Gjymishka Altin, Pi Liya, Oh Seh-Hoon, Jorgensen Marda, Liu Chen, Protopapadakis Yianni, Patel Ashnee, Petersen Bryon E
Department of Pediatrics, University of Florida, Gainesville, Florida.
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida.
Am J Pathol. 2016 May;186(5):1092-102. doi: 10.1016/j.ajpath.2015.12.022. Epub 2016 Mar 3.
miRNAs are involved in liver regeneration, and their expression is dysregulated in hepatocellular carcinoma (HCC). Connective tissue growth factor (CTGF), a direct target of miR-133b, is crucial in the ductular reaction (DR)/oval cell (OC) response for generating new hepatocyte lineages during liver injury in the context of hepatotoxin-inhibited hepatocyte proliferation. Herein, we investigate whether miR-133b regulation of CTGF influences HCC cell proliferation and migration, and DR/OC response. We analyzed miR-133b expression and found it to be down-regulated in HCC patient samples and induced in the rat DR/OC activation model of 2-acetylaminofluorene with partial hepatectomy. Furthermore, overexpression of miR-133b via adenoviral system in vitro led to decreased CTGF expression and reduced proliferation and Transwell migration of both HepG2 HCC cells and WBF-344 rat OCs. In vivo, overexpression of miR-133b in DR/OC activation models of 2-acetylaminofluorene with partial hepatectomy in rats, and 3,5-diethoxycarbonyl-1,4-dihydrocollidine in mice, led to down-regulation of CTGF expression and OC proliferation. Collectively, these results show that miR-133b regulation of CTGF is a novel mechanism critical for the proliferation and migration of HCC cells and OC response.
微小RNA（miRNA）参与肝脏再生，且其表达在肝细胞癌（HCC）中失调。结缔组织生长因子（CTGF）是miR - 133b的直接靶标，在肝毒素抑制肝细胞增殖的情况下，其在肝损伤期间生成新肝细胞谱系的小胆管反应（DR）/卵圆细胞（OC）反应中起关键作用。在此，我们研究miR - 133b对CTGF的调控是否影响HCC细胞增殖和迁移以及DR/OC反应。我们分析了miR - 133b的表达，发现其在HCC患者样本中下调，并在2 - 乙酰氨基芴联合部分肝切除术的大鼠DR/OC激活模型中被诱导。此外，通过腺病毒系统在体外过表达miR - 133b导致CTGF表达降低，同时HepG2 HCC细胞和WBF - 344大鼠OC的增殖及Transwell迁移减少。在体内，在大鼠2 - 乙酰氨基芴联合部分肝切除术以及小鼠3,5 - 二乙氧基羰基 - 1,4 - 二氢可力丁的DR/OC激活模型中过表达miR - 133b，导致CTGF表达下调以及OC增殖减少。总的来说，这些结果表明miR - 133b对CTGF的调控是一种对HCC细胞增殖和迁移以及OC反应至关重要的新机制。
