Background. The goals of this study were to elucidate the use of the expression of microRNA-30e (miR-30e) and microRNA-223 (miR-223) as diagnostic biomarkers for early diagnosis of hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) infection. Methods. The study included three groups, the first group included thirty patients with HCC associated with HCV, the second group included thirty patients with cirrhosis with HCV and the third group included thirty healthy control subjects. Blood samples were obtained for determination of serum expression of miR-30e and miR-223 by real time polymerase chain reaction. Results. There was significant decrease of miR-30e of expression in patients with HCC (0.16 ± 0.1) compared to both patients with cirrhosis (0.4 ± 0.2, P<0.01) and healthy control subjects (1.2 ± 0.4, P<0.001). There was also significant reduction of miR-223 expression levels in patients with HCC (0.2 ± 0.1) compared to patients with cirrhosis (0.5 ± 0.2, P<0.01) and healthy control subjects (1.0 ± 0.1, P<0.001). There was also significant decrease of miR-30e expression in late stage versus early stage of HCC (0.1 ± 0.0 vs. 0.22 ± 0.1, P<0.001), while there was no significant difference of alpha-fetoprotein (AFP) between patients with late and early HCC. Also, values of miR-223 had significantly reduced levels in late HCC compared to its expression values in early HCC (0.1± 0.0 vs. 0.23 ± 0.2, P<001). Conclusion. There was significant reduction of expression of miR-30e and miR-223 in serum of HCC patients compared to either patients with cirrhosis or healthy subjects. These results show that the combined use of both biomarkers had better sensitivity in the diagnosis of HCC compared to AFP.
hepatocellular carcinoma, microRNA-30e, microRNA-223, hepatitis C virus, alpha-fetoprotein
Ibrahim AS, Khaled HM, Mikhail NN, Baraka H, Kamel H. Cancer incidence in Egypt: results of the national population-based cancer registry program. J Cancer Epidemiol. 2014;2014:437971-89.
Gomaa AI, Hashim MS, Waked I. Comparing staging systems for predicting prognosis and survival in patients with hepatocellular carcinoma in Egypt. PLoS One 2014; 9:e90929.
Hepatitic C. WHO fact sheets, 9 July 2019, https://www.who.int/news-room/fact-sheets/detail/hepatitis-c
Jefferies M, Rauff B, Rashid H, Lam T, Rafiq S. Update on global epidemiology of viral hepatitis and preventive strategies. World J Clin Cases. 2018;6(13):589-99.
An Y, Gao S, Zhao WC, Qiu BA, Xia NX, Zhang PJ, Fan ZP. Novel serum microRNAs panel on the diagnostic and prognostic implications of hepatocellular carcinoma. World J Gastroenterol.2018;24(24):2596-604.
Yu NC, Chaudhari V, Raman SS, Lassman C, Tong MJ, Busuttil RW, Lu DS. CT and MRI improve detection of hepatocellular carcinoma, compared with ultrasound alone, in patients with cirrhosis. Clin Gastroenterol Hepatol. 2011;9(2):161-7.
Ambros V. MicroRNAs: tiny regulators with great potential. Cell. 2001;107:823–6
Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–97.
Acunzo M, Romano G, Wernicke D. MicroRNA and cancer – a brief overview. Adv Biol Regul. 2015; 57:1–9.
Witwer KW. Circulating microRNA biomarker studies: pitfalls and potential solutions. Clin Chem. 2015; 61:56–63.
Bhattacharya S, Steele R, Shrivastava S, Chakraborty S, Di Bisceglie AM, Ray RB. Serum miR-30e and miR-223 as novel noninvasive biomarkers for hepatocellular carcinoma. Am J Pathol. 2016;186(2):242-7.
Zhang Y, Li T, Qiu Y, Zhang T, Guo P, Ma X, Wei Q, Han L. Serum microRNA panel for early diagnosis of the onset of hepatocellular carcinoma. Medicine (Baltimore). 2017;96(2):e5642.
Hand N.J., Master Z.R., Eauclaire S.F., et al. The microRNA-30 family is required for vertebrate hepatobiliary development. Gastroenterology. 2009; 136:1081–1090.
Soh J., Iqbal J., Queiroz J., et al. MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion. Nat Med. 2013; 19:892–900.
Xiaolong Tu, Xiuxiu Zheng, Huanan Li, Zhipeng Cao, Hanwen Chang, Shaoyuan Luan, Jie Zhu, Jiangning Chen, Yuhui Zang, Junfeng Zhang, MicroRNA-30 protects against carbon tetrachloride-induced liver fibrosis by attenuating transforming growth factor beta signaling in hepatic stellate cells. Toxicol Sci.
D'Aiuto F, Callari M, Dugo M, Merlino G, Musella V, Miodini P, Paolini B, Cappelletti V, Daidone MG. miR-30e* is an independent subtype-specific prognostic marker in breast cancer. Br J Cancer. 2015;113(2):290-8.
Gasparini P, Cascione L, Fassan M, Lovat F, Guler G, Balci S, Irkkan C, Morrison C, Croce CM, Shapiro CL, Huebner K. MicroRNA expression profiling identifies a four microRNA signature as a novel diagnostic and prognostic biomarker in triple negative breast cancers. Oncotarget. 2014;5(5):1174-84.
Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science. 2004;303(5654):83-6.
Calin GA, Sevignani C, Dumitru CD, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Nat Acad Sci USA. 2004; 101:2999–3004
Li G, Shen Q, Li C, et al., Identification of circulating MicroRNAs as novel potential biomarkers for hepatocellular carcinoma detection: a systematic review and meta-analysis, Clin. Transl. Oncol. 17 (9) 2015; 684-93.
Llovet JM, Fuster J, Bruix J; Barcelona-Clínic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. 2004;10(2 Suppl 1):S115-20.
Shi M, Mu Y, Zhang H, Liu M, Wan J, Qin X, Li C. MicroRNA-200 and microRNA-30 family as prognostic molecular signatures in ovarian cancer: A meta-analysis. Medicine (Baltimore). 2018;97(32):e11505.
Debernardi S, Massat NJ, Radon TP, Sangaralingam A, Banissi A, Ennis DP, Dowe T, Chelala C, Pereira SP, Kocher HM, Young BD, Bond-Smith G, Hutchins R, Crnogorac- Jurcevic T. Noninvasive urinary miRNA biomarkers for early detection of pancreatic adenocarcinoma. Am J Cancer Res. 2015;15(5):3455-66.
Xu X, Tao Y, Shan L, Chen R, Jiang H, Qian Z, Cai F, Ma L, Yu Y. The Role of MicroRNAs in hepatocellular carcinoma. J Cancer. 2018;9(19):3557-69.
Sasaki R, Sur S, Cheng Q, Steele R, Ray RB. Repression of MicroRNA-30e by hepatitis C virus enhances fatty acid synthesis. Hepatol Commun. 2019;3:943-53.
Wang H, Liu G, Shen D, Ye H, Huang J, Jiao L, Sun Y. HOXA1 enhances the cell proliferation, invasion and metastasis of prostate cancer cells. Oncol Rep. 2015;34:1203–1210.
Zhang C, Zhang J. Decreased expression of microRNA-223 promotes cell proliferation in hepatocellular carcinoma cells via the insulin-like growth factor-1 signaling pathway. Exp Ther Med. 2018;15(5):4325-31.
Wong QW, Lung RW, Law PT, Lai PB, Chan KY, To KF, Wong N. MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1.
Dong Z, Qi R, Guo X, Zhao X, Li Y, Zeng Z, Bai W, Chang X, Hao L, Chen Y, Lou M, Li Z, Lu Y. MiR-223 modulates hepatocellular carcinoma cell proliferation through promoting apoptosis via the Rab1-mediated mTOR activation. Biochem Biophys Res Commun. 2017;483(1):630-37.
Dhanasekaran R, Khanna V, Kooby DA, Kauh JS, Carew JD, Kim HS. Chemoembolization combined with RFA for HCC: survival benefits and tumor treatment response. J Cancer Ther. 2013;4(2):493-99.
Ronot M, Bouattour M, Wassermann J, Bruno O, Dreyer C, Larroque B, Castera L, Vilgrain V, Belghiti J, Raymond E, Faivre S. Alternative Response Criteria (Choi, European association for the study of the liver, and modified Response Evaluation Criteria in Solid Tumors [RECIST]) Versus RECIST 1.1 in patients with advanced hepatocellular carcinoma treated with sorafenib. Oncologist. 2014;19(4):394-402.