MicroRNA-101 inhibits human hepatocellular carcinoma progression through EZH2 downregulation and increased cytostatic drug sensitivity

• Published in: Journal of hepatology 2014-03, Vol.60 (3), p.590-598
• Main Authors: Xu, Leibo, Beckebaum, Susanne, Iacob, Speranta, Wu, Gang, Kaiser, Gernot M, Radtke, Arnold, Liu, Chao, Kabar, Iyad, Schmidt, Hartmut H, Zhang, Xiaoyong, Lu, Mengji, Cicinnati, Vito R
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Autophagy; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - prevention & control; Disease Progression; Down-Regulation; Enhancer of Zeste Homolog 2 Protein; Female; Gastroenterology and Hepatology; HCC; Hep G2 Cells; Humans; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Liver Neoplasms - prevention & control; Mice, Inbred BALB C; microRNA; MicroRNAs - physiology; Neoplasm Invasiveness; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - physiology; Target gene
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2013.10.028

Background & Aims Oncogene polycomb group protein enhancer of zeste homolog 2 ( EZH 2) has been proposed to be a target gene of putative tumor suppressor microRNA-101 (miR-101). The aim of our study was to investigate the functional role of both miR-101 and EZH 2 in human hepatocellular carcinoma (HCC). Methods MiR-101 and EZH 2 expressions were evaluated in tumor tissues of 99 HCC patients and 7 liver cancer cell lines by real-time PCR. Luciferase reporter assay was employed to validate whether EZH 2 represents a target gene of miR-101. The effect of miR-101 on HCC growth as well as programmed cell death was studied in vitro and in vivo. Results MiR-101 expression was significantly downregulated in most of HCC tissues and all cell lines, whereas EZH 2 was significantly overexpressed in most of HCC tissues and all cell lines. There was a negative correlation between expression levels of miR-101 and EZH 2. Luciferase assay results confirmed EZH 2 as a direct target gene of miR-101, which negatively regulates EZH 2 expression in HCC. Ectopic overexpression of miR-101 dramatically repressed proliferation, invasion, colony formation as well as cell cycle progression in vitro and suppressed tumorigenicity in vivo . Furthermore, miR-101 inhibited autophagy and synergized with either doxorubicin or fluorouracil to induce apoptosis in tumor cells. Conclusion Tumor suppressor miR-101 represses HCC progression through directly targeting EZH 2 oncogene and sensitizes liver cancer cells to chemotherapeutic treatment. Our findings provide significant insights into molecular mechanisms of hepatocarcinogenesis and may have clinical relevance for the development of novel targeted therapies for HCC.