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Circ_0007031 Silencing Inhibits Cell Proliferation and Induces Cell Apoptosis via Downregulating MELK at a miR-485-3p-Dependent Way in Colorectal Cancer

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Abstract

Colorectal cancer (CRC) is a malignant cancer with an increasing incidence. Circular RNA (circRNA) is recently found to participate in the regulation of CRC progression. However, the role of circ_0007031 in CRC malignant progression remains elusive. 50 CRC patients were implicated in this study. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the RNA expression of circ_0007031, microRNA-485-3p (miR-485-3p) and maternal embryonic leucine zipper kinase (MELK). Western blot analysis was conducted to determine protein expression. Cell viability and proliferation were demonstrated by cell counting kit-8 and 5-Ethynyl-29-deoxyuridine (EdU) assays, respectively. Cell cycle and apoptosis were investigated by flow cytometry analysis. The interaction among circ_0007031, miR-485-3p and MELK was predicted by online databases, and identified by dual-luciferase reporter assay. Mouse model assay was conducted to reveal the effect of circ_0007031 on tumor formation in vivo. Circ_0007031 and MELK expression were obviously increased, while miR-485-3p expression was decreased in CRC tissues and cells compared with normal colorectal tissues or cells. Circ_0007031 knockdown repressed proliferation, whereas induced cell arrest at G0/G1 phase and apoptosis. On the opposite, circ_0007031 overexpression promoted cell proliferation and induced cell arrest at S phase. Additionally, miR-485-3p inhibitors attenuated circ_0007031 silencing-mediated CRC cell malignancy. MiR-485-3p was unveiled to regulate CRC cell processes via targeting MELK. Circ_0007031 controlled MELK expression via interacting with miR-485-3p. Furthermore, circ_0007031 contributed to tumor formation in vivo. Circ_0007031 knockdown repressed CRC malignant progression by reducing MELK expression through associating with miR-485-3p, suggesting that circ_0007031 was a potential target for the therapy of CRC.

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References

  • Aini S, Yan H, Ding W, Adi L, Su P (2020) Long-chain non-coding RNA MALAT1 regulates paclitaxel resistance of breast cancer cells by targeting miR-485-3p. Nan Fang Yi Ke Da Xue Xue Bao 40(5):698–702

    PubMed  Google Scholar 

  • Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68(6):394–424

    Article  Google Scholar 

  • Chen LL (2016) The biogenesis and emerging roles of circular RNAs. Nat Rev Mol Cell Biol 17(4):205–211

    Article  CAS  PubMed  Google Scholar 

  • Chen LL, Yang L (2015) Regulation of circRNA biogenesis. RNA Biol 12(4):381–388

    Article  PubMed  PubMed Central  Google Scholar 

  • Chen LY, Wang L, Ren YX, Pang Z, Liu Y, Sun XD et al (2020a) The circular RNA circ-ERBIN promotes growth and metastasis of colorectal cancer by miR-125a-5p and miR-138-5p/4EBP-1 mediated cap-independent HIF-1α translation. Mol Cancer 19(1):164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen X, Xu X, Pan B, Zeng K, Xu M, Liu X et al (2018) miR-150-5p suppresses tumor progression by targeting VEGFA in colorectal cancer. Aging 10(11):3421–3437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen S, Zhou Q, Guo Z, Wang Y, Wang L, Liu X et al (2020b) Inhibition of MELK produces potential anti-tumour effects in bladder cancer by inducing G1/S cell cycle arrest via the ATM/CHK2/p53 pathway. J Cell Mol Med 24(2):1804–1821

    Article  CAS  PubMed  Google Scholar 

  • Choi S, Ku JL (2011) Resistance of colorectal cancer cells to radiation and 5-FU is associated with MELK expression. Biochem Biophys Res Commun 412(2):207–213

    Article  CAS  PubMed  Google Scholar 

  • Du H, He Z, Feng F, Chen D, Zhang L, Bai J et al (2020) Hsa_circ_0038646 promotes cell proliferation and migration in colorectal cancer via miR-331-3p/GRIK3. Oncol Lett 20(1):266–274

    CAS  PubMed  PubMed Central  Google Scholar 

  • Gong X, Chen Z, Han Q, Chen C, Jing L, Liu Y et al (2018) Sanguinarine triggers intrinsic apoptosis to suppress colorectal cancer growth through disassociation between STRAP and MELK. BMC Cancer 18(1):578

    Article  PubMed  PubMed Central  Google Scholar 

  • Gu C, Banasavadi-Siddegowda YK, Joshi K, Nakamura Y, Kurt H, Gupta S et al (2013) Tumor-specific activation of the C-JUN/MELK pathway regulates glioma stem cell growth in a p53-dependent manner. Stem Cells 31(5):870–881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • He X, Ma J, Zhang M, Cui J, Yang H (2020) Circ_0007031 enhances tumor progression and promotes 5-fluorouracil resistance in colorectal cancer through regulating miR-133b/ABCC5 axis. Cancer Biomark 29(4):531–542

    Article  CAS  PubMed  Google Scholar 

  • Hua Y, Duan S, Murmann AE, Larsen N, Kjems J, Lund AH et al (2011) miRConnect: identifying effector genes of miRNAs and miRNA families in cancer cells. PLoS ONE 6(10):e26521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Janostiak R, Rauniyar N, Lam TT, Ou J, Zhu LJ, Green MR et al (2017) MELK promotes melanoma growth by stimulating the NF-κB pathway. Cell Rep 21(10):2829–2841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang W, Li T, Wang J, Jiao R, Shi X, Huang X et al (2019) miR-140-3p suppresses cell growth and induces apoptosis in colorectal cancer by targeting PD-L1. Onco Targets Ther 12:10275–10285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jin C, Wang A, Liu L, Wang G, Li G (2019) Hsa_circ_0136666 promotes the proliferation and invasion of colorectal cancer through miR-136/SH2B1 axis. J Cell Physiol 234(5):7247–7256

    Article  CAS  PubMed  Google Scholar 

  • Kohler RS, Kettelhack H, Knipprath-Mészaros AM, Fedier A, Schoetzau A, Jacob F et al (2017) MELK expression in ovarian cancer correlates with poor outcome and its inhibition by OTSSP167 abrogates proliferation and viability of ovarian cancer cells. Gynecol Oncol 145(1):159–166

    Article  CAS  PubMed  Google Scholar 

  • Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW et al (2009) Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 27(22):3677–3683

    Article  PubMed  PubMed Central  Google Scholar 

  • Lai J, Xin J, Fu C, Zhang W (2020) CircHIPK3 promotes proliferation and metastasis and inhibits apoptosis of renal cancer cells by inhibiting MiR-485-3p. Cancer Cell Int 20:248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li Y, Zang H, Zhang X, Huang G (2020) circ_0136666 facilitates the progression of colorectal cancer via miR-383/CREB1 axis. Cancer Manag Res 12:6795–6806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Liu X, Li R (2020a) LncRNA SNHG6 enhances the radioresistance and promotes the growth of cervical cancer cells by sponging miR-485-3p. Cancer Cell Int 20:424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu R, Lv QL, Yu J, Hu L, Zhang LH, Cheng Y et al (2015) Correlating transcriptional networks with pathological complete response following neoadjuvant chemotherapy for breast cancer. Breast Cancer Res Treat 151(3):607–618

    Article  CAS  PubMed  Google Scholar 

  • Liu G, Zhan W, Guo W, Hu F, Qin J, Li R et al (2020b) MELK accelerates the progression of colorectal cancer via activating the FAK/Src pathway. Biochem Genet 58(5):771–782

    Article  CAS  PubMed  Google Scholar 

  • Liu Z, Zhou Y, Liang G, Ling Y, Tan W, Tan L et al (2019) Circular RNA hsa_circ_001783 regulates breast cancer progression via sponging miR-200c-3p. Cell Death Dis 10(2):55

    Article  PubMed  PubMed Central  Google Scholar 

  • Lou C, Xiao M, Cheng S, Lu X, Jia S, Ren Y et al (2016) MiR-485-3p and miR-485-5p suppress breast cancer cell metastasis by inhibiting PGC-1α expression. Cell Death Dis 7(3):e2159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu TX, Rothenberg ME (2018) MicroRNA. J Allergy Clin Immunol 141(4):1202–1207

    Article  CAS  PubMed  Google Scholar 

  • Qu S, Yang X, Li X, Wang J, Gao Y, Shang R et al (2015) Circular RNA: a new star of noncoding RNAs. Cancer Lett 365(2):141–148

    Article  CAS  PubMed  Google Scholar 

  • Rupaimoole R, Calin GA, Lopez-Berestein G, Sood AK (2016) miRNA deregulation in cancer cells and the tumor microenvironment. Cancer Discov 6(3):235–246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shi L, Tao C, Tang Y, Xia Y, Li X, Wang X (2020) Hypoxia-induced hsa_circ_0000826 is linked to liver metastasis of colorectal cancer. J Clin Lab Anal 34(9):e23405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel RL, Miller KD, Fedewa SA, Ahnen DJ, Meester RGS, Barzi A et al (2017) Colorectal cancer statistics, 2017. CA Cancer J Clin 67(3):177–193

    Article  PubMed  Google Scholar 

  • Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC et al (2020) Colorectal cancer statistics, 2020. CA Cancer J Clin 70(3):145–164

    Article  PubMed  Google Scholar 

  • Song Z, Zhang Q, Zhu J, Yin G, Lin L, Liang C (2020) Identification of urinary hsa_circ _0137439 as potential biomarker and tumor regulator of bladder cancer. Neoplasma 67(1):137–146

    Article  CAS  PubMed  Google Scholar 

  • Taherdangkoo K, Kazemi Nezhad SR, Hajjari MR, Tahmasebi BM (2020) miR-485-3p suppresses colorectal cancer via targeting TPX2. Bratisl Lek Listy 121(4):302–307

    CAS  PubMed  Google Scholar 

  • Tang Q, Hann SS (2020) biological roles and mechanisms of circular RNA in human cancers. Onco Targets Ther 13:2067–2092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Q, Liu MJ, Bu J, Deng JL, Jiang BY, Jiang LD et al (2021) miR-485–3p regulated by MALAT1 inhibits osteosarcoma glycolysis and metastasis by directly suppressing c-MET and AKT3/mTOR signalling. Life Sci 268:118925

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Mo Y, Gong Z, Yang X, Yang M, Zhang S et al (2017) Circular RNAs in human cancer. Mol Cancer 16(1):25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Wang H, Zhang J, Chu Z, Liu P, Zhang X et al (2020a) Circ_0007031 serves as a sponge of mir-760 to regulate the growth and chemoradiotherapy resistance of colorectal cancer via regulating DCP1A. Cancer Manag Res 12:8465–8479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang L, Yang L, Wang C, Zhao W, Ju Z, Zhang W et al (2020b) Inhibition of the ATM/Chk2 axis promotes cGAS/STING signaling in ARID1A-deficient tumors. J Clin Invest 130(11):5951–5966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang N, Zeng L, Li Z, Zhen Y, Chen H (2019) Serum miR-663 expression and the diagnostic value in colorectal cancer. Artif Cells Nanomed Biotechnol 47(1):2650–2653

    Article  CAS  PubMed  Google Scholar 

  • Xu P, Jia S, Wang K, Fan Z, Zheng H, Lv J et al (2020) MiR-140 inhibits classical swine fever virus replication by targeting Rab25 in swine umbilical vein endothelial cells. Virulence 11(1):260–269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang F, Hu A, Li D, Wang J, Guo Y, Liu Y et al (2019) Circ-HuR suppresses HuR expression and gastric cancer progression by inhibiting CNBP transactivation. Mol Cancer 18(1):158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Z, Zhang J, Lu D, Sun Y, Zhao X, Wang X et al (2020) Hsa_circ_0137008 suppresses the malignant phenotype in colorectal cancer by acting as a microRNA-338-5p sponge. Cancer Cell Int 20:67

    Article  PubMed  PubMed Central  Google Scholar 

  • Yuan Y, Liu W, Zhang Y, Zhang Y, Sun S (2018) CircRNA circ_0026344 as a prognostic biomarker suppresses colorectal cancer progression via microRNA-21 and microRNA-31. Biochem Biophys Res Commun 503(2):870–875

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Sui R, Chen Y, Liang H, Shi J, Piao H (2019) Downregulation of miR-485-3p promotes glioblastoma cell proliferation and migration via targeting RNF135. Exp Ther Med 18(1):475–482

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Y, Zhou X, Li Y, Xu Y, Lu K, Li P et al (2018) Inhibition of maternal embryonic leucine zipper kinase with OTSSP167 displays potent anti-leukemic effects in chronic lymphocytic leukemia. Oncogene 37(41):5520–5533

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Du T, Du L, Li P, Li J, Duan W et al (2019) Long noncoding RNA LINC02418 regulates MELK expression by acting as a ceRNA and may serve as a diagnostic marker for colorectal cancer. Cell Death Dis 10(8):568

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhu M, Xu Y, Chen Y, Yan F (2017) Circular BANP, an upregulated circular RNA that modulates cell proliferation in colorectal cancer. Biomed Pharmacother 88:138–144

    Article  CAS  PubMed  Google Scholar 

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SS was responsible for drafting the manuscript. SS, WL, JL and LL contributed to the analysis and interpretation of data. SS, LL, XL, DY and ZY contributed in the data collection. All authors read and approved the final manuscript.

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Correspondence to Zhigao Yu.

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Written informed consent was obtained from patients with approval by the Institutional Review Board in Xiantao First People’s Hospital Affiliated to Yangtze University.

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Su, S., Lu, W., Liu, J. et al. Circ_0007031 Silencing Inhibits Cell Proliferation and Induces Cell Apoptosis via Downregulating MELK at a miR-485-3p-Dependent Way in Colorectal Cancer. Biochem Genet 60, 576–597 (2022). https://doi.org/10.1007/s10528-021-10111-5

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