Characterization of hypoxia-induced gene (HIG2) and hypoxia-inducible autophagy as novel pathways of tumor growth.

摘要

Hypoxic tumors are significantly more malignant, metastatic, radio- and chemoresistant, and have poor prognosis. This study sought to investigate the separate contributions that HIG2, a hypoxia-inducible gene, and hypoxia-induced autophagy make to cell growth and tumorigenesis. We showed that HIG2 ( Hypoxia-inducible Gene 2) is regulated by HIF-1 (Hypoxia- inducible Factor 1) and localized to discrete cytoplasmic foci in cells. Clinical studies indicate HIG2 to be an independent negative prognostic indicator of patient survival in head and neck cancer. Overexpression of HIG2 in human cancer cells led to increased cell growth and survival, as well as accelerated tumor growth and progression in mouse xenografts. Taken together, our findings suggest that HIG2 could be a potential candidate as a molecular target for cancer therapy. We also investigated the process of autophagy during hypoxia and determined that it occurs independent of the presence of HIF-1. Characterization of hypoxia-induced autophagy was confirmed through a myriad of biochemical, molecular and ultrastructural assays. We determined that the molecular pathways for the observed hypoxia-induced autophagy does not signal through the PERK and IREI arms of the unfolded protein response, the TSC-mTOR pathway, nor is it dependent on the p53 protein. We showed that inhibition of Atg5, an autophagic gene, was sufficient to increase cellular survival under prolonged hypoxia, as well as contribute to increased tumor growth in vivo. In summary, hypoxia-induced autophagy appears to play a role in increasing cell death and decreasing tumorigenicity.