Hou Zhouhua, Xu Xuwen, Fu Xiaoyu, Tao Shuhui, Zhou Jiebin, Liu Shuiping, Tan Deming
Department of Infectious Disease, Xiangya Hospital, Central South UniversityChangsha 410008, P. R. China.
Department of Microbiology, Xiangya Medical College, Central South UniversityChangsha 410008, P. R. China.
Am J Cancer Res. 2017 Apr 1;7(4):845-856. eCollection 2017.
Though it is widely known that hepatitis B virus X protein (HBx) is involved in the progression of hepatocellular carcinoma (HCC), the underlying mechanisms are not entirely clear. In recent years, metastasis associated with lung adenocarcinoma transcript 1 (MALAT1), which is an oncogenic long non-coding RNA (lncRNA), has been proved to be associated with many kinds of tumors, including liver cancer. In this study, we demonstrated that MALAT1 was involved in the HBx-mediated hepatocarcinogenesis. Firstly, we found that expression of MALAT1 was strongly up-regulated in HCC tissues and was directly proportional to the expression of HBx. Moreover, in HBx transfected LO2 and HepG2 cells, MALAT1 was also up-regulated compared with non-transfected cells. Then, we observed up-regulated MALAT1 in HepG2 cells could promote cell invasion and migration, whereas knockdown of MALAT1 in HBx-expressing hepatic cells (HepG2-HBx) resulted in a markedly inhibition of cell invasion and migration both and . To further obtain a deeper understanding of the effect of MALAT1, we took latent transforming growth factor β-binding protein 3 (LTBP3) into account by using several assays such as RNA interference, luciferase, transwell and wound healing. Results showed that MALAT1 could promote tumor growth and metastasis by activating LTBP3, which could also be up-regulated by HBx. Meanwhile, the similar results were detected in nude mice. These findings could demonstrate an important mechanism of hepatocarcinogenesis through the signaling of HBx-MALAT1/LTBP3 axis, and may give a potential target for treatment of HCC.
尽管众所周知乙型肝炎病毒X蛋白（HBx）参与肝细胞癌（HCC）的进展，但其潜在机制尚不完全清楚。近年来，与肺腺癌转移相关转录本1（MALAT1），一种致癌性长链非编码RNA（lncRNA），已被证明与包括肝癌在内的多种肿瘤有关。在本研究中，我们证明MALAT1参与了HBx介导的肝癌发生。首先，我们发现MALAT1在肝癌组织中的表达强烈上调，且与HBx的表达成正比。此外，在转染了HBx的LO2和HepG2细胞中，与未转染细胞相比，MALAT1也上调。然后，我们观察到HepG2细胞中上调的MALAT1可促进细胞侵袭和迁移，而在表达HBx的肝细胞（HepG2-HBx）中敲低MALAT1则导致细胞侵袭和迁移均明显受到抑制。为了进一步深入了解MALAT1的作用，我们通过RNA干扰、荧光素酶、Transwell和伤口愈合等多种实验考虑了潜伏转化生长因子β结合蛋白3（LTBP3）。结果表明，MALAT1可通过激活LTBP3促进肿瘤生长和转移，而LTBP3也可被HBx上调。同时，在裸鼠中也检测到了类似的结果。这些发现可以证明通过HBx-MALAT1/LTBP3轴信号传导的肝癌发生的重要机制，并可能为肝癌治疗提供一个潜在靶点。
