The role of Aurora A in hypoxia-inducible factor 1?-promoting malignant phenotypes of hepatocelluar carcinoma.

ABSTRACT: Overexpression of both hypoxia-inducible factor 1? (HIF-1?) and Aurora A has been found in hepatocellular carcinoma (HCC). However, whether HIF-1? and Aurora A synergistically promote malignant phenotypes of HCC cells is unknown. The purpose of this study was to investigate the roles and functional correlation of HIF-1? and Aurora A in HCC progression. Immunohistochemistry was performed to detect HIF-1? and Aurora A protein expression in 55 primary HCC and corresponding non-tumor tissues and their clinical significance. Gene knockout technology using short hairpin RNA (shRNA) was used to knockdown expression of HIF-1? or Aurora A and analyze their effects on malignant phenotypes of HCC cells. The transcriptional regulation of Aurora A by HIF-1? and the possible downstream molecular signaling pathways were also determined. Results showed that hypoxia could induce the increased expression of HIF-1? and Aurora A in HCC cells. Also, shRNA-mediated HIF-1? downregulation could lead to the decreased Aurora A expression and inhibition of growth or invasion in HCC cells. Moreover, HIF-1? could transcriptionally regulate Aurora A expression by binding to hypoxia-responsive elements in the Aurora A promoter and recruiting the coactivator-p300/CBP. Additionally, shRNA-mediated Aurora A knockdown could mimic the effects of HIF-1? downregulation on phenotypes of HCC cells, and overexpression of Aurora A could partially rescue the phenotypical changes of HCC cells induced by HIF-1? downregulation. Further research indicated that activation of Akt and p38-MAPK signaling pathways mediated the downstream effects of HIF-1? and Aurora A in HCC cells under hypoxic condition. Taken together, our findings indicated that Aurora A might be a key regulator of HIF-1?-promoting malignant phenotypes of HCC by activation of Akt and p38-MAPK signaling pathways.

SUBMITTER: Cui SY 

PROVIDER: S-EPMC3899198 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature