title: The role of Aurora A in hypoxia-inducible factor 1α-promoting malignant phenotypes of hepatocelluar carcinoma.
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.
authors: Department of Medical Oncology; Jinling Hospital; School of Medicine; Nanjing University; Nanjing, PR China.
authors: Shi-Yun
authors: SY
authors: Cui
authors: Jia-Yuan
authors: JY
authors: Huang
authors: Yi-Tian
authors: YT
authors: Chen
authors: Hai-Zhu
authors: HZ
authors: Song
authors: Gui-Chun
authors: GC
authors: Huang
authors: Wei
authors: W
authors: De
authors: Rui
authors: R
authors: Wang
authors: Long-Bang
authors: LB
authors: Chen
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000235:genetics; D064096:Aurora Kinase A / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D015687:Cell Hypoxia / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010641:Phenotype; D011485:Protein Binding / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D014410:Tumor Stem Cell Assay; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C576917:AURKA protein, human; D064096:Aurora Kinase A; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Aurora A; hepatocelluar carcinoma; hypoxia-inducible factor 1α; malignant phenotype; promoter
references: Surg Oncol. 2007 Dec;16 Suppl 1:S25-7
references: 18023174
references: Acta Physiol Hung. 2009 Mar;96(1):19-28
references: 19264039
references: Anticancer Agents Med Chem. 2011 Jul;11(6):493-9
references: 21554201
references: Histol Histopathol. 2007 May;22(5):559-72
references: 17330811
references: Biochem Pharmacol. 2007 Feb 1;73(3):450-7
references: 17101119
references: Cancer Gene Ther. 2006 Feb;13(2):131-40
references: 16096651
references: Cancer Sci. 2008 Oct;99(10):2055-61
references: 19016766
references: Cancer Sci. 2008 Nov;99(11):2209-17
references: 18803637
references: Int J Biol Markers. 2010 Apr-Jun;25(2):87-92
references: 20544685
references: Crit Rev Oncol Hematol. 2011 Jun;78(3):173-84
references: 20627616
references: Bull Cancer. 2006 Aug;93(8):E73-80
references: 16935775
references: Cancer Sci. 2012 Aug;103(8):1586-94
references: 22587416
references: Trends Pharmacol Sci. 2012 Apr;33(4):207-14
references: 22398146
references: Drug Resist Updat. 2011 Jun;14(3):191-201
references: 21466972
references: Mol Carcinog. 2009 Sep;48(9):810-20
references: 19204928
references: Pflugers Arch. 2005 Sep;450(6):363-71
references: 16007431
references: Tumour Biol. 2011 Feb;32(1):159-66
references: 20845004
references: Clin Biochem. 2009 May;42(7-8):641-7
references: 19232520
references: Cancer Biother Radiopharm. 2011 Oct;26(5):565-71
references: 21950556
references: Mol Cancer Res. 2012 May;10(5):588-96
references: 22522455
references: Oncol Rep. 2012 Jun;27(6):1990-2002
references: 22470047
references: World J Gastroenterol. 2001 Aug;7(4):445-54
references: 11819809
references: Endocr Relat Cancer. 2006 Sep;13(3):739-49
references: 16954428
references: Korean J Hepatol. 2010 Sep;16(3):280-7
references: 20924210
references: Curr Opin Genet Dev. 2007 Feb;17(1):71-7
references: 17208433
references: J Biol Chem. 2009 Apr 10;284(15):10004-12
references: 19211554
references: Oral Oncol. 2012 Nov;48(11):1120-7
references: 22694909
references: Exp Mol Med. 2009 Dec 31;41(12):849-57
references: 19942820
references: Int J Biol Sci. 2009 Nov 26;5(7):758-62
references: 20011137
references: Mol Cancer. 2009 Nov 05;8:95
references: 19891769
references: J Gastroenterol Hepatol. 2007 Aug;22(8):1178-82
references: 17559361
references: Eur J Cancer Prev. 2012 May;21(3):289-99
references: 22113109
references: Carcinogenesis. 2008 Oct;29(10):1930-7
references: 18667445
references: Clin Cancer Res. 2010 Dec 15;16(24):5928-35
references: 20962028
references: Future Oncol. 2011 Oct;7(10):1149-67
references: 21992728
references: Int J Hematol. 2012 May;95(5):457-63
references: 22535382
references: Eur Rev Med Pharmacol Sci. 2010 Apr;14(4):249-58
references: 20496531
references: Mol Biol Cell. 2008 Sep;19(9):3667-75
references: 18562694
references: Urology. 2012 Mar;79(3):744.e17-24
references: 22196409
references: J Cell Biochem. 2006 Mar 1;97(4):755-65
references: 16229017
references: Strahlenther Onkol. 2003 Dec;179(12):801-11
references: 14652668
references: Cancer Res. 2003 Mar 1;63(5):1138-43
references: 12615733
references: J Exp Clin Cancer Res. 2009 Feb 26;28:29
references: 19245702
references: Dis Esophagus. 2011 Apr;24(3):177-81
references: 21073615
references: Methods Mol Biol. 2009;487:283-301
references: 19301653
references: Expert Rev Anticancer Ther. 2012 Oct;12(10):1347-57
references: 23176622