Xue Jing, Chen Li-Zhang, Li Zhan-Zhan, Hu Ying-yun, Yan Shi-peng, Liu Li-Ya
Department of Epidemiology, Public Health School of Central South University, Changsha, 410078, China,
Mol Cell Biochem. 2015 Jan;399(1-2):77-86. doi: 10.1007/s11010-014-2234-9. Epub 2014 Nov 20.
Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. P21-activated kinase 4 (PAK4) has been identified as an oncogenic protein in a variety of cancers. However, the contribution and regulation of PAK4 in HCC remain poorly understood. In the present study, we found that inhibition of PAK4 expression by specific shRNA significantly attenuated HCC cell proliferation. Moreover, we show that microRNA-433 (miRNA-433) could directly target PAK4 through the miRNA-433 binding sequence at the 3'-UTR of PAK4 mRNA, and inhibit PAK4 protein expression. We further show that miRNA-433 expression was downregulated in HCC tissues and cell culture as well, which inversely correlated with PAK4 expression levels. Overexpression of miRNA-433 significantly suppressed the proliferation of HepG2 cells, while this effect was partially rescued by forced expression of PAK4 through restoring PI3K/AKT signaling in HepG2 cells. These findings will shed light on the roles and mechanisms of miRNA-433 in regulating HCC proliferation, and may benefit future development of therapeutics targeting miRNA-433 and PAK4 in HCC.
肝细胞癌（HCC）是全球最常见的癌症之一。p21激活激酶4（PAK4）已被确定为多种癌症中的致癌蛋白。然而，PAK4在肝癌中的作用和调控机制仍知之甚少。在本研究中，我们发现通过特异性短发夹RNA（shRNA）抑制PAK4表达可显著减弱肝癌细胞增殖。此外，我们发现微小RNA-433（miRNA-433）可通过PAK4 mRNA 3'-非翻译区（UTR）的miRNA-433结合序列直接靶向PAK4，并抑制PAK4蛋白表达。我们进一步发现，miRNA-433在肝癌组织和细胞培养中表达下调，且与PAK4表达水平呈负相关。miRNA-433过表达显著抑制HepG2细胞增殖，而通过恢复HepG2细胞中的PI3K/AKT信号通路强制表达PAK4可部分逆转这种效应。这些发现将有助于揭示miRNA-433在调控肝癌增殖中的作用和机制，并可能为未来针对肝癌中miRNA-433和PAK4的治疗药物开发提供帮助。
