1. The role of Aurora A in hypoxia-inducible factor 1α-promoting malignant phenotypes of hepatocelluar carcinoma.
- Author
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Cui SY, Huang JY, Chen YT, Song HZ, Huang GC, De W, Wang R, and Chen LB
- Subjects
- Aged, Apoptosis genetics, Aurora Kinase A genetics, Base Sequence, Carcinoma, Hepatocellular genetics, Cell Hypoxia genetics, Cell Movement genetics, Cell Proliferation, Down-Regulation genetics, Female, Gene Expression Regulation, Neoplastic, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Kaplan-Meier Estimate, Liver Neoplasms genetics, Male, Middle Aged, Molecular Sequence Data, Phenotype, Protein Binding genetics, Proto-Oncogene Proteins c-akt metabolism, Response Elements genetics, Signal Transduction genetics, Transcription, Genetic, Tumor Stem Cell Assay, p38 Mitogen-Activated Protein Kinases metabolism, Aurora Kinase A metabolism, Carcinoma, Hepatocellular enzymology, Carcinoma, Hepatocellular pathology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Liver Neoplasms enzymology, Liver Neoplasms pathology
- Abstract
Overexpression of both hypoxia-inducible factor 1α (HIF-1α) and Aurora A has been found in hepatocellular carcinoma (HCC). However, whether HIF-1α 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-1α and Aurora A in HCC progression. Immunohistochemistry was performed to detect HIF-1α 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-1α or Aurora A and analyze their effects on malignant phenotypes of HCC cells. The transcriptional regulation of Aurora A by HIF-1α and the possible downstream molecular signaling pathways were also determined. Results showed that hypoxia could induce the increased expression of HIF-1α and Aurora A in HCC cells. Also, shRNA-mediated HIF-1α downregulation could lead to the decreased Aurora A expression and inhibition of growth or invasion in HCC cells. Moreover, HIF-1α 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-1α downregulation on phenotypes of HCC cells, and overexpression of Aurora A could partially rescue the phenotypical changes of HCC cells induced by HIF-1α downregulation. Further research indicated that activation of Akt and p38-MAPK signaling pathways mediated the downstream effects of HIF-1α and Aurora A in HCC cells under hypoxic condition. Taken together, our findings indicated that Aurora A might be a key regulator of HIF-1α-promoting malignant phenotypes of HCC by activation of Akt and p38-MAPK signaling pathways.
- Published
- 2013
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