Hypoxia-activated oxidative stress mediates SHP2/PI3K signaling pathway to promote hepatocellular carcinoma growth and metastasis.

Hepatocellular carcinoma is considered to be the fifth most rampant type of cancer in the whole world and has a high death rate. The hypoxic microenvironment is one of the typical features of tumor tissues and has an important impact on the activity of multiple signaling pathways. It is of great significance to study the effects of hypoxia on the pathophysiological processes and molecular mechanisms of HCC. Signalling pathways associated with SHP2 were analysed using bioinformatics. Detection of relevant protein expression using Western blotting. Tube formation assay was used in evalution of the angiogenic potential. The concentrations of MDA and SOD were measured by ELISA. The cell migration and invasion ability were measured with a scratch wound assay and transwell assay in SMMC-7721, HepG2 and Huh-7 cells. The effect of hypoxia on the growth of hepatocellular carcinoma was examined using subcutaneous graft tumors and HE staining experiments in nude mice. Bioinformatics analysis of SHP2 negatively correlates with the PI3K signalling pathway. Hypoxia promotes the concentration of MDA and inhibited the concentration of SOD. Hypoxia may up-regulate NOX2, NOX4 and p-PI3K and down-regulate the treatment of p-SHP2. Compared with NC group, the expression of SHP2 and p-SHP2 was inhibited in SHP2 KD group and the expression of p-PI3K, HIF1α, COX2, FOXM1, β-catenin and MMP9 was promoted. However, the differences of the expression of p-PI3K, HIF1α, COX2, FOXM1, β-catenin and MMP9 between the two groups were abolished after the addition of PI3K inhibitor. The angiogenesis, migration and invasion abilities were significantly increased in SHP2 KD group compared with NC group. Similarly, after the addition of PI3K inhibitor, the difference of these abilities between the two groups was eliminated. Hypoxia can promote the growth of hepatocellular carcinoma. Hypoxia can activate the oxidative stress-mediated SHP2/PI3K signaling pathway to promote angiogenesis, migration, and invasion in hepatocellular carcinoma, thus advancing the development of hepatocellular carcinoma.