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

Autor: Gui-Chun Huang, Yitian Chen, Shi-Yun Cui, Wei De, Longbang Chen, Rui Wang, Haizhu Song, Jia-Yuan Huang
Rok vydání: 2013
Předmět:
Male
Carcinoma
Hepatocellular
Transcription
Genetic
Molecular Sequence Data
Aurora inhibitor
Down-Regulation
Apoptosis
Kaplan-Meier Estimate
Biology
Response Elements
p38 Mitogen-Activated Protein Kinases
Small hairpin RNA
Downregulation and upregulation
Cell Movement
Report
Transcriptional regulation
Humans
Molecular Biology
Protein kinase B
Tumor Stem Cell Assay
Aged
Aurora Kinase A
Cell Proliferation
Gene knockdown
Base Sequence
Liver Neoplasms
Cell Biology
Middle Aged
Hypoxia-Inducible Factor 1
alpha Subunit
Molecular biology
Cell Hypoxia
digestive system diseases
Gene Expression Regulation
Neoplastic
enzymes and coenzymes (carbohydrates)
Phenotype
embryonic structures
Cancer research
Female
biological phenomena
cell phenomena
and immunity
Signal transduction
Proto-Oncogene Proteins c-akt
Protein Binding
Signal Transduction
Developmental Biology
Zdroj: Cell Cycle. 12:2849-2866
ISSN: 1551-4005
1538-4101
DOI: 10.4161/cc.25916
Popis: 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.
Databáze: OpenAIRE
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