INSULIN ENHANCED K-RAS-DEPENDENT MIGRATION AND INVASION VIA SSTR2/AKT AXIS
Zipeng Lu*, Guangfu Wang, Lingdi Yin, Yunpeng Peng, Yong Gao, Hao Gao, Yi Miao
Pancreas Center, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
Background: Hyperinsulinemia has been reported to be a risk factor of PDAC, but the function of insulin in carcinogenesis still remain unclarified. This study is to elucidate the effect of insulin in PDAC tumorigenesis.
Methods: 20 nM was chosen as optimal concentration of insulin. Transwell, cell counting kit 8 and EDU assays showed that migration, invasion and proliferation were significantly enhanced after insulin co-incubation. Next generation sequencing was conducted to research the effect of K-Ras mutation on HPNE cells. qRT-PCR and Western blot were applied to evaluate the SSTR2 and its downstream regulators. The effect of insulin on the mutant cells was partly reversed by AKT inhibitor MK2206. Up-regulating SSTR2 or knock-down K-Ras supressed insulin-induced invasion, proliferation and AKT phosphorylation.
Results: We found that an increased migration and invasion ability of HPNE cells after introduction of mutated K-Ras gene. These effects were further enhanced by the simultaneous administration of insulin. NGS showed that SSTR2 was down-regulated in K-Ras mutant cells. qRT-PCR and Western blot further confirmed it. We found that insulin increased the phosphorylation of PI3K/AKT signaling in both cell lines and MK2206 significantly inhibited the invasion and migration of HPNE E6/E7/Ras/st cells. Furthermore, up-regulating SSTR2 or knock-downing K-Ras suppressed insulin-induced AKT phosphorylation.
Conclusions: Our study suggested that insulin might enhance the invasion, migration and proliferation of pancreatic ductal epithelial cells. This effect might be K-Ras dependent and mediated by SSTR2/AKT axis.
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