Reptin regulates insulin‐stimulated Akt phosphorylation in hepatocellular carcinoma via the regulation of SHP‐1/PTPN6

Abstract

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.

Antagonizing roles of SHP1 in the pathogenesis of Helicobacter pylori infection

“…Given that SHP1 inhibits PI3K/Akt signaling pathway in pituitary tumors and hepatocellular carcinoma, 39,40 and H. pylori infection causes an abnormal activation of PI3K/Akt pathway, we tested the effect of SHP1 on PI3K/Akt pathway activation in H. pylori ‐infected cells. As shown in Figure 3A; Figure S4A, H. pylori infection caused more phosphorylation of Akt, which was significantly reduced with the inhibition of PI3K.…”

“…Given that SHP1 inhibits PI3K/Akt signaling pathway in pituitary tumors and hepatocellular carcinoma, 39,40 raised level of phosphorylated Akt was aggravated further, and when overexpressing SHP1, it was opposite. But in cells transformed with empty overexpressed or knockdown vector, this situation did not occur (Figure 3B; Figure S4B).…”

Multilevel regulation of RUVBL2 expression predicts poor prognosis in hepatocellular carcinoma

“…Silencing RUVBL2 in HCC cells reduced cell growth, increased apoptosis and induced cell senescence and migration; therefore, it is associated with poor prognosis and chemoresistance [16, 21–23]. In addition, RUVBL2 controlled glucose and lipid metabolism and contributed to the pathogenesis of insulin resistance and non-alcoholic fatty liver disease via mTOR and PI3K–AKT pathways [24, 25]. However, the previous studies mainly investigated the mRNA expression characteristics of RUVBL2 in limited HCC samples using real-time reverse transcript-PCR, while its protein expression levels was detected in only 20 clinical samples by immunohistochemical staining [16, 23].…”