:1713–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Yang S, Yang L, Li X, Li B, Li Y, Zhang X, Ma Y, Peng X, Jin H, Li H. New insights into autophagy in hepatocellular carcinoma: mechanisms and therapeutic strategies. Am J Cancer Res. 2019;9:1329–53.

    PubMed  PubMed Central  Google Scholar 

  170. Xie B, He X, Guo G, Zhang X, Li J, Liu J, Lin Y. High-throughput screening identified mitoxantrone to induce death of hepatocellular carcinoma cells with autophagy involvement. Biochem Biophys Res Commun. 2020;521:232–7.

    Article  CAS  PubMed  Google Scholar 

  171. Liu F, Wang F, Dong X, Xiu P, Sun P, Li Z, Shi X, Zhong J. T7 peptide cytotoxicity in human hepatocellular carcinoma cells is mediated by suppression of autophagy. Int J Mol Med. 2019;44:523–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Stiuso P, Potenza N, Lombardi A, Ferrandino I, Monaco A, Zappavigna S, Vanacore D, Mosca N, Castiello F, Porto S, Addeo R, Prete SD, De Vita F, Russo A, Caraglia M. MicroRNA-423-5p promotes autophagy in cancer cells and is increased in serum from hepatocarcinoma patients treated with sorafenib. Mol Ther Nucleic Acids. 2015;4:e233.

    Article  CAS  PubMed  Google Scholar 

  173. Gavini J, Dommann N, Jakob MO, Keogh A, Bouchez LC, Karkampouna S, Julio MK, Medova M, Zimmer Y, Schlafli AM, Tschan MP, Candinas D, Stroka D, Banz V. Verteporfin-induced lysosomal compartment dysregulation potentiates the effect of sorafenib in hepatocellular carcinoma. Cell Death Dis. 2019;10:749.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Simioni C, Cani A, Martelli AM, Zauli G, Alameen AA, Ultimo S, Tabellini G, McCubrey JA, Capitani S, Neri LM. The novel dual PI3K/mTOR inhibitor NVP-BGT226 displays cytotoxic activity in both normoxic and hypoxic hepatocarcinoma cells. Oncotarget. 2015;6:17147–60.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Soltan MY, Sumarni U, Assaf C, Langer P, Reidel U, Eberle J. Key Role of Reactive Oxygen Species (ROS) in indirubin derivative-induced cell death in cutaneous t-cell lymphoma cells. Int J Mol Sci. 2019;20:1158.

    Article  CAS  PubMed Central  Google Scholar 

  176. Aggarwal V, Tuli HS, Varol A, Thakral F, Yerer MB, Sak K, Varol M, Jain A, Khan MA, Sethi G. Role of reactive oxygen species in cancer progression: molecular mechanisms and recent advancements. Biomolecules. 2019;9(11):735.

    Article  CAS  PubMed Central  Google Scholar 

  177. Takaki A, Yamamoto K. Control of oxidative stress in hepatocellular carcinoma: helpful or harmful? World J Hepatol. 2015;7:968–79.

    Article  PubMed  PubMed Central  Google Scholar 

  178. Cardin R, Piciocchi M, Bortolami M, Kotsafti A, Barzon L, Lavezzo E, Sinigaglia A, Rodriguez-Castro KI, Rugge M, Farinati F. Oxidative damage in the progression of chronic liver disease to hepatocellular carcinoma: an intricate pathway. World J Gastroenterol. 2014;20:3078–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Kim EK, Jang M, Song MJ, Kim D, Kim Y, Jang HH. Redox-mediated mechanism of chemoresistance in cancer cells. Antioxidants (Basel). 2019;8(10):471.

    Article  CAS  Google Scholar 

  180. Huang G, Pan S-T. ROS-mediated therapeutic strategy in chemo-/radiotherapy of head and neck cancer. Oxid Med Cell Longev. 2020;2020:5047987.

    Article  PubMed  PubMed Central  Google Scholar 

  181. Perillo B, Di Donato M, Pezone A, Di Zazzo E, Giovannelli P, Galasso G, Castoria G, Migliaccio A. ROS in cancer therapy: the bright side of the moon. Exp Mol Med. 2020;52:192–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Liou G-Y, Storz P. Reactive oxygen species in cancer. Free Radic Res. 2010;44:479–96.

    Article  CAS  PubMed  Google Scholar 

  183. Lv H, Wang C, Fang T, Li T, Lv G, Han Q, Yang W, Wang H. Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2. NPJ Precis Oncol. 2018;2:1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Hwang-Bo H, Jeong JW, Han MH, Park C, Hong SH, Kim GY, Moon SK, Cheong J, Kim WJ, Yoo YH, Choi YH. Auranofin, an inhibitor of thioredoxin reductase, induces apoptosis in hepatocellular carcinoma Hep3B cells by generation of reactive oxygen species. Gen Physiol Biophys. 2017;36:117–28.

    Article  PubMed  CAS  Google Scholar 

  185. Hwang-Bo H, Lee WS, Nagappan A, Kim HJ, Panchanathan R, Park C, Chang SH, Kim ND, Leem SH, Chang YC, Kwon TK, Cheong JH, Kim GS, Jung JM, Shin SC, Hong SC, Choi YH. Morin enhances auranofin anticancer activity by up-regulation of DR4 and DR5 and modulation of Bcl-2 through reactive oxygen species generation in Hep3B human hepatocellular carcinoma cells. Phytother Res. 2019;33:1384–93.

    Article  CAS  PubMed  Google Scholar 

  186. Wei PL, Huang CY, Chang YJ. Propyl gallate inhibits hepatocellular carcinoma cell growth through the induction of ROS and the activation of autophagy. PLoS ONE. 2019;14:e0210513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Yuan Z, Liang Z, Yi J, Chen X, Li R, Wu J, Sun Z. Koumine promotes ROS production to suppress hepatocellular carcinoma cell proliferation via NF-kappaB and ERK/p38 MAPK signaling. Biomolecules. 2019;9(10):559.

    Article  CAS  PubMed Central  Google Scholar 

  188. Li Y, Lu J, Chen Q, Han S, Shao H, Chen P, Jin Q, Yang M, Shangguan F, Fei M, Wang L, Liu Y, Liu N, Lu B. Artemisinin suppresses hepatocellular carcinoma cell growth, migration and invasion by targeting cellular bioenergetics and Hippo-YAP signaling. Arch Toxicol. 2019;93:3367–83.

    Article  CAS  PubMed  Google Scholar 

  189. Liu C, Yang S, Wang K, Bao X, Liu Y, Zhou S, Liu H, Qiu Y, Wang T, Yu H. Alkaloids from Traditional Chinese Medicine against hepatocellular carcinoma. Biomed Pharmacother. 2019;120:109543.

    Article  CAS  PubMed  Google Scholar 

  190. Singh A, Shafi S, Upadhyay T, Najmi AK, Kohli K, Pottoo FH. Insights into nanotherapeutic strategies as an impending approach to liver cancer treatment. Curr Top Med Chem. 2020;20:1839–54.

    Article  PubMed  Google Scholar 

  191. Wei W, Chua MS, Grepper S, So S. Small molecule antagonists of Tcf4/beta-catenin complex inhibit the growth of HCC cells in vitro and in vivo. Int J Cancer. 2010;126:2426–36.

    CAS  PubMed  Google Scholar 

  192. Jeng KS, Sheen IS, Jeng WJ, Yu MC, Tsai HH, Chang FY, Su JC. Blockade of the sonic hedgehog pathway effectively inhibits the growth of hepatoma in mice: An in vivo study. Oncol Lett. 2012;4:1158–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Tsang CM, Cheung KC, Cheung YC, Man K, Lui VW, Tsao SW, Feng Y. Berberine suppresses Id-1 expression and inhibits the growth and development of lung metastases in hepatocellular carcinoma. Biochim Biophys Acta. 2015;1852:541–51.

    Article  CAS  PubMed  Google Scholar 

  194. Wang H, Zhang C, Chi H, Meng Z. Synergistic anti-hepatoma effect of bufalin combined with sorafenib via mediating the tumor vascular microenvironment by targeting mTOR/VEGF signaling. Int J Oncol. 2018;52:2051–60.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Authors and Affiliations

  1. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Zahra Farzaneh

  2. Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Massoud Vosough

  3. Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, West Bengal, 721302, India

    Tarun Agarwal

  4. Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Maryam Farzaneh

Authors
  1. Zahra Farzaneh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Massoud Vosough
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tarun Agarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maryam Farzaneh
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZF has been involved in drafting the manuscript. MV and TA have made substantial contributions to the revising of the manuscript. MF has made a substantial contribution to the writing and revising of the manuscript and the design of the Figures. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zahra Farzaneh or Maryam Farzaneh.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that there is no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Farzaneh, Z., Vosough, M., Agarwal, T. et al. Critical signaling pathways governing hepatocellular carcinoma behavior; small molecule-based approaches. Cancer Cell Int 21, 208 (2021). https://doi.org/10.1186/s12935-021-01924-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12935-021-01924-w

Keywords

Cancer Cell International

ISSN: 1475-2867

Contact us