Regulation of hypoxic responses by Sprouty2 in hepatocellular carcinoma

Abstract

Sprouty2 (Spry2) is an inhibitor of receptor tyrosine kinases (RTKs) and decreases in its levels have been documented in breast, lung, liver, and prostate cancer. Decreases in Spry2 levels have been correlated with poor patient prognosis in hepatocellular carcinoma (HCC). During tumor growth, cells experience hypoxic periods and adapt to these by altering a variety of cellular processes mainly through the Hypoxia Inducible transcription Factors (HIFs). HIFs are composed of an α subunit (HIF1α or HIF2α) and a β subunit (HIF1β a.k.a. aryl hydrocarbon receptor nuclear translocator (ARNT)). In hypoxia, the HIFα subunits are stabilized, translocate to the nucleus, and dimerize with ARNT. The HIFs have been shown to be upregulated in cancers correlating to poor patient prognosis. We have shown that Spry2 protein levels are elevated in hypoxia. The objective of our study was to determine the role of Spry2 in regulating hypoxic responses in HCC cells as it could have an important impact in tumor growth and progression. We found that endogenous Spry2 by modulating ARNT protein levels alters the transcriptional activity of HIF. Thus, our data suggest that Spry2 regulates HIF activity in HCC cells.Supported by NIH grant GM 073181