Molecular mechanisms of microRNA-216a during tumor progression
Cancer Cell International volume 23, Article number: 19 (2023)
MicroRNAs (miRNAs) as the members of non-coding RNAs family are involved in post-transcriptional regulation by translational inhibiting or mRNA degradation. They have a critical role in regulation of cell proliferation and migration. MiRNAs aberrations have been reported in various cancers. Considering the importance of these factors in regulation of cellular processes and their high stability in body fluids, these factors can be suggested as suitable non-invasive markers for the cancer diagnosis. MiR-216a deregulation has been frequently reported in different cancers. Therefore, in the present review we discussed the molecular mechanisms of the miR-216a during tumor progression. It has been reported that miR-216a mainly functioned as a tumor suppressor through the regulation of signaling pathways and transcription factors. This review paves the way to suggest the miR-216a as a probable therapeutic and diagnostic target in cancer patients.
Cancer is regarded as one of the leading causes of human deaths in the current century. High rate of the cancer mortality and incidence has become a global health challenge . Despite of various therapeutic progresses during the recent decades, there is still a high rate of therapeutic resistance and tumor recurrence among these patients . Therefore, there is an urgent requirement to assess the molecular mechanisms of tumor progression to suggest novel therapeutic targets. Studies over the past two decades have clearly demonstrated that microRNAs (miRNAs) have critical roles in regulation of physiological and pathophysiological cellular processes . MiRNAs are involved in cell proliferation, differentiation, and apoptosis [4, 5]. They may also function as oncogenic or tumor-suppressor, depending on their intracellular roles and expression levels [6, 7]. Moreover, aberrant expression of miRNAs has been associated with therapeutic resistance in cancer that suggests these factors as probable efficient therapeutic targets in tumor cells . Combining miRNA-based therapies with other anticancer treatments is of interest due to the ability of miRNAs to target multiple target genes. Since the function of miRNAs varies according to the tumor type, it is highly desirable to investigate whether miRNA inhibition or replacement therapy can effectively interfere with the signaling pathway associated with therapeutic resistance to enhance the efficacy of anticancer therapy [9, 10]. In addition, early diagnosis can significantly improve treatment outcomes and prolong the survival of cancer patients. Given the high stability of the miRNAs in body fluids and blood, they may represent an excellent set of non-invasive biomarkers for the early cancer diagnosis and prognosis . Accordingly, understanding the regulatory role of these factors during tumor progression can be used for diagnostic and therapeutic purposes . MiR-216a-3p is located on human chromosome 2p16.1 and miR-216 region that contains the miR-216a-3p, miR-216a-5p, miR-216b3p, and miR-216b-5p . MiR-216a participates in various cellular processes and tumor progressions [14,15,16,17]. Therefore, in the present review we discussed the molecular mechanisms of miR-216a during tumor progression to introduce that as a reliable diagnostic and prognostic factor in cancer patients (Table 1).
JAK/STAT and MAPK signaling pathways
Cytokines, interleukins, and growth factors, lead to the activation of the JAK/STAT signaling pathway. Association of Cytokines with their correlative trans-membrane receptor subunits, causing multimerization with other subunits and conformational change in the receptor complex [18, 19]. JAK2 belongs to the Janus Kinases family of protein tyrosine kinases that plays an important role during tumor progression through STAT3 phosphorylation [20, 21]. The JAK2/STAT3 cascade plays a key role in many cellular processes, including growth, division, programmed cell death, immunological escape and resistance, and tumor angiogenesis [22, 23]. STAT3 is an inactive monomeric transcription factor in the cytoplasm. This transcription factor is dimerized and translocated into the nucleus after being phosphorylated by JAK2 to activate the target genes [24, 25]. STAT3 triggers cellular transformation and facilitates tumor initiation and progression by regulation of c-Myc, Bcl-xL, CCND1, and VEGF . It has been shown that miR-216a has a key role during tumor progression by regulation of JAK/STAT signaling pathway (Fig. 1). MiR-216a significantly suppressed cell proliferation while induced programmed cell death in pancreatic tumor cells by inhibiting JAK2. MiR-216a also suppressed STAT3 phosphorylation, which resulted in the down regulation of anti-apoptotic genes such as survivin and XIAP . MiR-216a reduced pancreatic tumor growth via JAK2 targeting . STAT3 up regulated the miR-216a that targeted PTEN. Suppression of miR-216a reduced the cisplatin resistance in ovarian tumor cells . Long noncoding RNAs (lncRNAs) are promising therapeutic targets and diagnostic factors in a variety of disorders [30, 31]. They are involved in biological processes such as chromatin remodeling, transcriptional activation, and chromosomal inactivation . LncRNAs mainly act as competing endogenous RNAs (ceRNAs), which compete for miRNAs to control various mRNA transcripts . GHET1 enhanced the glioma cell invasion by miR-216a down regulation that stimulated the JAK2/STAT3 and p53/survivin signaling pathways . MiR-216a was considerably down regulated in GC tissues as compared to corresponding healthy tissues that was associated with poor prognosis. MiR-216a inhibited JAK2/STAT3 cascade as well as the expression of downstream targets such as Slug, Snail, and Twist in GC cells .
The MAPK signaling plays an important role in cell biology and functions through receptor tyrosine kinases (RTKs) that activate the RAF/MEK/ERK axis [36, 37]. Activated ERKs are accumulated in the nucleus or remain in the cytoplasm, where they can phosphorylate several substrates that modulate cell activities . Sorafenib acts as a tyrosine kinase suppressor with multiple targets. It can inhibit tumor cell proliferation by suppressing the RAF/MEK/ERK cascade as well as many other signaling pathways. It can also suppress the VEGF and PDGF receptors, hence preventing tumor angiogenesis . MAPK14 activation has a crucial function in drug resistance in hepatocellular carcinoma (HCC) . MiR-216a has a key role during tumor progression by regulation of MAPK signaling pathway (Fig. 1). There was significant MAPK14 up regulation in sorafenib resistant HCC tumors. MiR-216a-3p increased sorafenib response in xenograft HCC tumor nude mice models by targeting MAPK14 and suppressing the MEK/ERK and ATF signaling cascades . KIAA1199 elevates cytosolic calcium through facilitating endoplasmic reticulum (ER) calcium leakage, which subsequently stimulates the PKCa-MEK1/2-ENK1/2 axis . KIAA1199 promoted EGF-induced EMT by EGFR stability and phosphorylation of MEK1, and ERK1/2 in cervical tumor cells . Under expression of KIAA1199 reduced CRC cell migration and invasion. MiR-216a inhibited CRC invasion by KIAA1199 targeting. KIAA1199 was significantly correlated with poor prognosis .
PI3K/AKT and TGF-β signaling pathways
PI3K/Akt pathway is known as one of the most critical pathways in modulating cell survival and proliferation . PI3K activates the AKT that induces cell proliferation by CCND1 up regulation . PTEN inhibits the growth and dissemination of HCC cells as a negative regulator of PI3K/AKT pathway . MiR-216a has a key role during tumor progression by regulation of PI3K/AKT signaling pathway (Fig. 2). Smad7 acts as a tumor suppressor in HCC by inhibiting cell growth while triggering programmed cell death . The A1BG antisense RNA 1 (A1BG-AS1) was down regulated in HCC. It inhibited HCC cell growth, metastasis, and invasion by miR-216a-5p sponging and PTEN and Smad7 up regulations . There was CTBP1-AS2 down regulation in ovarian cancer (OC). CTBP1-AS2 inhibited the OC cell proliferation by miR-216a sponging and subsequent PTEN up regulation . There was significant miR-216a up regulation in ovarian cancer tissues and cells that promoted cell proliferation and invasion by inhibiting PTEN . WT1 is an oncogene that has been identified to be overexpressed in a variety of solid tumors and blood cancers, making it a prospective therapeutic target for cancer treatment . Overexpression of miR-216a or knockdown of KRT7 inhibited PI3K and AKT phosphorylation in PC cells, whereas WT1 stimulated the PI3K/AKT signaling cascade. Therefore, miR-216a regulated the WT1/KRT7 axis and inhibited the PI3K/AKT pathway to prevent PC progression .
TGF-β as a growth factor is implicated in the modulation of cell growth, autophagy, apoptosis, and EMT . It principally participates in different biological processes in the body via two pathways: the classic SMAD-associated pathway and the non-SMAD-associated pathway. TGF-β receptors mediate the SMAD-related classical pathway [55, 56]. The association between TGF-β and TβRII can stimulate the kinase activity of TβRI and promotes the phosphorylation of TβRI. Consequently, activated TβRI could phosphorylate downstream SMAD proteins. These activated SMAD proteins could interact with the chaperone protein SMAD4 and translocated to the nucleus and modulate the expression of TGF-β target genes . MiR-216a has a pivotal role during tumor progression by regulation of TGF-β signaling pathway (Fig. 2). Epithelial-mesenchymal transition (EMT) is a normal developmental process involved in tumor invasion in which epithelial cells transform into mesenchymal cells. Vimentin is overexpressed while cell adhesion molecules such as E-cadherin are under expressed during EMT . As a member of the SMAD family of proteins, SMAD7 is a TGF-β superfamily ligand. By analyzing miRNA expression profiles in patients with HCC tissues with early-recurrent and non-recurrent HCC, researchers discovered that early HCC recurrent disease was correlated with miR-216a up regulation. MiR-216a positively regulated TGF-β and the canonical pathway implicated in the promotion of the PI3K/Akt cascade in HCC cells by inhibiting SMAD7 and PTEN, resulting in tumor relapse and sorafenib resistance . There was HOTTIP up regulation in prostate cancer (PCa) tissues that was correlated with larger tumor size and a higher TNM stage. HOTTIP inhibition down regulated the Vimentin and Snai1, while up regulated the CDH1. HOTTIP enhanced the growth and metastasis of PCa cells by miR-216a-5p sponging .
Developmental signaling pathways
Wnt is a pivotal signaling pathway for tissue morphogenesis and regeneration that is activated by the canonical or non-canonical pathways . The activation of the canonical pathway occurs in the presence of Wnt ligands. Wnt ligands could interact with the Frizzled (Fz) receptor and LRP5/6 co-receptor that finally stabilizes the cytoplasmic β-catenin [62, 63]. β-catenin is translocated to the nucleus where it is associated with LEF/TCF family members to regulate the WNT target genes [64, 65]. DANCR silencing has been shown to diminish cell migration, survival, and stem-like properties. DANCR increased β-catenin expression, which was then inhibited by miR-216a in non-small-cell lung cancer (NSCLC) cells. DANCR promoted NSCLC stemness and chemo resistance by activating Wnt and Sox2 . LGR5 as an orphan G protein-coupled receptor (GPCR) is involved in developmental processes [67, 68]. It regulates Wnt signaling cascade via interacting with its associated ligand R-spondin and mediates the accumulation of nuclear β-catenin. LGR5 exerts as a stem cell factor and promotes the maintenance of cancer stem cells, self-renewal, and stem cell proliferation by activation of downstream Wnt/β-catenin-signaling cascade . It has been indicated that LGR5 could induce cell mobility, invasion, tumorigenesis, and EMT in cancer cells through activation of the Wnt/β-catenin pathway . MiR-216a markedly inhibited glioma cell growth and invasion by inhibiting LGR5 .
The Sonic hedgehog (Shh) is also another developmental signaling pathway that has key roles in tumor cell growth and differentiation. It can be activated through the interaction of Shh with the cell surface receptor Patched (PTCH) that leads to the phosphorylation of the SMO receptor . The association between Hh ligands and PTCH induces GLI transcription factors . The GLI proteins translocate into the nucleus, where they promote the target genes expression and also induce cell growth, survival, and differentiation . Tectonic family member 1 (TCTN1) is a member of the tectonic trans-membrane protein family that is implicated in the Hedgehog (Hh) signaling pathway . Bcl-2 is a negative regulator of apoptosis that is located in inner mitochondrial membrane . Bad is capable of triggering programmed cell death by suppressing Bcl-2 and Bcl-xL [76, 77]. TCTN1 knockdown was discovered to promote apoptosis in thyroid cancer cells via up regulation of CASP3 and PARP, while suppression of Bcl-2 . Increased miR-216a-5p expression in ESCC cells was discovered to significantly inhibit cell growth by TCTN1 targeting. MiR-216a-5p suppressed cell proliferation by PCNA down regulation. Overexpression of miR-216a-5p in ESCC cells resulted in a significant reduction in PCNA and Bcl-2 expression levels while Bad up regulation. MiR-216a-5p repressed esophageal squamous cell carcinoma (ESCC) cell proliferation while promoted apoptosis via TCTN1 targeting .
Hippo signaling plays a vital role in tumor progression. Activation of the Hippo pathway leads to MST1/2 phosphorylation and stimulates LATS1/2, which can phosphorylate YAP/TAZ, causing the YAP/TAZ suppression . The phosphorylation of LATS induces the cytoplasmic translocation of YAP proteins via association with 14-3-3 proteins [81, 82]. MiR-216a has a key role during tumor progression by regulation of Hippo signaling pathway (Fig. 1). Actin-like 6A (ACTL6A) is a component of the SWI/SNF that regulates chromatin remodeling, nuclear transition, and transcription regulation . ACTL6A is overexpressed in progenitor and stem cells, and is involved in cell self-renewal [84, 85]. Yes-associated protein (YAP) is an essential member of Hippo pathway and plays a key role in the regulation of tissue homeostasis processes . YAP is dephosphorylated in response to a variety of stimuli, and then it is transferred into the nucleus where it interacts with a transcriptional co-activator with a PDZ binding motif to increase the expression of the target gene . MiR-216a-3p reduced the cervical tumor cell growth and invasion by inhibiting ACTL6A that subsequently enhanced YAP phosphorylation while reduced YAP/TAZ-mediated transcriptional activity .
Transcription factors are the key molecular targets for the miR-216a during tumor progression (Fig. 3). Y-box binding protein 1 (YBX1) belongs to the cold-shock protein superfamily that is involved in transcriptional and translational regulations [88, 89]. It has different pro-oncogenic roles in cancers, including tumor metastasis and chemotherapy resistance . It has been demonstrated that phosphorylation of YBX1 through numerous kinases such as AKT, S6K, and RSK via receptor tyrosine kinase and integrin-associated kinase promotes nuclear transportation of YBX1 in different tissues with transcriptional activation of several genes containing drug resistance and tumor growth linked genes . YB-1 expression was shown to be elevated in pancreatic cancer cells and tissue samples. It has anti-metastatic activity in pancreatic cancer and has been recognized as a target of miR-216a. MiR-216a reduced pancreatic tumor cell invasion by YB-1 targeting . The MAPK/ERK cascade stimulates YBX1 and subsequently transfer it into the nucleus, promoting the development of B-cell lymphoma . YBX1 is also involved in tumor progression via the PI3K/Akt/mTOR signaling cascade . MiR-216a suppressed Diffuse Large B Cell Lymphoma (DLBCL) cell survival, growth, and invasion by targeting YBX1 . There was miR-216a-5p down regulation in colorectal cancer (CRC) tissues that was correlated with poor prognosis. MiR-216a-5p suppressed CRC cell growth and invasion by inhibiting YBX1. PVT1 overexpression has been proposed to overturn the anti-tumor impact of miR-216a-5p on CRC cells. MiR-216a5p also caused CDH1 up regulation while CDH2, Vimentin, and Snail down regulations .
BRD4 enhances tumor progression and induces EMT tumor cells . It induced the stemness characteristic of gastric cancer (GC) cells by MIR216A promoter methylation and subsequent miR-216a-3p down regulation. Wnt3a was found to be a direct downstream effector of miR-216a3p, implying that the Wnt cascade is required for the regulation of stemness features in GC cells via the BRD4/miR-216a-3p axis . High mobility group box 3 (HMGB3) is involved in the regulation of self-renewal and cell differentiation . It has an important regulatory role in cell growth and apoptosis and its deregulation can lead to malignant breast cancer [100,101,102]. MiR-216a hyper methylation led to HMGB3 overexpression via binding to the 3'UTR, which subsequently stimulated the Wnt/β-catenin signaling pathway and enhanced malignant growth and migration of esophageal tumor cells . There were significant DANCR up regulation while miR-216a-5p down regulation in HCC cells. DANCR suppression reduced HCC cell growth and division through the miR-216a-5p/KLF12 axis . There were significant DANCR up regulation while miR-216a-5p down regulation in Oral Squamous Cell Carcinoma (OSCC) tissues and cells that were associated with a higher TNM stage, lower differentiation level, and node metastasis. DANCR up regulated the KLF12 by functioning as a molecular sponge of miR-126-5p, facilitating OSCC metastasis and invasion .
Autophagy is a mechanism within the cell that eliminates and recycles defective organelles and proteins [106, 107]. SRY-related high-mobility-group box 5 (SOX5) is a developmental transcription factor that promotes tumor progression in a variety of cancers . There was DANCR up regulation in osteosarcoma tissues that was positively correlated with the grade of tumor. DANCR inhibition suppressed osteosarcoma cell growth and invasion while induced apoptosis via miR-216a-5p/SOX5 axis . There was DANCR up regulation in lung cancer tissues that was correlated with poor prognosis. DANCR promoted lung tumor cell invasion via miR-216a targeting .
Zinc finger E-box binding homeobox 1 (ZEB1) is also a critical mediator of EMT activation and self-renewal. ZEB1 could directly interact with the promoter regions of epithelial genes to inhibit their transcription and induce EMT through regulating the transcription of mesenchymal genes [111, 112]. ZEB-1 regulates the inhibition of CDH1 which promotes the EGFR/ERK axis in tumor cells . There was SNHG16 up regulation in cervical cancer tissues that was correlated with advanced FIGO stage, larger tumor size, and lower differentiation. It was involved in cervical cancer progression by regulation of miR-216-5p/ZEB1 axis . SNHG3 was found to be up regulated in NSCLC tissues and cells. SNHG3 inhibition reduced NSCLC cell growth and invasion while promoted apoptosis through miR-216a/ZEB1 axis .
RUNX1 is a transcription factor that has key role in hematopoiesis . It reduces the tumor sphere formation and directly declines ZEB1 expression and also suppress the stem cell phenotype . RUNX1 has been demonstrated to suppress NF-kB pathway by interacting with the IkB kinase. MiR-216a-3p may function as a tumor promoter in GC via inhibiting RUNX1 and stimulating the NF-kB signaling pathway. MiR-216a-3p was markedly up regulated in GC tissues that were associated with the prognosis. MiR-216a-3p significantly up regulated the CCND1, Bcl-2, MMP2, and MMP9 .
Autophagy, apoptosis, and cell cycle regulation
Autophagy is a catabolic process that degrades cytosolic proteins and organelles in response to cellular stress. This process is assumed to be the underlying cause of cancer cell radiation resistance . In autophagy as a self-proteolytic cellular degradation mechanism, defective proteins and organelles are transported to lysosomes for destruction . MiR-216a has a key role during tumor progression by regulation of autophagy and apoptosis (Fig. 4). This process removes highly toxic chemicals, preserves tissue homeostasis, and promotes cancer cell survival. Nevertheless, highly active autophagy results in apoptosis . The production of autophagosomes is induced by class III phosphoinositide 3-kinase and beclin-1 during autophagy . Beclin-1 is an autophagosome-forming factor that is up regulated in autophagy . MiR-216a was discovered to markedly inhibit beclin-1 and autophagy processes in radio resistant pancreatic tumor cells, resulting in increased sensitivity to radiotherapy . HOTTIP was strongly associated with GC recurrence in patients who received cisplatin treatment. HOTTIP increased cisplatin resistance and suppressed autophagy and apoptosis in GC cells through miR-216a-5p sponging and Bcl-2/Beclin1 axis regulation . Microtubule associated protein 1S (MAP1S) plays a key regulatory role in promoting autophagy flux . There is also a relationship between TGF-β/MAP1S-pathway-mediated autophagy and carcinogenesis inhibition . There were miR-216a down regulations in CRC tissues and cells. MiR-216a inhibited autophagy by disrupting the TGF-β/MAP1S cascade in CRC cells . Translationally controlled tumor protein (TCTP) is a highly conserved protein participated in cell proliferation and apoptosis . It is also known as a modulator of tumor recurrence that reduces the expression level of p53 . TPT1 has also been demonstrated to operate as a negative regulator of autophagy via BECN1 and the mTORC1-mediated pathway . There was miR-216a-5p down regulation in pancreatic cancer (PC) tissues that was correlated with poor prognosis and increased tumor cell migration. MiR-216a-5p inhibited pancreatic tumor cell growth and motility by TPT1 targeting. LINC01133 was also reported to enhance PC cell growth, division, and migration via inhibiting miR-216a-5p . B cell lymphoma-2-like 2 protein (BCL2L2) is a member of the BCL2 family that plays a crucial role in human malignancies . BCL2L2 enhances tumor progression by facilitating cell growth and division . Circ-0011946 inhibition reduced OSCC cell growth and metastasis while induced apoptosis via the miR-216a-5p/BCL2L2 axis . HOTTIP induced chemo resistance in small cell lung cancer through the miR-216a/BCL-2 axis . MiR-216a-5p reduced cell growth, division, and metastasis in lung cancer through regulating Bcl-2/Bax/Bad protein expression .
Cyclin-dependent kinases (CDKs) are a group of cell cycle related kinases that have important regulatory functions during cell cycle progression . CDKs are important regulators of cell cycle progression and have been proposed as potential therapeutic targets for cancer therapy . CDK14 is an important cell cycle regulator by interacting with CCND3 [140, 141]. It promotes Wnt signaling by mediating LRP6 phosphorylation [140, 142]. CDK14 silencing down regulated PI3K and inhibited AKT phosphorylation in pancreatic cancer cells . CDK14 was discovered to be associated with overall survival and prognosis in osteosarcoma patients. Patients with overexpressed miR-216a showed improved overall survival, implying that miR-216a plays a predictive and prognostic function in osteosarcoma. MiR-216a inhibited osteosarcoma cell growth and invasion by down regulating CDK14. The miR-216a/CDK14 axis promoted Wnt pathway in osteosarcoma cells via modulating LRP6 phosphorylation and Wnt downstream genes. MiR-216a/CDK14 axis was also essential in the phosphorylation of PI3K and Akt in osteosarcoma cells. MiR-216a down regulated CDH2 while up regulated CDH1 via CDK14 targeting in osteosarcoma . BTG2 as a member of the TOB/BTG gene family is involved in G1/S cell cycle progression [145, 146]. BTG2 negatively mediates CCND1 and reduces the expression level of FoxM1 via suppressing the association of CCNB1/CDKs . CircFLNA reduced the bladder tumor growth via miR-216a-3p/BTG2 axis .
Various structural proteins involved in immune response, cell adhesion, cellular metabolism, and DNA repair can also be targeted by miR-216a during tumor progression (Fig. 5). The tumor microenvironment plays a key role in the modulation of oncogenic events through macrophages, neutrophils, mast cells, T/B lymphocytes, and also stromal cells . There are three types of interactions between tumor microenvironment components as well as between these components and tumor cells, including direct contact, paracrine, or autocrine signaling [150, 151]. Cancer-associated fibroblasts (CAFs) constitute the majority of tumor stroma . CAFs secrete inflammatory cytokines, which results in the stimulation of pathways that promote tumor cell growth and self-renewal preservation . Toll-like receptors (TLRs) are a class of cell surface recognition receptors that form a connection between the tumor microenvironment and tumor cells. They are not only implicated in the defense against pathogen attack, but they can also enhance tumor cell proliferation . TLR4 activation causes a pro-inflammatory response, which results in the synthesis and release of cytokines such as IL-6 and IL-8 [155, 156]. TLR4 is involved in tumor cell adhesion and invasion in a variety of human malignancies [157, 158]. MiR-216a-5p functioned as an inhibitor of breast tumor progression and promoted the secretion of IL-6 pro-inflammatory cytokine by TLR4 targeting . There was significant miR-216a down regulation in renal cell carcinoma (RCC) tissues. It reduced RCC cell growth and invasion, while induced apoptosis via TLR4 targeting .
COX and 5-lipoxygenase (ALOX5) play a key role in the synthesis of prostaglandins and leukotrienes, respectively. These were first recognized as being essential in the regulation of inflammation. Anti-inflammatory drugs, such as COX2 suppressors are conventional drugs used in the treatment of breast cancer . Although, ALOX5 and COX2 play their roles via different cellular pathways, they have comparable mechanisms for modulating cell survival. MiR-216a-3p suppressed CRC cell growth by negatively modulating the expression of COX2 and ALOX5 in CRC cells. CRC patients with T3 and T4 stages had significantly higher levels of COX2 and ALOX5 expressions compared to healthy tissues. COX2/ALOX5 up regulation was significantly correlated with poor prognosis. MiR-216a-3p inhibited CRC cell growth by suppressing COX2 and ALOX2 .
Aerobic glycolysis, which exhibits aberrant metabolism defined by excessive glycolysis despite the presence of sufficient oxygen, is recognized as a typical characteristic of tumor cells .[163, 164] This process increases the lactate synthesis and glucose uptake, which stimulates tumor growth. Hexokinase 2 (HK2) as the first enzyme in glycolysis catalyzes the glucose-6-phosphate production . HK2 up regulation has been reported in numerous malignancies and promotes tumor growth by the glycolysis induction [166, 167]. MiR-216a-5p has been discovered to reduce the glycolysis and cell growth by HK2 targeting in uveal melanoma cancer cells .
RAP2B belongs to the Ras superfamily that is involved in the regulation of cell proliferation and migration [169, 170]. CCAT1 promoted NSCLC proliferation while reduced apoptosis via the miR-216a-5p/RAP2B axis . CDC42 is a component of the Rho GTPase family and is involved in cell proliferation and migration [172, 173]. HCP5 promoted the cervical tumor initiation and progression via the miR-216a-5p/CDC42 axis .
PAK2 is a kinase involved in a variety of intracellular processes, including cytoskeletal remodeling and cell migration [175, 176]. The Rac and CDC42 stimulate PAK2 [175, 177]. The size and prognosis of malignant tumors have been correlated with PAK2 activation [178, 179]. MiR-216a-5p reduced breast tumor cell growth and invasion via PAK2 targeting . Protein kinase C alpha (PKCα) is a member of the PKC family . PKCα expression is contributed with poor prognosis in ER-positive breast cancers [182, 183]. It promotes breast tumor cell migration via FOXC2-mediated inhibition of p120-catenin . There was significant miR-216a down regulation in breast cancer cells. It promoted the breast tumor cell apoptosis via PKCα targeting .
The coatomer protein complex subunit beta 2 (COPB2) plays a vital role in intracellular transportation by forming transport vesicles . It has been indicated that COPB2 participates in the modulation of extracellular membrane transportation and stimulation of retrograde transport between the Golgi complex and ER . COPB2 can mediate the growth and apoptosis of cancer cells by activating the RTKs- and JNK/c-Jun-signaling cascades . Under expression of COPB2 induces tumor cell apoptosis [189, 190]. COPB2 inhibition significantly up regulated the CDH1 while down regulated the CDH2 and Vimentin that reduced lung tumor cell invasion. MiR-216a-3p reduced lung tumor cell invasion while promoted the apoptosis by COPB2 targeting [190, 191].
Aquaporin-4 (AQP4) is a critical molecule in the central nervous system that participated in preserving water and ion homeostasis and has been indicated to play a key role in tumor cell invasion . AQP4 is also associated with α-syntrophin which interacts with the actin cytoskeleton and β-dystroglycan. Therefore, AQP4 can be involved in modification of the cellular cytoskeleton . There were LINC00461 up regulations in glioma tissues and cells. LINC00461 silencing inhibited glioma cell growth, invasion, and temozolomide (TMZ) tolerance via miR-216a/ AQP4 axis .
Tetraspanin 1 (TSPAN1) is a small trans-membrane protein engaged in cell migration and proliferation [195, 196]. Integrins as the cell adhesion receptors, directly bind to diverse extracellular matrix (ECM) molecules and regulate cell growth, apoptosis, and invasion . Deregulation of integrin is associated with tumor progression by disrupting the cell migration . Integrin alpha 2 (ITGA2) is a trans-membrane receptor that facilitates cell adherence to the ECM that is deregulated in various tumor types [199, 200]. TSPAN1 has the ability to modulate methylation-related enzymes and thereby influence the methylation level of the ITGA2 promoter. TSPAN1 up regulated TET2 while down regulated DNMT3B and DNMT1. TSPAN1 regulated methyltransferases that resulted in ITGA2 hypo methylation in PC. MiR-216a/TSPAN1/ITGA2 axis was implicated in the regulation of PC progression .
KIAA0101 or proliferation cell nuclear antigen (PCNA) protein is implicated in the modulation of DNA repair and cell proliferation, cell cycle development, and migration . It preserve cells from UV-associated cell death . Down regulation of KIAA0101 suppresses tumor cell progression and glycolysis by inactivating the PI3K/AKT/mTOR pathway . The KIAA0101 protein has been deregulated in multiple malignancies that were associated with poor prognosis [202, 205]. There was miR-216a-5p down regulation in ESCC tissues that was correlated with poor prognosis. MiR-216a-5p suppressed ESCC cell growth and invasion by KIAA0101 targeting .
Considering the importance of identifying non-invasive markers to facilitate early tumor detection, in the present review we investigated the role of miR-216a during tumor progression. It has been reported that miR-216a has mainly a tumor suppressor function through the regulation of signaling pathways and transcription factors, which ultimately changes the cell cycle, apoptosis, and autophagy. This study can be an effective step towards introducing the miR-216a as a non-invasive marker in tumor detection and treatment. MiRNA-based cancer therapy is designed based on the miRNA function inside the tumor cells by the inhibition of oncogenic miRNAs or induction of tumor suppressor miRNAs. However, there are some challenges to use the miRNAs in tumor targeted therapy including the miRNA degradation by the cytoplasmic nucleases and the adverse influences of the selected miRNAs in normal biological cellular functions. Therefore, the side effects can be expected following the miRNA targeted therapy. Optimization of the site specific and delivery methods can reduce the optimal antagomiRs or mimics concentrations that finally reduces the probable side effects of miRNA-based therapies in cancer patients. Since, miR-216a has mainly a tumor suppressive function in different tumor types, miR-216a mimics can be used as a method of choice in cancer patients. However, it is required to perform the in-vitro and animal studies to confirm the miR-216a as an efficient candidate for the targeted therapy in clinics. Moreover, assessment of the circulating miR-216a levels in different cancers is required to suggest that as a reliable non-invasive diagnostic marker in cancer patients.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
A1BG antisense RNA 1
B cell lymphoma-2-like 2 protein
Coatomer protein complex subunit beta 2
Competing endogenous RNAs
Diffuse Large B Cell Lymphoma
G protein-coupled receptor
High mobility group box 3
Integrin alpha 2
Long noncoding RNAs
Microtubule associated protein 1S
Non-small-cell lung cancer
Oral Squamous Cell Carcinoma
Proliferation cell nuclear antigen
Protein kinase C alpha
Receptor tyrosine kinases
Renal cell carcinoma
SRY-related high-mobility-group box 5
Tectonic family member 1
Translationally controlled tumor protein
Y-box binding protein 1
Zinc finger E-box binding homeobox 1
Cui W, Aouidate A, Wang S, Yu Q, Li Y, Yuan S. Discovering anti-cancer drugs via computational methods. Front Pharmacol. 2020;11:733.
Kathawala RJ, Gupta P, Ashby CR Jr, Chen ZS. The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade. Drug Resist Updat. 2015;18:1–17.
Peng Y. Non-coding RNAs in human cancer. Semin Cancer Biol. 2021;75:1–2.
Moghbeli M. Molecular interactions of miR-338 during tumor progression and metastasis. Cell Mol Biol Lett. 2021;26(1):13.
Moghbeli M, Zangouei AS, Nasrpour Navaii Z, Taghehchian N. Molecular mechanisms of the microRNA-132 during tumor progressions. Cancer Cell Int. 2021;21(1):439.
Hamidi AA, Taghehchian N, Basirat Z, Zangouei AS, Moghbeli M. MicroRNAs as the critical regulators of cell migration and invasion in thyroid cancer. Biomark Res. 2022;10(1):40.
Moghbeli M. MicroRNAs as the critical regulators of Cisplatin resistance in ovarian cancer cells. J Ovarian Res. 2021;14(1):127.
Maharati A, Zanguei AS, Khalili-Tanha G, Moghbeli M. MicroRNAs as the critical regulators of tyrosine kinase inhibitors resistance in lung tumor cells. Cell Commun Signal. 2022;20(1):27.
Zangouei AS, Alimardani M, Moghbeli M. MicroRNAs as the critical regulators of Doxorubicin resistance in breast tumor cells. Cancer Cell Int. 2021;21(1):213.
Zangouei AS, Moghbeli M. MicroRNAs as the critical regulators of cisplatin resistance in gastric tumor cells. Genes Environ. 2021;43(1):21.
Chen X, Ba Y, Ma L, Cai X, Yin Y, Wang K, et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 2008;18(10):997–1006.
Manvati MKS, Khan J, Verma N, Dhar PK. Association of miR-760 with cancer: an overview. Gene. 2020;747: 144648.
Yonemori K, Seki N, Idichi T, Kurahara H, Osako Y, Koshizuka K, et al. The microRNA expression signature of pancreatic ductal adenocarcinoma by RNA sequencing: anti-tumour functions of the microRNA-216 cluster. Oncotarget. 2017;8(41):70097–115.
Cui Y, Wang J, Liu S, Qu D, Jin H, Zhu L, et al. miR-216a promotes breast cancer cell apoptosis by targeting PKCalpha. Fundam Clin Pharmacol. 2019;33(4):397–404.
Kara N, Kent MR, Didiano D, Rajaram K, Zhao A, Summerbell ER, et al. The miR-216a-Dot1l regulatory axis is necessary and sufficient for Muller Glia reprogramming during retina regeneration. Cell Rep. 2019;28(8):2037-47 e4.
Sun CX, Zhu F, Qi L. Demethylated miR-216a regulates high mobility group box 3 promoting growth of esophageal cancer cells through Wnt/beta-catenin pathway. Front Oncol. 2021;11: 622073.
Zhao J, Li L, Yang T. MiR-216a-3p suppresses the proliferation and invasion of cervical cancer through downregulation of ACTL6A-mediated YAP signaling. J Cell Physiol. 2020;235(12):9718–28.
Rah B, Rather RA, Bhat GR, Baba AB, Mushtaq I, Farooq M, et al. JAK/STAT signaling: molecular targets, therapeutic opportunities, and limitations of targeted inhibitions in solid malignancies. Front Pharmacol. 2022;13:821344.
Brooks AJ, Putoczki T. JAK-STAT signalling pathway in cancer. Cancers (Basel). 2020;12:1971.
Judd LM, Menheniott TR, Ling H, Jackson CB, Howlett M, Kalantzis A, et al. Inhibition of the JAK2/STAT3 pathway reduces gastric cancer growth in vitro and in vivo. PLoS ONE. 2014;9(5): e95993.
Wörmann SM, Song L, Ai J, Diakopoulos KN, Kurkowski MU, Görgülü K, et al. Loss of P53 function activates JAK2-STAT3 signaling to promote pancreatic tumor growth, stroma modification, and gemcitabine resistance in mice and is associated with patient survival. Gastroenterology. 2016;151(1):180-93.e12.
Wang T, Niu G, Kortylewski M, Burdelya L, Shain K, Zhang S, et al. Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med. 2004;10(1):48–54.
Frank DA. STAT3 as a central mediator of neoplastic cellular transformation. Cancer Lett. 2007;251(2):199–210.
Zhong Z, Wen Z, Darnell JE Jr. Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science. 1994;264(5155):95–8.
Shuai K, Horvath CM, Huang LH, Qureshi SA, Cowburn D, Darnell JE Jr. Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions. Cell. 1994;76(5):821–8.
Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.
Wang S, Chen X, Tang M. MicroRNA-216a inhibits pancreatic cancer by directly targeting Janus kinase 2. Oncol Rep. 2014;32(6):2824–30.
Hou BH, Jian ZX, Cui P, Li SJ, Tian RQ, Ou JR. miR-216a may inhibit pancreatic tumor growth by targeting JAK2. FEBS Lett. 2015;589(17):2224–32.
Jin P, Liu Y, Wang R. STAT3 regulated miR-216a promotes ovarian cancer proliferation and cisplatin resistance. 2018. Biosci Rep. https://doi.org/10.1042/BSR20180547.
Quinn JJ, Chang HY. Unique features of long non-coding RNA biogenesis and function. Nat Rev Genet. 2016;17(1):47–62.
Rahmani Z, Mojarrad M, Moghbeli M. Long non-coding RNAs as the critical factors during tumor progressions among Iranian population: an overview. Cell Biosci. 2020;10:6.
Hamidi AA, Khalili-Tanha G, Nasrpour Navaei Z, Moghbeli M. Long non-coding RNAs as the critical regulators of epithelial mesenchymal transition in colorectal tumor cells: an overview. Cancer Cell Int. 2022;22(1):71.
Khalili-Tanha G, Moghbeli M. Long non-coding RNAs as the critical regulators of doxorubicin resistance in tumor cells. Cell Mol Biol Lett. 2021;26(1):39.
Cao W, Liu B, Ma H. Long non-coding RNA GHET1 promotes viability, migration and invasion of glioma cell line U251 by down-regulation of miR-216a. Eur Rev Med Pharmacol Sci. 2019;23(4):1591–9.
Tao Y, Yang S, Wu Y, Fang X, Wang Y, Song Y, et al. MicroRNA-216a inhibits the metastasis of gastric cancer cells by targeting JAK2/STAT3-mediated EMT process. Oncotarget. 2017;8(51):88870–81.
Braicu C, Buse M, Busuioc C, Drula R, Gulei D, Raduly L, et al. A comprehensive review on MAPK: a promising therapeutic target in cancer. Cancers. 2019;11(10):1618.
Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene. 2007;26(22):3279–90.
Yuan J, Dong X, Yap J, Hu J. The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy. J Hematol Oncol. 2020;13(1):1–19.
Ma R, Chen J, Liang Y, Lin S, Zhu L, Liang X, et al. Sorafenib: a potential therapeutic drug for hepatic fibrosis and its outcomes. Biomed Pharmacother. 2017;88:459–68.
Avila M, Berasain C. Making sorafenib irresistible: In vivo screening for mechanisms of therapy resistance in hepatocellular carcinoma hits on Mapk14. Hepatology. 2015;61(5):1755–7.
Wan Z, Liu T, Wang L, Wang R, Zhang H. MicroRNA-216a-3p promotes sorafenib sensitivity in hepatocellular carcinoma by downregulating MAPK14 expression. Aging (Albany NY). 2020;12(18):18192–208.
Evensen NA, Kuscu C, Nguyen HL, Zarrabi K, Dufour A, Kadam P, et al. Unraveling the role of KIAA1199, a novel endoplasmic reticulum protein, in cancer cell migration. J Natl Cancer Inst. 2013;105(18):1402–16.
Shostak K, Zhang X, Hubert P, Göktuna SI, Jiang Z, Klevernic I, et al. NF-κB-induced KIAA1199 promotes survival through EGFR signalling. Nat Commun. 2014;5:5232.
Zhang D, Zhao L, Shen Q, Lv Q, Jin M, Ma H, et al. Down-regulation of KIAA1199/CEMIP by miR-216a suppresses tumor invasion and metastasis in colorectal cancer. Int J Cancer. 2017;140(10):2298–309.
He Y-Y, Council SE, Feng L, Chignell CF. UVA-induced cell cycle progression is mediated by a disintegrin and metalloprotease/epidermal growth factor receptor/AKT/Cyclin D1 pathways in keratinocytes. Can Res. 2008;68(10):3752–8.
Lien EC, Lyssiotis CA, Cantley LC. Metabolic reprogramming by the PI3K-Akt-mTOR pathway in cancer. Metabol Cancer. 2016;207:39–72.
Tu K, Liu Z, Yao B, Han S, Yang W. MicroRNA-519a promotes tumor growth by targeting PTEN/PI3K/AKT signaling in hepatocellular carcinoma. Int J Oncol. 2016;48(3):965–74.
Wang J, Zhao J, Chu ES, Mok MT, Go MY, Man K, et al. Inhibitory role of Smad7 in hepatocarcinogenesis in mice and in vitro. J Pathol. 2013;230(4):441–52.
Bai J, Yao B, Wang L, Sun L, Chen T, Liu R, et al. lncRNA A1BG-AS1 suppresses proliferation and invasion of hepatocellular carcinoma cells by targeting miR-216a-5p. J Cell Biochem. 2019;120(6):10310–22.
Cui K, Zhu G. LncRNA CTBP1-AS2 regulates miR-216a/ PTEN to suppress ovarian cancer cell proliferation. J Ovarian Res. 2020;13(1):84.
Liu H, Pan Y, Han X, Liu J, Li R. MicroRNA-216a promotes the metastasis and epithelial-mesenchymal transition of ovarian cancer by suppressing the PTEN/AKT pathway. Onco Targets Ther. 2017;10:2701–9.
Oka Y, Kawase I. Cancer antigen WT1-targeting treatment for the malignancies. Nihon Rinsho Meneki Gakkai Kaishi. 2008;31(5):375–82.
Wang W, Wang J, Yang C, Wang J. MicroRNA-216a targets WT1 expression and regulates KRT7 transcription to mediate the progression of pancreatic cancer—A transcriptome analysis. IUBMB Life. 2021;73(6):866–82.
Zhang M, Zhang YY, Chen Y, Wang J, Wang Q, Lu H. TGF-β signaling and resistance to cancer therapy. Front Cell Dev Biol. 2021. https://doi.org/10.3389/fcell.2021.786728.
Colak S, Ten Dijke P. Targeting TGF-β signaling in cancer. Trends Cancer. 2017;3(1):56–71.
Liu S, Chen S, Zeng J. TGF-β signaling: a complex role in tumorigenesis. Mol Med Rep. 2018;17(1):699–704.
Yang Y, Ye W-L, Zhang R-N, He X-S, Wang J-R, Liu Y-X, et al. The role of TGF-β signaling pathways in cancer and its potential as a therapeutic target. Evid Based Complement Alternat Med. 2021. https://doi.org/10.1155/2021/6675208.
Forghanifard MM, Rad A, Farshchian M, Khaleghizadeh M, Gholamin M, Moghbeli M, et al. TWIST1 upregulates the MAGEA4 oncogene. Mol Carcinog. 2017;56(3):877–85.
Xia H, Ooi LLPJ, Hui KM. MicroRNA-216a/217-induced epithelial-mesenchymal transition targets PTEN and SMAD7 to promote drug resistance and recurrence of liver cancer. Hepatology (Baltimore, MD). 2013;58(2):629–41.
Yang B, Gao G, Wang Z, Sun D, Wei X, Ma Y, et al. Long non-coding RNA HOTTIP promotes prostate cancer cells proliferation and migration by sponging miR-216a-5p. 2018. Biosci Rep. https://doi.org/10.1042/BSR20180566.
Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis. 2008;4(2):68–75.
Azbazdar Y, Karabicici M, Erdal E, Ozhan G. Regulation of Wnt signaling pathways at the plasma membrane and their misregulation in cancer. Front Cell Dev Biol. 2021;9: 631623.
Katoh M, Katoh M. WNT signaling pathway and stem cell signaling network. Clin Cancer Res. 2007;13(14):4042–5.
Hayat R, Manzoor M, Hussain A. Wnt signaling pathway: a comprehensive review. Cell Biol Int. 2022. https://doi.org/10.1002/cbin.11797.
Chen C, Luo L, Xu C, Yang X, Liu T, Luo J, et al. Tumor specificity of WNT ligands and receptors reveals universal squamous cell carcinoma oncogenes. BMC Cancer. 2022;22(1):1–14.
Yu JE, Ju JA, Musacchio N, Mathias TJ, Vitolo MI. Long noncoding RNA DANCR activates Wnt/β-Catenin signaling through MiR-216a inhibition in non-small cell lung cancer. Biomolecules. 2020. https://doi.org/10.3390/biom10121646.
Schuijers J, Clevers H. Adult mammalian stem cells: the role of Wnt, Lgr5 and R-spondins. Embo J. 2012;31(12):2685–96.
de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature. 2011;476(7360):293–7.
Wang X, Wang X, Liu Y, Dong Y, Wang Y, Kassab MA, et al. LGR5 regulates gastric adenocarcinoma cell proliferation and invasion via activating Wnt signaling pathway. Oncogenesis. 2018;7(8):1–14.
Xu L, Lin W, Wen L, Li G. Lgr5 in cancer biology: functional identification of Lgr5 in cancer progression and potential opportunities for novel therapy. Stem Cell Res Ther. 2019;10(1):1–9.
Zhang J, Xu K, Shi L, Zhang L, Zhao Z, Xu H, et al. Overexpression of MicroRNA-216a suppresses proliferation, migration, and invasion of glioma cells by targeting leucine-rich repeat-containing G protein-coupled receptor 5. Oncol Res. 2017;25(8):1317–27.
Onishi H, Katano M. Hedgehog signaling pathway as a therapeutic target in various types of cancer. Cancer Sci. 2011;102(10):1756–60.
Jeng KS, Jeng CJ, Jeng WJ, Sheen I, Li SY, Leu CM, et al. Sonic Hedgehog signaling pathway as a potential target to inhibit the progression of hepatocellular carcinoma. Oncol Lett. 2019;18(5):4377–84.
Zhang JX, Chen ZH, Xu Y, Chen JW, Weng HW, Yun M, et al. Downregulation of MicroRNA-644a promotes esophageal squamous cell carcinoma aggressiveness and stem cell-like phenotype via dysregulation of PITX2. Clin Cancer Res. 2017;23(1):298–310.
Sun C, Liu Z, Li S, Yang C, Xue R, Xi Y, et al. Down-regulation of c-Met and Bcl2 by microRNA-206, activates apoptosis, and inhibits tumor cell proliferation, migration and colony formation. Oncotarget. 2015;6(28):25533–74.
Lam LT, Lin X, Faivre EJ, Yang Z, Huang X, Wilcox DM, et al. Vulnerability of small-cell lung cancer to apoptosis induced by the combination of BET bromodomain proteins and BCL2 inhibitors. Mol Cancer Ther. 2017;16(8):1511–20.
Karpel-Massler G, Ishida CT, Bianchetti E, Shu C, Perez-Lorenzo R, Horst B, et al. Inhibition of mitochondrial matrix chaperones and antiapoptotic Bcl-2 family proteins empower antitumor therapeutic responses. Cancer Res. 2017;77(13):3513–26.
Xu P, Xia X, Yang Z, Tian Y, Di J, Guo M. Silencing of TCTN1 inhibits proliferation, induces cell cycle arrest and apoptosis in human thyroid cancer. Exp Ther Med. 2017;14(4):3720–6.
Chai L, Yang G. MiR-216a-5p targets TCTN1 to inhibit cell proliferation and induce apoptosis in esophageal squamous cell carcinoma. Cell Mol Biol Lett. 2019;24(1):46.
Han Y. Analysis of the role of the Hippo pathway in cancer. J Transl Med. 2019;17(1):1–17.
Xiao Y, Dong J. The hippo signaling pathway in cancer: a cell cycle perspective. Cancers. 2021;13(24):6214.
Yang D, Zhang N, Li M, Hong T, Meng W, Ouyang T. The Hippo signaling pathway: the trader of tumor microenvironment. Front Oncol. 2021;11:772134.
Krasteva V, Buscarlet M, Diaz-Tellez A, Bernard MA, Crabtree GR, Lessard JA. The BAF53a subunit of SWI/SNF-like BAF complexes is essential for hemopoietic stem cell function. Blood. 2012;120(24):4720–32.
Bao X, Tang J, Lopez-Pajares V, Tao S, Qu K, Crabtree GR, et al. ACTL6a enforces the epidermal progenitor state by suppressing SWI/SNF-dependent induction of KLF4. Cell Stem Cell. 2013;12(2):193–203.
Ho L, Crabtree GR. Chromatin remodelling during development. Nature. 2010;463(7280):474–84.
Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 2015;163(4):811–28.
Zhao B, Ye X, Yu J, Li L, Li W, Li S, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008;22(14):1962–71.
Lim JP, Shyamasundar S, Gunaratne J, Scully OJ, Matsumoto K, Bay BH. YBX1 gene silencing inhibits migratory and invasive potential via CORO1C in breast cancer in vitro. BMC Cancer. 2017;17(1):1–15.
Xu L, Li H, Wu L, Huang S. YBX1 promotes tumor growth by elevating glycolysis in human bladder cancer. Oncotarget. 2017;8(39):65946.
Prabhu L, Hartley AV, Martin M, Warsame F, Sun E, Lu T. Role of post-translational modification of the Y box binding protein 1 in human cancers. Genes Dis. 2015;2(3):240–6.
Shibata T, Tokunaga E, Hattori S, Watari K, Murakami Y, Yamashita N, et al. Y-box binding protein YBX1 and its correlated genes as biomarkers for poor outcomes in patients with breast cancer. Oncotarget. 2018;9(98):37216.
Lu J, Li X, Wang F, Guo Y, Huang Y, Zhu H, et al. YB-1 expression promotes pancreatic cancer metastasis that is inhibited by microRNA-216a. Exp Cell Res. 2017;359(2):319–26.
Shen H, Xu W, Luo W, Zhou L, Yong W, Chen F, et al. Upregulation of mdr1 gene is related to activation of the MAPK/ERK signal transduction pathway and YB-1 nuclear translocation in B-cell lymphoma. Exp Hematol. 2011;39(5):558–69.
Prabhu L, Hartley AV, Martin M, Warsame F, Sun E, Lu T. Role of post-translational modification of the Y box binding protein 1 in human cancers. Genes Dis. 2015;2(3):240–6.
Li Y, Qian J, Yang L. Inhibition of YBX1 by miR-216a suppresses proliferation and invasion of diffuse large B-cell lymphoma. Balkan Med J. 2021;38(3):171–6.
Zeng X, Liu Y, Zhu H, Chen D, Hu W. Downregulation of miR-216a-5p by long noncoding RNA PVT1 suppresses colorectal cancer progression via modulation of YBX1 expression. Cancer Manag Res. 2019;11:6981–93.
Zhang P, Dong Z, Cai J, Zhang C, Shen Z, Ke A, et al. BRD4 promotes tumor growth and epithelial-mesenchymal transition in hepatocellular carcinoma. Int J Immunopathol Pharmacol. 2015;28(1):36–44.
Song H, Shi L, Xu Y, Xu T, Fan R, Cao M, et al. BRD4 promotes the stemness of gastric cancer cells via attenuating miR-216a-3p-mediated inhibition of Wnt/β-catenin signaling. Eur J Pharmacol. 2019;852:189–97.
Nemeth MJ, Kirby MR, Bodine DM. Hmgb3 regulates the balance between hematopoietic stem cell self-renewal and differentiation. Proc Natl Acad Sci USA. 2006;103(37):13783–8.
Gu J, Xu T, Huang QH, Zhang CM, Chen HY. HMGB3 silence inhibits breast cancer cell proliferation and tumor growth by interacting with hypoxia-inducible factor 1α. Cancer Manag Res. 2019;11:5075–89.
Gu J, Xu T, Zhang CM, Chen HY, Huang QH, Zhang Q. HMGB3 small interfere RNA suppresses mammosphere formation of MDA-MB-231 cells by down-regulating expression of HIF1α. Eur Rev Med Pharmacol Sci. 2019;23(21):9506–16.
Elgamal OA, Park JK, Gusev Y, Azevedo-Pouly AC, Jiang J, Roopra A, et al. Tumor suppressive function of mir-205 in breast cancer is linked to HMGB3 regulation. PLoS ONE. 2013;8(10): e76402.
Sun CX, Zhu F, Qi L. Demethylated miR-216a regulates high mobility group box 3 promoting growth of esophageal cancer cells through Wnt/β-catenin pathway. Front Oncol. 2021;11: 622073.
Wang J, Pu J, Zhang Y, Yao T, Luo Z, Li W, et al. DANCR contributed to hepatocellular carcinoma malignancy via sponging miR-216a-5p and modulating KLF12. J Cell Physiol. 2019;234(6):9408–16.
Qu XH, Shi YL, Ma Y, Bao WW, Yang L, Li JC, et al. LncRNA DANCR regulates the growth and metastasis of oral squamous cell carcinoma cells via altering miR-216a-5p expression. Hum Cell. 2020;33(4):1281–93.
Mizushima N. Autophagy: process and function. Genes Dev. 2007;21(22):2861–73.
Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell. 2008;132(1):27–42.
Hu J, Tian J, Zhu S, Sun L, Yu J, Tian H, et al. Sox5 contributes to prostate cancer metastasis and is a master regulator of TGF-β-induced epithelial mesenchymal transition through controlling Twist1 expression. Br J Cancer. 2018;118(1):88–97.
Pan Z, Wu C, Li Y, Li H, An Y, Wang G, et al. LncRNA DANCR silence inhibits SOX5-medicated progression and autophagy in osteosarcoma via regulating miR-216a-5p. Biomed Pharmacother. 2020;122: 109707.
Zhen Q, Gao LN, Wang RF, Chu WW, Zhang YX, Zhao XJ, et al. LncRNA DANCR promotes lung cancer by sequestering miR-216a. Cancer Control. 2018;25(1):1073274818769849.
Eger A, Aigner K, Sonderegger S, Dampier B, Oehler S, Schreiber M, et al. DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene. 2005;24(14):2375–85.
Bindels S, Mestdagt M, Vandewalle C, Jacobs N, Volders L, Noël A, et al. Regulation of vimentin by SIP1 in human epithelial breast tumor cells. Oncogene. 2006;25(36):4975–85.
Bae G-Y, Choi S-J, Lee J-S, Jo J, Lee J, Kim J, et al. Loss of E-cadherin activates EGFR-MEK/ERK signaling, which promotes invasion via the ZEB1/MMP2 axis in non-small cell lung cancer. Oncotarget. 2013;4(12):2512.
Zhu H, Zeng Y, Zhou CC, Ye W. SNHG16/miR-216-5p/ZEB1 signal pathway contributes to the tumorigenesis of cervical cancer cells. Arch Biochem Biophys. 2018;637:1–8.
Zhao S, Gao X, Zhong C, Li Y, Wang M, Zang S. SNHG3 knockdown suppresses proliferation, migration and invasion, and promotes apoptosis in non-small cell lung cancer through regulating miR-216a/ZEB1 Axis. Onco Targets Ther. 2020;13:11327–36.
Ichikawa M, Yoshimi A, Nakagawa M, Nishimoto N, Watanabe-Okochi N, Kurokawa M. A role for RUNX1 in hematopoiesis and myeloid leukemia. Int J Hematol. 2013;97(6):726–34.
Hong D, Fritz AJ, Finstad KH, Fitzgerald MP, Weinheimer A, Viens AL, et al. Suppression of breast cancer stem cells and tumor growth by the RUNX1 transcription FactorRUNX1 inhibits breast cancer stem cells. Mol Cancer Res. 2018;16(12):1952–64.
Wu Y, Zhang J, Zheng Y, Ma C, Liu XE, Sun X. miR-216a-3p inhibits the proliferation, migration, and invasion of human gastric cancer cells via targeting RUNX1 and activating the NF-κB signaling pathway. Oncol Res. 2018;26(1):157–71.
Han MW, Lee JC, Choi JY, Kim GC, Chang HW, Nam HY, et al. Autophagy inhibition can overcome radioresistance in breast cancer cells through suppression of TAK1 activation. Anticancer Res. 2014;34(3):1449–55.
Mehrpour M, Esclatine A, Beau I, Codogno P. Overview of macroautophagy regulation in mammalian cells. Cell Res. 2010;20(7):748–62.
Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 2012;19(1):107–20.
Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 2005;5(9):726–34.
Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8(9):741–52.
Zhang X, Shi H, Lin S, Ba M, Cui S. MicroRNA-216a enhances the radiosensitivity of pancreatic cancer cells by inhibiting beclin-1-mediated autophagy. Oncol Rep. 2015;34(3):1557–64.
Zhao R, Zhang X, Zhang Y, Zhang Y, Yang Y, Sun Y, et al. HOTTIP predicts poor survival in gastric cancer patients and contributes to cisplatin resistance by sponging miR-216a-5p. Front Cell Dev Biol. 2020;8:348.
Li W, Zou J, Yue F, Song K, Chen Q, McKeehan WL, et al. Defects in MAP1S-mediated autophagy cause reduction in mouse lifespans especially when fibronectin is overexpressed. Aging Cell. 2016;15(2):370–9.
Song K, Hu W, Yue F, Zou J, Li W, Chen Q, et al. Transforming growth factor TGFβ increases levels of microtubule-associated protein MAP1S and autophagy flux in pancreatic ductal adenocarcinomas. PLoS ONE. 2015;10(11): e0143150.
Wang Y, Zhang S, Dang S, Fang X, Liu M. Overexpression of microRNA-216a inhibits autophagy by targeting regulated MAP1S in colorectal cancer. Onco Targets Ther. 2019;12:4621–9.
Du J, Yang P, Kong F, Liu H. Aberrant expression of translationally controlled tumor protein (TCTP) can lead to radioactive susceptibility and chemosensitivity in lung cancer cells. Oncotarget. 2017;8(60): 101922.
Chang C-J, Chao C-H, Xia W, Yang J-Y, Xiong Y, Li C-W, et al. p53 regulates epithelial–mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol. 2011;13(3):317–23.
Bae SY, Byun S, Bae SH, Min DS, Woo HA, Lee K. TPT1 (tumor protein, translationally-controlled 1) negatively regulates autophagy through the BECN1 interactome and an MTORC1-mediated pathway. Autophagy. 2017;13(5):820–33.
Zhang J, Gao S, Zhang Y, Yi H, Xu M, Xu J, et al. MiR-216a-5p inhibits tumorigenesis in Pancreatic Cancer by targeting TPT1/mTORC1 and is mediated by LINC01133. Int J Biol Sci. 2020;16(14):2612–27.
Hartman ML, Czyz M. BCL-w: apoptotic and non-apoptotic role in health and disease. Cell Death Dis. 2020;11(4):260.
Wang X, Li GH. MicroRNA-16 functions as a tumor-suppressor gene in oral squamous cell carcinoma by targeting AKT3 and BCL2L2. J Cell Physiol. 2018;233(12):9447–57.
Zhou Y, Zhang S, Min Z, Yu Z, Zhang H, Jiao J. Knockdown of circ_0011946 targets miR-216a-5p/BCL2L2 axis to regulate proliferation, migration, invasion and apoptosis of oral squamous cell carcinoma cells. BMC Cancer. 2021;21(1):1085.
Sun Y, Hu B, Wang Q, Ye M, Qiu Q, Zhou Y, et al. Long non-coding RNA HOTTIP promotes BCL-2 expression and induces chemoresistance in small cell lung cancer by sponging miR-216a. Cell Death Dis. 2018;9(2):85.
Sun Y, Hu B, Wang Y, Li Z, Wu J, Yang Y, et al. miR-216a-5p inhibits malignant progression in small cell lung cancer: involvement of the Bcl-2 family proteins. Cancer Manag Res. 2018;10:4735–45.
Otto T, Sicinski P. Cell cycle proteins as promising targets in cancer therapy. Nat Rev Cancer. 2017;17(2):93–115.
Pitts TM, Davis SL, Eckhardt SG, Bradshaw-Pierce EL. Targeting nuclear kinases in cancer: development of cell cycle kinase inhibitors. Pharmacol Ther. 2014;142(2):258–69.
Davidson G, Niehrs C. Emerging links between CDK cell cycle regulators and Wnt signaling. Trends Cell Biol. 2010;20(8):453–60.
Shu F, Lv S, Qin Y, Ma X, Wang X, Peng X, et al. Functional characterization of human PFTK1 as a cyclin-dependent kinase. Proc Natl Acad Sci USA. 2007;104(22):9248–53.
Wang X, Jia Y, Fei C, Song X, Li L. Activation/Proliferation-associated protein 2 (Caprin-2) positively regulates CDK14/Cyclin Y-mediated lipoprotein receptor-related protein 5 and 6 (LRP5/6) constitutive phosphorylation. J Biol Chem. 2016;291(51):26427–34.
Zheng L, Zhou Z, He Z. Knockdown of PFTK1 inhibits tumor cell proliferation, invasion and epithelial-to-mesenchymal transition in pancreatic cancer. Int J Clin Exp Pathol. 2015;8(11):14005–12.
Ji Q, Xu X, Li L, Goodman SB, Bi W, Xu M, et al. miR-216a inhibits osteosarcoma cell proliferation, invasion and metastasis by targeting CDK14. Cell Death Dis. 2017;8(10): e3103.
Buanne P, Corrente G, Micheli L, Palena A, Lavia P, Spadafora C, et al. Cloning of PC3B, a novel member of the PC3/BTG/TOB family of growth inhibitory genes, highly expressed in the olfactory epithelium. Genomics. 2000;68(3):253–63.
Mao B, Zhang Z, Wang G. BTG2: a rising star of tumor suppressors (review). Int J Oncol. 2015;46(2):459–64.
Chiang K-C, Tsui K-H, Chung L-C, Yeh C-N, Feng T-H, Chen W-T, et al. Cisplatin modulates B-cell translocation gene 2 to attenuate cell proliferation of prostate carcinoma cells in both p53-dependent and p53-independent pathways. Sci Rep. 2014;4(1):1–10.
Lin S, Wang L, Shi Z, Zhu A, Zhang G, Hong Z, et al. Circular RNA circFLNA inhibits the development of bladder carcinoma through microRNA miR-216a-3p/BTG2 axis. Bioengineered. 2021;12(2):11376–89.
Yu T, Di G. Role of tumor microenvironment in triple-negative breast cancer and its prognostic significance. Chin J Cancer Res. 2017;29(3):237–52.
Krueger TE, Thorek DLJ, Meeker AK, Isaacs JT, Brennen WN. Tumor-infiltrating mesenchymal stem cells: drivers of the immunosuppressive tumor microenvironment in prostate cancer? Prostate. 2019;79(3):320–30.
Qiu SQ, Waaijer SJH, Zwager MC, de Vries EGE, van der Vegt B, Schröder CP. Tumor-associated macrophages in breast cancer: innocent bystander or important player? Cancer Treat Rev. 2018;70:178–89.
Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6(5):392–401.
Costa A, Kieffer Y, Scholer-Dahirel A, Pelon F, Bourachot B, Cardon M, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018;33(3):463-79.e10.
Bhatelia K, Singh K, Singh R. TLRs: linking inflammation and breast cancer. Cell Signal. 2014;26(11):2350–7.
Nyati KK, Masuda K, Zaman MM, Dubey PK, Millrine D, Chalise JP, et al. TLR4-induced NF-κB and MAPK signaling regulate the IL-6 mRNA stabilizing protein Arid5a. Nucleic Acids Res. 2017;45(5):2687–703.
He W, Qu T, Yu Q, Wang Z, Lv H, Zhang J, et al. LPS induces IL-8 expression through TLR4, MyD88, NF-kappaB and MAPK pathways in human dental pulp stem cells. Int Endod J. 2013;46(2):128–36.
Hsu RY, Chan CH, Spicer JD, Rousseau MC, Giannias B, Rousseau S, et al. LPS-induced TLR4 signaling in human colorectal cancer cells increases beta1 integrin-mediated cell adhesion and liver metastasis. Cancer Res. 2011;71(5):1989–98.
Ikebe M, Kitaura Y, Nakamura M, Tanaka H, Yamasaki A, Nagai S, et al. Lipopolysaccharide (LPS) increases the invasive ability of pancreatic cancer cells through the TLR4/MyD88 signaling pathway. J Surg Oncol. 2009;100(8):725–31.
Roscigno G, Cirella A, Affinito A, Quintavalle C, Scognamiglio I, Palma F, et al. miR-216a acts as a negative regulator of breast cancer by modulating stemness properties and tumor microenvironment. Int J Mol Sci. 2020;21(7):2313.
Wang W, Zhao E, Yu Y, Geng B, Zhang W, Li X. MiR-216a exerts tumor-suppressing functions in renal cell carcinoma by targeting TLR4. Am J Cancer Res. 2018;8(3):476–88.
Regulski M, Regulska K, Prukała W, Piotrowska H, Stanisz B, Murias M. COX-2 inhibitors: a novel strategy in the management of breast cancer. Drug Discov Today. 2016;21(4):598–615.
Wang D, Li Y, Zhang C, Li X, Yu J. MiR-216a-3p inhibits colorectal cancer cell proliferation through direct targeting COX-2 and ALOX5. J Cell Biochem. 2018;119(2):1755–66.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.
Jiao L, Zhang HL, Li DD, Yang KL, Tang J, Li X, et al. Regulation of glycolytic metabolism by autophagy in liver cancer involves selective autophagic degradation of HK2 (hexokinase 2). Autophagy. 2018;14(4):671–84.
Wei L, Zhou Y, Dai Q, Qiao C, Zhao L, Hui H, et al. Oroxylin A induces dissociation of hexokinase II from the mitochondria and inhibits glycolysis by SIRT3-mediated deacetylation of cyclophilin D in breast carcinoma. Cell Death Dis. 2013;4(4): e601.
Mukherjee A, Ma Y, Yuan F, Gong Y, Fang Z, Mohamed EM, et al. Lysophosphatidic acid up-regulates hexokinase II and glycolysis to promote proliferation of ovarian cancer cells. Neoplasia. 2015;17(9):723–34.
Liu Y, Huo Y, Wang D, Tai Y, Li J, Pang D, et al. MiR-216a-5p/Hexokinase 2 axis regulates uveal melanoma growth through modulation of Warburg effect. Biochem Biophys Res Commun. 2018;501(4):885–92.
Qu D, Huang H, Di J, Gao K, Lu Z, Zheng J. Structure, functional regulation and signaling properties of Rap2B. Oncol Lett. 2016;11(4):2339–46.
Canobbio I, Trionfini P, Guidetti GF, Balduini C, Torti M. Targeting of the small GTPase Rap2b, but not Rap1b, to lipid rafts is promoted by palmitoylation at Cys176 and Cys177 and is required for efficient protein activation in human platelets. Cell Signal. 2008;20(9):1662–70.
Pang L, Zhang Q, Wu Y, Yang Q, Zhang J, Liu Y, et al. Long non-coding RNA CCAT1 promotes non-small cell lung cancer progression by regulating the miR-216a-5p/RAP2B axis. Exp Biol Med (Maywood). 2021;246(2):142–52.
Kazanietz MG, Caloca MJ. The Rac GTPase in cancer: from old concepts to new paradigms. Cancer Res. 2017;77(20):5445–51.
Haga RB, Ridley AJ. Rho GTPases: regulation and roles in cancer cell biology. Small GTPases. 2016;7(4):207–21.
Li X, Chen B, Huang A, Ren C, Wang L, Zhu T, et al. LncRNA HCP5 enhances the proliferation and migration of cervical cancer via miR-216a-5p/CDC42 axis. J Cancer. 2022;13(6):1882–94.
Dorrance AM, De Vita S, Radu M, Reddy PNG, McGuinness MK, Harris CE, et al. The Rac GTPase effector p21-activated kinase is essential for hematopoietic stem/progenitor cell migration and engraftment. Blood. 2013;121(13):2474–82.
Radu M, Semenova G, Kosoff R, Chernoff J. PAK signalling during the development and progression of cancer. Nat Rev Cancer. 2014;14(1):13–25.
Deng WW, Wu L, Bu LL, Liu JF, Li YC, Ma SR, et al. PAK2 promotes migration and proliferation of salivary gland adenoid cystic carcinoma. Am J Transl Res. 2016;8(8):3387–97.
Flate E, Stalvey JR. Motility of select ovarian cancer cell lines: effect of extra-cellular matrix proteins and the involvement of PAK2. Int J Oncol. 2014;45(4):1401–11.
Gao C, Ma T, Pang L, Xie R. Activation of P21-activated protein kinase 2 is an independent prognostic predictor for patients with gastric cancer. Diagn Pathol. 2014;9:55.
Zhang Y, Lin P, Zou JY, Zou G, Wang WZ, Liu YL, et al. MiR-216a-5p act as a tumor suppressor, regulating the cell proliferation and metastasis by targeting PAK2 in breast cancer. Eur Rev Med Pharmacol Sci. 2019;23(6):2469–75.
Pham TND, Perez White BE, Zhao H, Mortazavi F, Tonetti DA. Protein kinase C α enhances migration of breast cancer cells through FOXC2-mediated repression of p120-catenin. BMC Cancer. 2017;17(1):832.
Tonetti DA, Morrow M, Kidwai N, Gupta A, Badve S. Elevated protein kinase C alpha expression may be predictive of tamoxifen treatment failure. Br J Cancer. 2003;88(9):1400–2.
Lønne GK, Cornmark L, Zahirovic IO, Landberg G, Jirström K, Larsson C. PKCα expression is a marker for breast cancer aggressiveness. Mol Cancer. 2010;9(1):76.
Assender JW, Gee JM, Lewis I, Ellis IO, Robertson JF, Nicholson RI. Protein kinase C isoform expression as a predictor of disease outcome on endocrine therapy in breast cancer. J Clin Pathol. 2007;60(11):1216–21.
Cui Y, Wang J, Liu S, Qu D, Jin H, Zhu L, et al. miR-216a promotes breast cancer cell apoptosis by targeting PKCalpha. Fundam Clin Pharmacol. 2019;33(4):397–404.
Beck R, Ravet M, Wieland F, Cassel D. The COPI system: molecular mechanisms and function. FEBS Lett. 2009;583(17):2701–9.
DiStasio A, Driver A, Sund K, Donlin M, Muraleedharan RM, Pooya S, et al. Copb2 is essential for embryogenesis and hypomorphic mutations cause human microcephaly. Hum Mol Genet. 2017;26(24):4836–48.
Tewari D, Patni P, Bishayee A, Sah AN, Bishayee A, editors. Natural products targeting the PI3K-Akt-mTOR signaling pathway in cancer: a novel therapeutic strategy Seminars in cancer biology. Amsterdam: Elsevier; 2019.
Wang Y, Chai Z, Wang M, Jin Y, Yang A, Li M. COPB2 suppresses cell proliferation and induces cell cycle arrest in human colon cancer by regulating cell cycle-related proteins. Exp Ther Med. 2018;15(1):777–84.
An C, Li H, Zhang X, Wang J, Qiang Y, Ye X, et al. Silencing of COPB2 inhibits the proliferation of gastric cancer cells and induces apoptosis via suppression of the RTK signaling pathway. Int J Oncol. 2019;54(4):1195–208.
Wang M, Yu R, Ling X, Cao W, Liu Y, Fang L, et al. COPB2 promotes metastasis and inhibits apoptosis of lung adenocarcinoma cells through functioning as a target of miR-216a-3p. Transl Cancer Res. 2020;9(4):2648–59.
Behnam M, Motamedzadeh A, Aalinezhad M, Dadgostar E, Rashidi Noshabad FZ, Pourfridoni M, et al. The role of aquaporin 4 in brain tumors: implications for pathophysiology, diagnosis and therapy. Mol Biol Rep. 2022. https://doi.org/10.1007/s11033-022-07656-y.
Ding T, Gu F, Fu L, Ma Y-J. Aquaporin-4 in glioma invasion and an analysis of molecular mechanisms. J Clin Neurosci. 2010;17(11):1359–61.
Peng Y, Wu W, Shang Z, Li W, Chen S. Inhibition of lncRNA LINC00461/miR-216a/aquaporin 4 pathway suppresses cell proliferation, migration, invasion, and chemoresistance in glioma. Open Life Sci. 2020;15(1):532–43.
Richardson MM, Jennings LK, Zhang XA. Tetraspanins and tumor progression. Clin Exp Metastasis. 2011;28(3):261–70.
Lazo PA. Functional implications of tetraspanin proteins in cancer biology. Cancer Sci. 2007;98(11):1666–77.
Barczyk M, Carracedo S, Gullberg D. Integrins. Cell Tissue Res. 2010;339(1):269–80.
Taherian A, Li X, Liu Y, Haas TA. Differences in integrin expression and signaling within human breast cancer cells. BMC Cancer. 2011;11:293.
Ding W, Fan XL, Xu X, Huang JZ, Xu SH, Geng Q, et al. Epigenetic silencing of ITGA2 by MiR-373 promotes cell migration in breast cancer. PLoS ONE. 2015;10(8): e0135128.
Gong J, Lu X, Xu J, Xiong W, Zhang H, Yu X. Coexpression of UCA1 and ITGA2 in pancreatic cancer cells target the expression of miR-107 through focal adhesion pathway. J Cell Physiol. 2019;234(8):12884–96.
Wang S, Liu X, Khan AA, Li H, Tahir M, Yan X, et al. miR-216a-mediated upregulation of TSPAN1 contributes to pancreatic cancer progression via transcriptional regulation of ITGA2. Am J Cancer Res. 2020;10(4):1115–29.
Cheng Y, Li K, Diao D, Zhu K, Shi L, Zhang H, et al. Expression of KIAA0101 protein is associated with poor survival of esophageal cancer patients and resistance to cisplatin treatment in vitro. Lab Invest. 2013;93(12):1276–87.
Simpson F, van Bueren KL, Butterfield N, Bennetts JS, Bowles J, Adolphe C, et al. The PCNA-associated factor KIAA0101/p15PAF binds the potential tumor suppressor product p33ING1b. Exp Cell Res. 2006;312(1):73–85.
Wang K, Li J, Zhou B. KIAA0101 knockdown inhibits glioma progression and glycolysis by inactivating the PI3K/AKT/mTOR pathway. Metab Brain Dis. 2022;37(2):489–99.
Jain M, Zhang L, Patterson EE, Kebebew E. KIAA0101 is overexpressed, and promotes growth and invasion in adrenal cancer. PLoS ONE. 2011;6(11): e26866.
Sun T, An Q, Yan R, Li K, Zhu K, Dang C, et al. MicroRNA-216a-5p suppresses esophageal squamous cell carcinoma progression by targeting KIAA0101. Oncol Rep. 2020;44(5):1971–84.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Hamidi, A.A., Taghehchian, N., Zangouei, A.S. et al. Molecular mechanisms of microRNA-216a during tumor progression. Cancer Cell Int 23, 19 (2023). https://doi.org/10.1186/s12935-023-02865-2