Skip to main content
Download PDF

Molecular mechanism of circRNAs in drug resistance in renal cell carcinoma

Cancer Cell International volume 22, Article number: 369 (2022) Cite this article

Abstract

Renal cell carcinoma (RCC) is one of the most common malignant tumors with a poor response to radiotherapy and chemotherapy. The advent of molecular targeted drugs has initiated great breakthroughs in the treatment of RCC. However, drug resistance to targeted drugs has become an urgent problem. Various studies across the decades have confirmed the involvement of circular RNAs (circRNAs) in multiple pathophysiological processes and its abnormal expression in many malignant tumors. This review speculated that circRNAs can provide a new solution to drug resistance in RCC and perhaps be used as essential markers for the early diagnosis and prognosis of RCC. Through the analysis and discussion of relevant recent research, this review explored the relationship of circRNAs to and their regulatory mechanisms in drug resistance in RCC. The results indicate an association between the expression of circRNAs and the development of RCC, as well as the involvement of circRNAs in drug resistance in RCC.

Background

Renal cell carcinoma (RCC) is one of the most common malignant tumors [1, 2] that respond poorly to radiotherapy and chemotherapy effect [3]. Currently, tyrosine kinase inhibitor (TKI) drugs, such as sunitinib and sorafenib, are the most commonly used molecular targeted drugs to treat RCC. However, with the massive application of targeted drugs in clinical practice, drug resistance has gradually become an important concern in targeted drug use. Over the years, many researchers have explored the mechanisms of targeted drug resistance in RCC at the cellular and molecular levels. Studies have shown that the development of various tumors, such as glioblastoma, hepatocellular carcinoma, lung carcinoma, and breast carcinoma, is closely related to the expression of circular RNAs (circRNAs) [4,5,6,7]. This review explores the relationship between the molecular mechanism of circRNAs and the mechanism of drug resistance to targeted drugs in RCC and describes the association of circRNAs with the occurrence of drug resistance in RCC.

Biological characteristics of circRNAs

CircRNAS are formed by the reverse shearing of precursor RNAs from end to end, which creates a very stable ring structure [8], 9]. CircRNAs are spatio-temporal and are variously expressed in different tissues and cells [10], 11]. CircRNAs can be divided into EcRNAs, CiRNAs, and EIcRNAs. CircRNAs are involved in cellular function, mainly through competitive endogenous RNA mechanisms [12,13,14]. CircRNAs act as the “sponges” of miRNAs because circRNAs have abundant miRNA loci on the circRNA ring structure, which can bind with various miRNAs, thereby influencing the regulation of downstream target genes. In addition, circRNAs can also alter splicing patterns or mRNA stability by binding RNA-binding proteins (RBPs) related to mRNA regulation [15]. CircRNAs can also interact with RNA polymerase and regulate transcription [16, 17]. Although circRNAs are noncoding RNAs, some circRNAs can encode regulatory peptides [18], 19]. CircRNAs play an essential role in regulating tumor genesis, proliferation, invasion, metastasis, drug resistance, and prognosis [20,21,22].

Association between circRNA expression and RCC

Since the discovery of circRNAs, many studies have shown their close association with the biological behavior of tumors. The relationship between circRNAs and RCC has also been confirmed by several studies involving RNA sequencing, which has revealed abnormal circRNA expression in many tumor tissues [23]. CircRNAs are also involved in the growth, reproduction, invasion, and death of tumor cells [24, 25]. The analysis of the abnormal expression of circRNAs in RCC, along with tumor stage, histological grade, metastasis, and prognosis, has shown that the level of abnormal circRNA expression is correlated with tumor development, proliferation, invasion, and apoptosis.

Studies have also demonstrated that the expression of circRNAs, such as circ PUM1, circRNA ZNF609, circPTCH1, circPCNXL2, circRNA_001287, and circRNA SCARB1, significantly changes in RCC (Table 1). Furthermore, the enhanced expression of these circRNAs can promote the development of RCC [25,26,27,28,29,30]. Using data from existing miRNA databases, researchers screened out circRNAs differentially expressed in tumor and normal cells and subsequently compared and analyzed the effects of differentially expressed circRNAs on RCC at the molecular, cellular, individual, and population levels. Li et al. [31] found that circTLK1 was overexpressed in RCC and that such overexpression was related to the clinical manifestations of and poor prognosis in malignant tumor progression. Their experiments revealed that circTLK1 functioned as a sponge for miR-136-5p and positively regulated CBX4 expression. The overexpression of miR-136-5p significantly inhibited the mRNA and protein expression of CBX4. Conversely, in RCC tissues, miR-136-5p was significantly downregulated, whereas CBX4 was upregulated. The contrasting expressions of miR-136-5p and CBX4 were positively correlated with tumor size, distant metastasis, and poor prognosis. Li et al. further confirmed that circTLK1 knockdown inhibited the migration and invasion of RCC cells. CBX4 (also called polycomb 2) is a small ubiquitin-related modifier E3 ligase that facilitates the sumoylation of other proteins involved in tumorigenesis [32, 33] and increases vascular endothelial growth factor A expression and angiogenesis in hepatocellular carcinoma cells by promoting the sumoylation of HIF-1a [34]. In breast cancer [35], CBX4 promotes cell growth and metastasis in vitro and in vivo by regulating the miR-137/Notch1 signaling pathway. The CircRNAs cRAPGEF5 [31], hsa-circ-0072309 [37], circ-AKT3 [38], circUBAP2 [39], and circHIPK3 [40] are seldom expressed in RCC tissues. The variable expression of circRNA in normal and tumor tissues and cells suggests that circRNAs can be used as tumor biomarkers [41].

Table 1 Role of circRNAs in regulating renal tumor cells
Full size table

CircRNAs and the mechanisms of drug resistance in RCC

Drug resistance in tumors is a common cause of therapeutic failure. During tumor drug therapy, possible mechanisms of drug resistance include the abnormal activation of tumor stem cells, increased metabolic rate of chemotherapeutic drugs, enhanced repair ability after DNA damage, loss of activity of apoptotic signaling pathways, redistribution of intracellular drug accumulation, and increased expression of transporters that recognize and exclude drugs [42,43,44]. Sanger et al. [45] first discovered circRNAs in the 1970s, whereas Hsu et al. [46] observed the circular structure of circRNAs in Hela cells under electron microscopy. Studies in recent decades have consistently confirmed the relationship between circRNAs and tumors. In addition to influencing the malignant progression of tumors, circRNAs have been associated with tumor drug resistance [47,48,49,50]. This suggests that circRNAs may function as regulatory agents of drug resistance in human cancers [51].

As competing endogenous RNAs (ceRNAs), circRNAs mostly perform their normal biological functions through circRNA–miRNA–mRNA regulation networks. miRNA are considered essential in a variety of biological processes in the body and important factors affecting the normal functioning of cells, including participation in the generation and progression of diseases [52,53,54]. CircRNAs are abundant in miRNA sites, which means that they can bind to various miRNAs with various roles in cells, promote or inhibit the expression of target genes, and thus regulate pathological processes in cells and the body [55, 56]. Studies that explored the relationship between the expression level of circRNAs and the clinical efficacy of RCC have found an association of many circRNAs with drug resistance in RCC and have described the mechanisms involved.

Yan et al. [57] analyzed circRNAs variously expressed in RCC by high-throughput sequencing and further investigated hsa_circ_0035483. The expressions of hsa_circ_0035483, hsa-miR-335, cyclin B1 (CCNB1), and the autophagy-related proteins were detected by RT-PCR or Western blot. Yan et al. further confirmed that hsa_circ_0035483 promoted autophagy by binding to hsa-miR-335 and enhanced gemcitabine resistance in RCC by promoting CCNB1 expression (Fig. 1). However, silencing hsa_circ_0035483 enhanced sensitivity to gemcitabine in vivo.

Fig. 1
figure 1

hsa_circ_0035483 and gemcitabine resistance in RCC

Full size image

The circSNX6/miR-1184/GPCPD1 axis plays a crucial role in regulating intracellular LPA levels and sunitinib resistance in RCC. Specifically, Huang et al. [58] found that circSNX6 promoted sunitinib resistance in RCC by suppressing the inhibitory effect of miR-1184 on its target gene, GPCPD1, and increasing intracellular lysophosphatidic acid (LPA) levels. Tan et al. [59] showed that circRNA-001895 expression in sunitinib-resistant RCC was higher than that in chemotherapy-sensitive tissues. Upregulated circRNA-001895 expression in tumor cells was related to sunitinib resistance in RCC through controlled trials. Chen et al. [60] revealed that circRNA-001895 expression in tumor cells was related to sunitinib resistance in RCC and that hsa-circ-001895 regulated the downstream target gene FOX2 through miR-296-5P. Li et al. [61] reported increased circEHD2 expression in sunitinib-resistant cell lines and tissues, which was linked to sunitinib resistance. Conversely, the knockdown of CircEHD2 reduced the progression of sunitinib-resistant cancer cells. Li et al. further reported that miR-4731-5p has a repressive function in RCC and reduces sunitinib resistance by targeting ABCF2, a member of the ABCF transporter family, which is a subgroup of the ATP-binding cassette transporter superfamily. ABCF2 is linked to drug resistance in several cancers [62]. The investigation further confirmed that ABCF2 was upregulated in RCC cells and that it mitigated the inhibitory effect of circEHD2 knockdown on sunitinib resistance in RCC. Additionally, they found that circEHD2 binds with miR-4731-5p in RCC, thereby confirming the essential role of circEHD2 in sunitinib resistance in RCC. However, Li et al.’s study could not establish a clear relationship between ABCF2 and circEHD2. CircRNAs indirectly regulate RCC by regulating the expression and activity of tumor-related target genes through a regulatory network mediated by miRNAs. These circRNAs maintain intracellular homeostasis in physiological states. Once their expression changes in RCC cells, they will not only promote tumor development, proliferation, invasion, and metastasis but also significantly increase the probability of drug resistance in tumor cells.

CircRNAs can regulate cellular physiological and pathological processes through ceRNA mechanisms and by binding to RBPs and RNA polymerase. Furthermore, ribosomes can translate some circRNAs and encode peptides to enable them to perform regulatory functions. Zhang et al. [63] identified a novel circRNA named circME1, which was highly expressed in sunitinib-resistant clear-cell RCC cells, and found that circME1 promotes aerobic glycolysis and sunitinib resistance in clear-cell RCC through the cis-regulation of malic enzyme 1 (ME1). CircME1 enhanced the expression of its parental gene ME1 in cis-regulation by interacting with U1 snRNP at the promoter of ME1. Aerobic glycolysis, also known as the Warburg effect, is involved in tumor progression and the development of sunitinib resistance [64,65,66]. The role of noncoding RNA-mediated overexpression of ABC transporters in chemotherapy-resistant tumors also cannot be ignored [67].

A potential mechanism of chemoresistance or targeted drug resistance in tumor cells may be the cytoprotective functions of autophagy. Furthermore, circRNAs are variously expressed in response to cisplatin, suggesting their involvement in the pathophysiology of cisplatin-induced nephrotoxicity [68]. A study investigated the potential impact of radiation therapy on circRNA expression and reported that the irradiation of human embryonic kidney cells resulted in a clear variation in circRNA expression signatures [69]. These data suggest a possible involvement of circRNAs in treatment resistance in RCC, but further studies are needed to clarify these relationships.

The tumor angiogenesis theory proposed by Folkman in the twentieth century pointed out that tumor angiogenesis is an essential process of tumor growth [70, 71]. Currently, the most widely used TKI drugs in the treatment of RCC have been developed based on this principle. A VEGF/VEGFR-targeted antibody specifically binds VEGF/VEGFR to inhibit the downstream signaling pathway, thus inhibiting the generation of tumor blood vessels and limiting tumor growth. However, with the massive application of targeted drugs in clinical practice, drug resistance has gradually become an important concern in targeted drug use. Few literature reviews have described the role of circRNAs in the mechanism of sunitinib resistance in RCC. This may be a valuable line of further research.

Conclusions

The development of molecular targeted drugs has dramatically improved the therapeutic outcomes for RCC. Still, increasing resistance to targeted drugs has become an urgent problem. Drug resistance is a complex process, and the activation of multiple pro-angiogenic pathways may be associated with TKI resistance. This review discussed the role of circRNAs in the mechanism of drug resistance in RCC. CircRNAs were once thought to be the product of RNA mishearing [72]. However, several studies have shown that circRNA plays a vital role in both physiological and pathological states and is associated with tumorigenesis in various cancers, including RCC.

In conclusion, current studies suggest that circRNAs play a crucial role in mediating drug resistance in RCC. CircRNAs enhance RCC’s resistance to sunitinib and gemcitabine primarily through ceRNA mechanisms. Further studies are required to elucidate further the involvement and mechanisms of circRNAs in drug resistance in RCC. The research and discussion on the involvement of circRNAs in the mechanism of anti-tumor drug resistance provides new insights on developing strategies to overcome drug resistance in clinical practice, as well as on developing more effective treatments for RCC.

Availability of data and materials

Not applicable.

Abbreviations

RCC:

Renal cell carcinoma

TKI:

Tyrosine kinase inhibitors

VEGF:

vascular endothelial growth factor

VEGFR:

vascular endothelial growth factor receptor

RBPs:

RNA binding protein

ceRNAs:

Competing endogenous RNAs

CCNB1:

Cyclin B1

GPCPD1:

Glycerophosphocholine phosphodiesterase 1

LPA:

Lysophosphatidic acid

References

  1. Hyuna Sung, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. Cancer J Clini. 2021;71(3):209–49.

    Google Scholar 

  2. Ochocki JD, et al. Arginase 2 suppresses renal carcinoma progression via biosynthetic cofactor pyridoxal phosphate depletion and increased polyamine toxicity[J]. Cell Metab. 2018;27(6):1263-1280.e6.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Powles T, Staehler M, Ljungberg B, Bensalah K, Canfield SE, Dabestani S, Giles R, Hofmann F, Hora M, Kuczyk MA, Lam T, Marconi L, Merseburger AS, Volpe A, Bex A. Updated EAU guidelines for clear cell renal cancer patients who fail VEGF targeted therapy. Eur Urol. 2016;69(1):4–6. https://doi.org/10.1016/j.eururo.2015.10.017 (Epub 2015 Oct 24 PMID: 26508312).

    Article  PubMed  Google Scholar 

  4. Chen B, Wang M, Huang R, Liao K, Wang T, Yang R, Zhang W, Shi Z, Ren L, Lv Q, Ma C, Lin Y, Qiu Y. Circular RNA circLGMN facilitates glioblastoma progression by targeting miR-127-3p/LGMN axis. Cancer Lett. 2021;1(522):225–37. https://doi.org/10.1016/j.canlet.2021.09.030 (Epub 2021 Sep 25 PMID: 34582975).

    Article  CAS  Google Scholar 

  5. Qiu Lipeng, et al. Circular RNAs in hepatocellular carcinoma: Biomarkers, functions and mechanisms[J]. Life Sci. 2019;231:116660.

    CAS  PubMed  Google Scholar 

  6. Qin Si, et al. Circular RNA PVT1 acts as a competing endogenous RNA for miR-497 in promoting non-small cell lung cancer progression[J]. Biomed Pharmacother. 2019;111:244–50.

    CAS  PubMed  Google Scholar 

  7. Song Xiaojin, et al. circHMCU promotes proliferation and metastasis of breast cancer by sponging the let-7 Family[J]. Mol Ther Nucleic Acids. 2020;20:518–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Sanger HL, Klotz G, Riesner D, Gross HJ, Kleinschmidt AK. Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. Proc Natl Acad Sci USA. 1976;73(11):3852–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Danan M, Schwartz S, Edelheit S, Sorek R. Transcriptome-wide discovery of circular RNAs in Archaea. Nucleic Acids Res. 2012;40:3131–42. https://doi.org/10.1093/nar/gkr1009.

    Article  CAS  PubMed  Google Scholar 

  10. Rybak-Wolf A, et al. Circular RNAs in the mammalian brain are highly abundant, conserved, and dynamically expressed[J]. Mol Cell. 2015;58(5):870–85.

    CAS  PubMed  Google Scholar 

  11. Tianyi Xu, et al. Circular RNA expression profiles and features in human tissues: a study using RNA-seq data[J]. BMC genomics. 2017;18(Suppl 6):680.

    Google Scholar 

  12. Hansen Thomas B, et al. Natural RNA circles function as efficient microRNA sponges[J]. Nature. 2013;495(7441):384–8.

    CAS  PubMed  Google Scholar 

  13. Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J. Natural RNA circles function as efficient microRNA sponges. Nature. 2013;495:384–8. https://doi.org/10.1038/nature11993.

    Article  CAS  PubMed  Google Scholar 

  14. Ferdin J, Kunej T, Calin GA. Non-coding RNAs: identification of cancer-associated microRNAs by gene profiling. Technol Cancer Res Treat. 2010;9:123–38. https://doi.org/10.1177/153303461000900202.

    Article  CAS  PubMed  Google Scholar 

  15. Kristensen LS, Andersen MS, Stagsted LVW, et al. The biogenesis, biology and characterization of circular RNAs[J]. Nat Rev Genet. 2019;20(11):675–91.

    CAS  PubMed  Google Scholar 

  16. Wilusz JE. A 360view of circular RNAs: from biogenesis to functions[J]. Wiley Interdiscip Rev RNA. 2018;9(4):e1478-1500.

    PubMed  PubMed Central  Google Scholar 

  17. Chen LL. The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol. 2016;17(4):205–11.

    CAS  PubMed  Google Scholar 

  18. Rong DW, Sun HD, Li ZX, et al. An emerging function of circRNA-miRNAs-mRNA axis in human diseases. Oncotarget. 2017;8(42):73271–81.

    PubMed  PubMed Central  Google Scholar 

  19. Pamudurti NR, Bartok O, Jens M, Ashwal-Fluss R, Stottmeister C, Ruhe L. Translation of CircRNAs. Mol Cell. 2017;66(1):9–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Lv Q, Ma C, Li H, Tan X, Wang G, Zhang Y, Wang P. Circular RNA microarray expression profile and potential function of circ0005875 in clear cell renal cell carcinoma. J Cancer. 2020;11(24):7146–56. https://doi.org/10.7150/jca.48770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Geng X, Jia Y, Zhang Y, et al. Circular RNA:biogenesis degradation, functions and potential roles in mediating resistance to anti carcinogens[J]. Epigenomics. 2020;12(3):267–83.

    CAS  PubMed  Google Scholar 

  22. Zhang Y, Lin X, Geng X, et al. Advances in circular RNAs and their role in glioma[J]. Int J Oncol. 2020;57(1):67–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Huang G, et al. Recent progress in circular RNAs in human cancers[J]. Cancer Lett. 2017;404:8–18.

    CAS  PubMed  Google Scholar 

  24. Lv Q, Wang G, Zhang Y, Shen A, Tang J, Sun Y, Ma C, Wang P. CircAGAP1 promotes tumor progression by sponging miR-15-5p in clear cell renal cell carcinoma. J Exp Clin Cancer Res. 2021;40(1):76. https://doi.org/10.1186/s13046-021-01864-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zeng F, Luo L, Song M, et al. Silencing of circular RNA PUM1 inhibits clear cell renal cell carcinoma progression through the miR-340–5p/FABP7 axis[J]. J Recept Signal Transduct Res. 2021;3:1033–41.

    Google Scholar 

  26. Yunhe Xiong, Jiabin Zhang, Chao Song. CircRNA ZNF609 functions as a competitive endogenous RNA to regulate FOXP4 expression by sponging miR-138–5p in renal carcinoma[J]. J Cell Physiol. 2019;234(7):10646–54.

    Google Scholar 

  27. Liu H, Hu G, Wang Z, Liu Q, Zhang J, Chen Y, Huang Y, Xue W, Xu Y, Zhai W. circPTCH1 promotes invasion and metastasis in renal cell carcinoma via regulating miR-485-5p/MMP14 axis. Theranostics. 2020;10(23):10791–807. https://doi.org/10.7150/thno.47239.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bisheng Zhou, et al. CircPCNXL2 sponges miR-153 to promote the proliferation and invasion of renal cancer cells through upregulating ZEB2[J]. Cell Cycle. 2018;17(23):2644–54.

    Google Scholar 

  29. Feng J, Guo Y, Li Y, Zeng J, Wang Y, Yang Y, Xie G, Feng Q. Tumor promoting effects of circRNA_001287 on renal cell carcinoma through miR-144-targeted CEP55. J Exp Clin Cancer Res. 2020;39(1):269. https://doi.org/10.1186/s13046-020-01744-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sun J, Pan S, Cui H, Li H. CircRNA SCARB1 Promotes Renal Cell Carcinoma Progression Via Mir- 510–5p/SDC3 Axis. Curr Cancer Drug Targets. 2020;20(6):461–70. https://doi.org/10.2174/1568009620666200409130032 (PMID: 32271695).

    Article  CAS  PubMed  Google Scholar 

  31. Li J, Huang C, Zou Y, Ye J, Yu J, Gui Y. CircTLK1 promotes the proliferation and metastasis of renal cell carcinoma by sponging miR-136-5p. Mol Cancer. 2020;19(1):103. https://doi.org/10.1186/s12943-020-01225-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Li B, Zhou J, Liu P, Hu J, Jin H, Shimono Y, Takahashi M, Xu G. Polycomb protein Cbx4 promotes SUMO modification of de novo DNA methyltransferase Dnmt3a. Biochem J. 2007;405:369–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ismail IH, Gagne JP, Caron MC, McDonald D, Xu Z, Masson JY, Poirier GG, Hendzel MJ. CBX4-mediated SUMO modification regulates BMI1 recruitment at sites of DNA damage. Nucleic Acids Res. 2012;40:5497–510.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Li J, Xu Y, Long XD, Wang W, Jiao HK, Mei Z, Yin QQ, Ma LN, Zhou AW, Wang LS, Yao M, Xia Q, Chen GQ. Cbx4 governs HIF-1alpha to potentiate angiogenesis of hepatocellular carcinoma by its SUMO E3 ligase activity. Cancer Cell. 2014;25:118–31.

    CAS  PubMed  Google Scholar 

  35. Zeng JS, Zhang ZD, Pei L, Bai ZZ, Yang Y, Yang H, Tian QH. CBX4 exhibits oncogenic activities in breast cancer via Notch1 signaling. Int J Biochem Cell Biol. 2018;95:1–8.

    CAS  PubMed  Google Scholar 

  36. Chen Qiong, et al. CircRNA cRAPGEF5 inhibits the growth and metastasis of renal cell carcinoma via the miR-27a-3p/TXNIP pathway[J]. Cancer Lett. 2020;469:68–77.

    CAS  PubMed  Google Scholar 

  37. Tao Chen, et al. The circular RNA hsa-circ-0072309 plays anti-tumour roles by sponging miR-100 through the deactivation of PI3K/AKT and mTOR pathways in the renal carcinoma cell lines[J]. Artif Cells Nanomed Biotechnol. 2019;18(1):151.

    Google Scholar 

  38. Xue D, Wang H, Chen Y, et al. Circ-AKT3 inhibits clear cell renal carcinoma metastasis via altering miR-296–3P/E-cadherin signals[J]. Mol Cancer. 2019. https://doi.org/10.1186/s12943-019-1072-5.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Sun J, Yin A, Zhang W, et al. CircUBAP2 inhibits proliferation and metastasis of clear cell renal cell carcinoma via targeting miR-148a-3P/FOXK2 pathway[J]. Cell Transplant. 2020. https://doi.org/10.1177/0963689720925751.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Haomin Li, et al. Comprehensive profiling of circRNAs and the tumor suppressor function of circHIPK3 in clear cell renal carcinoma[J]. J Mol Histol. 2020;51(3):317–27.

    Google Scholar 

  41. Franz A, et al. Circular RNAs in clear cell renal cell carcinoma: their microarray-based identification, analytical validation, and potential use in a clinico-genomic model to improve prognostic accuracy[J]. Cancers. 2019;11(10):1473–1473.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Llovet JM, Villanueva A, Lachenmayer A, et al. Advances in targeted therapies for hepatocellular carcinoma in the genomic era[J]. Nat Rev Clin Oncol. 2015;12(7):408–24.

    CAS  PubMed  Google Scholar 

  43. Kartal-Yandim M, Adan-Gokbulut A, Baran Y. Molecular mechanisms of drug resistance and its reversal in cancer[J]. Crit Rev Biotechnol. 2016;36(4):716–26.

    CAS  PubMed  Google Scholar 

  44. Bukowski K, Kciuk M, Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy[J]. Int J Mol Sci. 2020;21(9):3233–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Sanger HL, Klotz G, Riesner D, et al. Viroids are single-stranded covalently closed circular RNA molecules existing as highly basepaired rod-like structures[J]. Proc Natl Acad Sci USA. 1976;73(11):38523856. https://doi.org/10.1073/pnas.73.11.3852.

    Article  Google Scholar 

  46. Hsu MT, Coca-Prados M. Electron microscopic evidence for the circular form of RNA in the cytoplasm of eukaryotic cells. Nature. 1979;280(5720):339–40.

    CAS  PubMed  Google Scholar 

  47. Ren TJ, Liu C, Hou JF, Shan FX. CircDDX17 reduces 5-fluorouracil resistance and hinders tumorigenesis in colorectal cancer by regulating miR-31-5p/KANK1 axis. Eur Rev Med Pharmacol Sci. 2020;24(4):1743–54. https://doi.org/10.26355/eurrev_202002_20351 (PMID: 32141542).

    Article  PubMed  Google Scholar 

  48. Xu J, Wan Z, Tang M, et al. N(6)-methyladenosine-modified CircRNA-SORE sustains sorafenib resistance in hepatocellular carcinoma by regulating β-catenin signaling[J]. Mol Cancer. 2020;19(1):163.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Huang W, Yang Y, Wu J, et al. Circular RNA cESRP1 sensitises small cell lung cancer to chemotherapy by sponging miR-93–5p to inhibit TGF-β signalling[J]. Cell Death Differ. 2020;27(5):1709–27.

    CAS  PubMed  Google Scholar 

  50. Wu Z, Gong Q, Yu Y, Zhu J, Li W. Knockdown of circ-ABCB10 promotes sensitivity of lung cancer cells to cisplatin via miR-556-3p/AK4 axis. BMC Pulm Med. 2020;20(1):10. https://doi.org/10.1186/s12890-019-1035-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jeyaraman S, Hanif EAM, Ab Mutalib NS, Jamal R, Abu N. Circular RNAs: potential regulators of treatment resistance in human cancers. Front Genet. 2020;28(10):1369. https://doi.org/10.3389/fgene.2019.01369.

    Article  CAS  Google Scholar 

  52. Jiang X-M, et al. microRNA-19a-3p promotes tumor metastasis and chemoresistance through the PTEN/Akt pathway in hepatocellular carcinoma[J]. Biomed Pharmacother. 2018;105:1147–54.

    CAS  PubMed  Google Scholar 

  53. Yingbin H, et al. Inhibition of microRNA-16 facilitates the paclitaxel resistance by targeting IKBKB via NF-κB signaling pathway in hepatocellular carcinoma[J]. Biochem Biophys Res Commun. 2018;503(2):1035–41.

    Google Scholar 

  54. Kai Zhang, et al. PU.1/microRNA-142–3p targets ATG5/ATG16L1 to inactivate autophagy and sensitize hepatocellular carcinoma cells to sorafenib[J]. Cell Death Dis. 2018;9(3):312.

    Google Scholar 

  55. Sebastian M, et al. Circular RNAs are a large class of animal RNAs with regulatory potency[J]. Nature. 2013;495(7441):333–8.

    Google Scholar 

  56. Salzman J, Gawad C, Wang PL, et al. Circular RNAs are the predominant transcript isoform from hundreds of human genes in diver se cell types[J]. PLoS ONE. 2012;7(2):e30733.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Yan L, Liu G, Cao H, Zhang H, Shao F. Hsa_circ_0035483 sponges hsa-miR-335 to promote the gemcitabine-resistance of human renal cancer cells by autophagy regulation. Biochem Biophys Res Commun. 2019;519(1):172–8. https://doi.org/10.1016/j.bbrc.2019.08.093 (Epub 2019 Sep 3 PMID: 31492499).

    Article  CAS  PubMed  Google Scholar 

  58. Huang KB, Pan YH, Shu GN, Yao HH, Liu X, Zhou M, Wei JH, Chen ZH, Lu J, Feng ZH, Chen W, Han H, Zheng ZS, Luo JH, Zhang JX. Circular RNA circSNX6 promotes sunitinib resistance in renal cell carcinoma through the miR-1184/GPCPD1/ lysophosphatidic acid axis. Cancer Lett. 2021;28(523):121–34. https://doi.org/10.1016/j.canlet.2021.10.003 (Epub 2021 Oct 7 PMID: 34626691).

    Article  CAS  Google Scholar 

  59. Tan L, Huang Z, Chen Z, Chen S, Ye Y, Chen T, Chen Z. CircRNA_001895 promotes sunitinib resistance of renal cell carcinoma through regulation of apoptosis and DNA damage repair. J Chemother. 2021. https://doi.org/10.1080/1120009X.2021.2009990 (Epub ahead of print. PMID: 34927575).

    Article  PubMed  Google Scholar 

  60. Zhuangfei Chen, et al. Circular RNA hsa_circ_001895 serves as a sponge of microRNA-296–5p to promote clear cell renal cell carcinoma progression by regulating SOX12[J]. Cancer Sci. 2020;111(2):713–26.

    Google Scholar 

  61. Li W, Li G, Cao L. Circular RNA Eps15-homology domain-containing protein 2 induce resistance of renal cell carcinoma to sunitinib via microRNA-4731-5p/ABCF2 axis. Bioengineered. 2022;13(4):9729–40. https://doi.org/10.1080/21655979.2022.2059960.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Tsuda H, Ito K, Yaegashi N, et al. Relationship between ABCF2 expression and response to chemotherapy or prognosis in clear cell adenocarcinoma of the ovary. Int J Gynecol Cancer. 2010;20(5):794–7.

    PubMed  Google Scholar 

  63. Zhang MX, Wang JL, Mo CQ, Mao XP, Feng ZH, Li JY, Lin HS, Song HD, Xu QH, Wang YH, Lu J, Wei JH, Han H, Chen W, Mao HP, Luo JH, Chen ZH. CircME1 promotes aerobic glycolysis and sunitinib resistance of clear cell renal cell carcinoma through cis-regulation of ME1. Oncogene. 2022. https://doi.org/10.1038/s41388-022-02386-8 (Epub ahead of print. PMID: 35798876).

    Article  PubMed  PubMed Central  Google Scholar 

  64. Pisarsky L, Bill R, Fagiani E, Dimeloe S, Goosen RW, Hagmann J, et al. Targeting metabolic symbiosis to overcome resistance to anti-angiogenic therapy. Cell Rep. 2016;15:1161–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells? Trends Biochem Sci. 2016;41:211–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Pascale RM, Calvisi DF, Simile MM, Feo CF, Feo F. The Warburg effect 97 years after its discovery. Cancers. 2020;12:2819.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Wang Y, Wang Y, Qin Z, Cai S, Yu L, Hu H, Zeng S. The role of non-coding RNAs in ABC transporters regulation and their clinical implications of multidrug resistance in cancer. Expert Opin Drug Metab Toxicol. 2021;17(3):291–306. https://doi.org/10.1080/17425255.2021.1887139 (Epub 2021 Feb 22 PMID: 33544643).

    Article  CAS  PubMed  Google Scholar 

  68. Li CM, Li M, Ye ZC, Huang JY, Li Y, Yao ZY, Peng H, Lou TQ. Circular RNA expression profiles in cisplatin-induced acute kidney injury in mice. Epigenomics. 2019;11(10):1191–207. https://doi.org/10.2217/epi-2018-0167 (Epub 2019 Jul 24 PMID: 31339054).

    Article  CAS  PubMed  Google Scholar 

  69. He N, Sun Y, Yang M, Lu Q, Wang J, Xiao C, Wang Y, Du L, Ji K, Xu C, Liu Q. Analysis of circular RNA expression profile in HEK 293T cells exposed to ionizing radiation. Dose Response. 2019;17(2):1559325819837795. https://doi.org/10.1177/1559325819837795.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Folkman MJ, Long DM, Becker FF. Growth and metastasis of tumor in organ culture. Cancer. 1963;16:453–67.

    CAS  PubMed  Google Scholar 

  71. Folkman J, Merler E, Abernathy C, et al. Isolation of a tumor fraction responsible for angiogenesis. J Exp Med. 1971;133:275–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Cocquerelle C, et al. Mis-splicing yields circular RNA molecules[J]. FASEB J. 1993;7(1):155–60.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

1 The project name: “Novel fluorescent/paramagnetic dual-modal-specific circular RNA probe for accurate prediction of the sensitivity of sunitinib for renal cancer”, item number: 22ZR1456600, Source of funding: Shanghai 2022 “Science and Technology Innovation Action Plan” Natural Science Fund project application guide. 2 The project name: “Establishment of an animal model of sunitinib-resistant renal carcinoma and its application in monitoring sunitinib drug sensitivity with a novel visualized circular RNA probe”, item number: 22140903600, Source of funding: Shanghai 2022 “Science and Technology Innovation Action Plan” experimental animal Research project application Guide/animal model research, development and application. 3 The project name: “Novel fluorescent/paramagnetic dual-modality specific circular RNA probe accurately predicts sensitivity of sunitinib to renal cancer”, item number: 22120210567, Source of funding: Fundamental Research Funds for central Universities of Tongji University.

Author information

Authors and Affiliations

  1. Department of Medical Imaging, Tongji Hospital, Tongji University School of Medicine, Xincun Road No. 389, Shanghai, 200065, China

    Shuang Qin, Yuting Wang, Peijun Wang & Qi Lv

Authors
  1. Shuang Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuting Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peijun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qi Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SQ was a major contributor in writing the manuscript. QL envisioned and participated in the revision of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Peijun Wang or Qi Lv.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have 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

Qin, S., Wang, Y., Wang, P. et al. Molecular mechanism of circRNAs in drug resistance in renal cell carcinoma. Cancer Cell Int 22, 369 (2022). https://doi.org/10.1186/s12935-022-02790-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12935-022-02790-w

Keywords

Cancer Cell International

ISSN: 1475-2867

Contact us