BACKGROUND/AIM: MicroRNAs (miRs) play an important role in the regulation of cancer-related processes and are promising candidates for cancer biomarkers. The aim of the study was to evaluate the association of response to anti-EGFR monoclonal antibodies (mAbs) with selected miR expression profiles, including miR-125b, let-7c, miR-99a, miR-17, miR-143 and miR-145 in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: This retrospective study included 46 patients with mCRC harbouring wild-type RAS gene treated with cetuximab or panitumumab combined with chemotherapy in first- or second-line therapy. The miR expression was assessed using qRT-PCR. RESULTS: Down-regulation of miR-125b and let-7c and up-regulation of miR-17 were found in the tumour tissue (p=0.0226, p=0.0040, p<0.0001). Objective response rate (ORR) was associated with up-regulation of miR-125b (p=0.0005). Disease control rate (DCR) was associated with up-regulation of miR-125b and let-7c (p=0.0383 and p=0.0255) and down-regulation of miR-17 (p=0.0464). MiR-125b showed correlation with progression-free and overall survival (p=0.055 and p=0.006). CONCLUSION: The results show that up-regulation of miR-125b is associated with higher ORR and DCR and longer survival; let-7c up-regulation and miR-17 down-regulation are associated with higher DCR in mCRC patients treated with anti-EGFR mAbs.

Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Department of Immunochemistry Diagnostics Faculty of Medicine and University Hospital in Pilsen Charles University Pilsen Czech Republic

Department of Oncology and Radiotherapeutics Faculty of Medicine and University Hospital in Pilsen Charles University Pilsen Czech Republic

Department of Surgery Faculty of Medicine and University Hospital in Pilsen Charles University Pilsen Czech Republic

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Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69–90. doi: 10.3322/caac.20107. PubMed DOI

Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, Penna C, Ducreux M, Rougier P, Penault-Llorca F, Laurent-Puig P. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66(8):3992–3995. doi: 10.1158/0008-5472.CAN-06-0191. PubMed DOI

Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359(17):1757–1765. doi: 10.1056/NEJMoa0804385. PubMed DOI

Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, Patterson SD, Chang DD. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626–1634. doi: 10.1200/JCO.2007.14.7116. PubMed DOI

Lièvre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, Ychou M, Bouché O, Landi B, Louvet C, André T, Bibeau F, Diebold MD, Rougier P, Ducreux M, Tomasic G, Emile JF, Penault-Llorca F, Laurent-Puig P. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26(3):374–379. doi: 10.1200/JCO.2007.12.5906. PubMed DOI

Irahara N, Baba Y, Nosho K, Shima K, Yan L, Dias-Santagata D, Iafrate AJ, Fuchs CS, Haigis KM, Ogino S. NRAS mutations are rare in colorectal cancer. Diagn Mol Pathol. 2010;19(3):157–163. doi: 10.1097/PDM.0b013e3181c93fd1. PubMed DOI PMC

Vaughn CP, Zobell SD, Furtado LV, Baker CL, Samowitz WS. Frequency of KRAS, BRAF, and NRAS mutations in colorectal cancer. Genes Chromosomes Cancer. 2011;50(5):307–312. doi: 10.1002/gcc.20854. PubMed DOI

Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocákova I, Ruff P, Błasińska-Morawiec M, Šmakal M, Canon JL, Rother M, Williams R, Rong A, Wiezorek J, Sidhu R, Patterson SD. Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 2013;369(11):1023–1034. doi: 10.1056/NEJMoa1305275. PubMed DOI

Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015;26(1):13–21. doi: 10.1093/annonc/mdu378. PubMed DOI

Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–297. doi: 10.1016/s0092-8674(04)00045-5. PubMed DOI

Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–216. doi: 10.1093/jnci/92.3.205. PubMed DOI

Fiala O, Pitule P, Hosek P, Liska V, Sorejs O, Bruha J, Vycital O, Buchler T, Poprach A, Topolcan O, Finek J. The association of miR-126-3p, miR-126-5p and miR-664-3p expression profiles with outcomes of patients with metastatic colorectal cancer treated with bevacizumab. Tumour Biol. 2017;39(7):1010428317709283. doi: 10.1177/1010428317709283. PubMed DOI

Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem. 2010;79:351–379. doi: 10.1146/annurev-biochem-060308-103103. PubMed DOI

Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259–269. doi: 10.1038/nrc1840. PubMed DOI

Weidle UH, Schmid D, Birzele F, Brinkmann U. MicroRNAs involved in metastasis of hepatocellular carcinoma: Target candidates, functionality and efficacy in animal models and prognostic relevance. Cancer Genomics Proteomics. 2020;17(1):1–21. doi: 10.21873/cgp.20163. PubMed DOI PMC

Weidle UH, Birzele F, Nopora A. Pancreatic ductal adenocarcinoma: MicroRNAs affecting tumor growth and metastasis in preclinical in vivo models. Cancer Genomics Proteomics. 2019;16(6):451–464. doi: 10.21873/cgp.20149. PubMed DOI PMC

Weidle UH, Birzele F, Nopora A. MicroRNAs as potential targets for therapeutic intervention with metastasis of non-small cell lung cancer. Cancer Genomics Proteomics. 2019;16(2):99–119. doi: 10.21873/cgp.20116. PubMed DOI PMC

Wang Y, Zeng G, Jiang Y. The Emerging Roles of miR-125b in Cancers. Cancer Manag Res. 2020;12:1079–1088. doi: 10.2147/CMAR.S232388. PubMed DOI PMC

Banzhaf-Strathmann J, Edbauer D. Good guy or bad guy: the opposing roles of microRNA 125b in cancer. Cell Commun Signal. 2014;12:30. doi: 10.1186/1478-811X-12-30. PubMed DOI PMC

Le MT, Shyh-Chang N, Khaw SL, Chin L, Teh C, Tay J, O’Day E, Korzh V, Yang H, Lal A, Lieberman J, Lodish HF, Lim B. Conserved regulation of p53 network dosage by microRNA-125b occurs through evolving miRNA-target gene pairs. PLoS Genet. 2011;7(9):e1002242. doi: 10.1371/journal.pgen.1002242. PubMed DOI PMC

Scott GK, Goga A, Bhaumik D, Berger CE, Sullivan CS, Benz CC. Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. J Biol Chem. 2007;282(2):1479–1486. doi: 10.1074/jbc.M609383200. PubMed DOI

Chen H, Xu Z. Hypermethylation-Associated Silencing of miR-125a and miR-125b: A Potential Marker in Colorectal Cancer. Dis Markers. 2015;2015:345080. doi: 10.1155/2015/345080. PubMed DOI PMC

Cappuzzo F, Sacconi A, Landi L, Ludovini V, Biagioni F, D’Incecco A, Capodanno A, Salvini J, Corgna E, Cupini S, Barbara C, Fontanini G, Crinò L, Blandino G. MicroRNA signature in metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies. Clin Colorectal Cancer. 2014;13(1):37–45.e4. doi: 10.1016/j.clcc.2013.11.006. PubMed DOI

Ruby JG, Jan C, Player C, Axtell MJ, Lee W, Nusbaum C, Ge H, Bartel DP. Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans. Cell. 2006;127(6):1193–1207. doi: 10.1016/j.cell.2006.10.040. PubMed DOI

Boyerinas B, Park SM, Hau A, Murmann AE, Peter ME. The role of let-7 in cell differentiation and cancer. Endocr Relat Cancer. 2010;17(1):F19–F36. doi: 10.1677/ERC-09-0184. PubMed DOI

Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, Slack FJ. RAS is regulated by the let-7 microRNA family. Cell. 2005;120(5):635–647. doi: 10.1016/j.cell.2005.01.014. PubMed DOI

Jung HJ, Suh Y. Regulation of IGF -1 signaling by microRNAs. Front Genet. 2015;5:472. doi: 10.3389/fgene.2014.00472. PubMed DOI PMC

Zhang K, Gao H, Wu X, Wang J, Zhou W, Sun G, Wang J, Wang Y, Mu B, Kim C, Chu P, Ho DM, Ann DK, Wong TT, Yen Y. Frequent overexpression of HMGA2 in human atypical teratoid/rhabdoid tumor and its correlation with let-7a3/let-7b miRNA. Clin Cancer Res. 2014;20(5):1179–1189. doi: 10.1158/1078-0432.CCR-13-1452. PubMed DOI

Mizuno R, Kawada K, Sakai Y. The molecular basis and therapeutic potential of Let-7 microRNAs against colorectal cancer. Can J Gastroenterol Hepatol. 2018;2018:5769591. doi: 10.1155/2018/5769591. PubMed DOI PMC

Han HB, Gu J, Zuo HJ, Chen ZG, Zhao W, Li M, Ji DB, Lu YY, Zhang ZQ. Let-7c functions as a metastasis suppressor by targeting MMP11 and PBX3 in colorectal cancer. J Pathol. 2012;226(3):544–555. doi: 10.1002/path.3014. PubMed DOI

Mei LL, Qiu YT, Huang MB, Wang WJ, Bai J, Shi ZZ. MiR-99a suppresses proliferation, migration and invasion of esophageal squamous cell carcinoma cells through inhibiting the IGF1R signaling pathway. Cancer Biomark. 2017;20(4):527–537. doi: 10.3233/CBM-170345. PubMed DOI

Zhu P, Liu J, Lu M, Wu G, Lin X, Cai L, Zhang X. Influence and mechanism of miR-99a suppressing development of colorectal cancer (CRC) with diabetes mellitus (DM) Onco Targets Ther. 2019;12:10311–10321. doi: 10.2147/OTT.S190998. PubMed DOI PMC

Molina-Pinelo S, Carnero A, Rivera F, Estevez-Garcia P, Bozada JM, Limon ML, Benavent M, Gomez J, Pastor MD, Chaves M, Suarez R, Paz-Ares L, de la Portilla F, Carranza-Carranza A, Sevilla I, Vicioso L, Garcia-Carbonero R. MiR-107 and miR-99a-3p predict chemotherapy response in patients with advanced colorectal cancer. BMC Cancer. 2014;14:656. doi: 10.1186/1471-2407-14-656. PubMed DOI PMC

Fang LL, Wang XH, Sun BF, Zhang XD, Zhu XH, Yu ZJ, Luo H. Expression, regulation and mechanism of action of the miR-17-92 cluster in tumor cells (Review) Int J Mol Med. 2017;40(6):1624–1630. doi: 10.3892/ijmm.2017.3164. PubMed DOI PMC

Xi XP, Zhuang J, Teng MJ, Xia LJ, Yang MY, Liu QG, Chen JB. MicroRNA-17 induces epithelial-mesenchymal transition consistent with the cancer stem cell phenotype by regulating CYP7B1 expression in colon cancer. Int J Mol Med. 2016;38(2):499–506. doi: 10.3892/ijmm.2016.2624. PubMed DOI

Huang C, Liu J, Xu L, Hu W, Wang J, Wang M, Yao X. MicroRNA-17 promotes cell proliferation and migration in human colorectal cancer by downregulating SIK1. Cancer Manag Res. 2019;11:3521–3534. doi: 10.2147/CMAR.S191087. PubMed DOI PMC

Lai H, Zhang J, Zuo H, Liu H, Xu J, Feng Y, Lin Y, Mo X. Overexpression of miR-17 is correlated with liver metastasis in colorectal cancer. Medicine (Baltimore) 2020;99(9):e19265. doi: 10.1097/MD.0000000000019265. PubMed DOI PMC

Huang C, Yu M, Yao X. MicroRNA-17 and the prognosis of human carcinomas: a systematic review and meta-analysis. BMJ Open. 2018;8(5):e018070. doi: 10.1136/bmjopen-2017-018070. PubMed DOI PMC

Cui SY, Wang R, Chen LB. MicroRNA-145: a potent tumour suppressor that regulates multiple cellular pathways. J Cell Mol Med. 2014;18(10):1913–1926. doi: 10.1111/jcmm.12358. PubMed DOI PMC

Bandrés E, Cubedo E, Agirre X, Malumbres R, Zárate R, Ramirez N, Abajo A, Navarro A, Moreno I, Monzó M, García-Foncillas J. Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol Cancer. 2006;5:29. doi: 10.1186/1476-4598-5-29. PubMed DOI PMC

Cummins JM, He Y, Leary RJ, Pagliarini R, Diaz LA Jr, Sjoblom T, Barad O, Bentwich Z, Szafranska AE, Labourier E, Raymond CK, Roberts BS, Juhl H, Kinzler KW, Vogelstein B, Velculescu VE. The colorectal microRNAome. Proc Natl Acad Sci USA. 2006;103(10):3687–3692. doi: 10.1073/pnas.0511155103. PubMed DOI PMC

Michael MZ, O’ Connor SM, van Holst Pellekaan NG, Young GP, James RJ. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res. 2003;1(12):882–991. PubMed

Arndt GM, Dossey L, Cullen LM, Lai A, Druker R, Eisbacher M, Zhang C, Tran N, Fan H, Retzlaff K, Bittner A, Raponi M. Characterization of global microRNA expression reveals oncogenic potential of miR-145 in metastatic colorectal cancer. BMC Cancer. 2009;9:374. doi: 10.1186/1471-2407-9-374. PubMed DOI PMC

Schetter AJ, Leung SY, Sohn JJ, Zanetti KA, Bowman ED, Yanaihara N, Yuen ST, Chan TL, Kwong DL, Au GK, Liu CG, Calin GA, Croce CM, Harris CC. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA. 2008;299(4):425–436. doi: 10.1001/jama.299.4.4. PubMed DOI PMC

Drebber U, Lay M, Wedemeyer I, Vallböhmer D, Bollschweiler E, Brabender J, Mönig SP, Hölscher AH, Dienes HP, Odenthal M. Altered levels of the onco-microRNA 21 and the tumor-supressor microRNAs 143 and 145 in advanced rectal cancer indicate successful neoadjuvant chemoradiotherapy. Int J Oncol. 2011;39(2):409–415. doi: 10.3892/ijo.2011.1036. PubMed DOI

Zhang J, Zhang K, Bi M, Jiao X, Zhang D, Dong Q. Circulating microRNA expressions in colorectal cancer as predictors of response to chemotherapy. Anticancer Drugs. 2014;25(3):346–352. doi: 10.1097/CAD.0000000000000049. PubMed DOI

Schee K, Boye K, Abrahamsen TW, Fodstad Ø, Flatmark K. Clinical relevance of microRNA miR-21, miR-31, miR-92a, miR-101, miR-106a and miR-145 in colorectal cancer. BMC Cancer. 2012;12:505. doi: 10.1186/1471-2407-12-505. PubMed DOI PMC