Raymond Anne-Aurélie, Javary Joaquim, Breig Osman, Neaud Véronique, Rosenbaum Jean
University of Bordeaux, INSERM, U1053, Bordeaux Research In Translational Oncology, BaRITOn, Bordeaux, France.
Cell Biochem Funct. 2017 Aug;35(6):289-295. doi: 10.1002/cbf.3274. Epub 2017 Aug 22.
Hepatocellular carcinoma (HCC) is the main primary cancer of the liver. Many studies have shown that insulin resistance is a risk factor for HCC. We previously discovered the overexpression and oncogenic role of the Reptin/RUVBL2 ATPase in HCC. Here, we found that Reptin silencing enhanced insulin sensitivity in 2 HCC cell lines, as shown by a large potentiation of insulin-induced AKT phosphorylation on Ser473 and Thr308, and of downstream signalling. Reptin silencing did not affect the tyrosine phosphorylation of the insulin receptor nor of IRS1, but it enhanced the tyrosine phosphorylation of the p85 subunit of PI3K. The expression of the SHP-1/PTPN6 phosphatase, which dephosphorylates p85, was reduced after Reptin depletion. Forced expression of SHP-1 restored a normal AKT phosphorylation after insulin treatment in cells where Reptin was silenced, demonstrating that the downregulation of SHP1 is mechanistically linked to increased Akt phosphorylation. In conclusion, we have uncovered a new function for Reptin in regulating insulin signalling in HCC cells via the regulation of SHP-1 expression. We suggest that the regulation of insulin sensitivity by Reptin contributes to its oncogenic action in the liver.
肝细胞癌（HCC）是肝脏的主要原发性癌症。许多研究表明，胰岛素抵抗是HCC的一个危险因素。我们之前发现Reptin/RUVBL2 ATP酶在HCC中过表达并具有致癌作用。在此，我们发现Reptin沉默增强了两种HCC细胞系中的胰岛素敏感性，这表现为胰岛素诱导的Ser473和Thr308位点AKT磷酸化以及下游信号的大幅增强。Reptin沉默不影响胰岛素受体或IRS1的酪氨酸磷酸化，但增强了PI3K的p85亚基的酪氨酸磷酸化。使p85去磷酸化的SHP-1/PTPN6磷酸酶的表达在Reptin缺失后降低。在Reptin沉默的细胞中，胰岛素处理后强制表达SHP-1可恢复正常的AKT磷酸化，这表明SHP1的下调在机制上与Akt磷酸化增加有关。总之，我们发现了Reptin在通过调节SHP-1表达来调控HCC细胞胰岛素信号传导方面的新功能。我们认为，Reptin对胰岛素敏感性的调节有助于其在肝脏中的致癌作用。
