Aurora kinase A promotes ovarian tumorigenesis through dysregulation of the cell cycle and suppression of BRCA2.

Abstract

PURPOSE:

Aurora kinase A (Aurora-A) is known to regulate genomic instability and tumorigenesis in multiple human cancers. The underlying mechanism, however, is not fully understood. We examined the molecular mechanism of Aurora-A regulation in human ovarian cancer.

EXPERIMENTAL DESIGN:

Retrovirus-mediated small hairpin RNA (shRNA) was used to silence the expression of Aurora-A in the ovarian cancer cell lines SKOV3, OVCA432, and OVCA433. Immunofluorescence, Western blotting, flow cytometry, cytogenetic analysis, and animal assay were used to test centrosome amplification, cell cycle alteration, apoptosis, DNA damage response, tumor growth, and genomic instability. Immunostaining of BRCA2 and Aurora-A was done in ovarian, pancreatic, breast, and colon cancer samples.

RESULTS:

Knockdown of Aurora-A reduced centrosome amplification, malformation of mitotic spindles, and chromosome aberration, leading to decreased tumor growth. Silencing Aurora-A attenuated cell cycle progression and enhanced apoptosis and DNA damage response by restoring p21, pRb, and BRCA2 expression. Aurora-A was inversely correlated with BRCA2 in high-grade ovarian serous carcinoma, breast cancer, and pancreatic cancer. In high-grade ovarian serous carcinoma, positive expression of BRCA2 predicted increased overall and disease-free survival, whereas positive expression of Aurora-A predicted poor overall and disease-free survival (P < 0.05). Moreover, an increased Aurora-A to BRCA2 expression ratio predicted poor overall survival (P = 0.047) compared with a decreased Aurora-A to BRCA2 expression ratio.

CONCLUSION:

Aurora-A regulates genomic instability and tumorigenesis through cell cycle dysregulation and BRCA2 suppression. The negative correlation between Aurora-A and BRCA2 exists in multiple cancers, whereas the expression ratio of Aurora-A to BRCA2 predicts ovarian cancer patient outcome.

• Authors: Gong Yang, Bin Chang, Fan Yang, Xiaoqing Guo, Kathy Qi Cai, Xue Sherry Xiao, Huamin Wang, Subrata Sen, Mien-Chie Hung, Gordon B Mills, Sandy Chang, Asha S Multani, Imelda Mercado-Uribe, Jinsong Liu
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 12 Pg. 3171-81 (Jun 15 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20423983 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2010 AACR.

Chemical References

• BRCA2 Protein
• AURKA protein, human
• Aurora Kinase A
• Aurora Kinases
• Protein Serine-Threonine Kinases

Topics

• Apoptosis
• Aurora Kinase A
• Aurora Kinases
• BRCA2 Protein (antagonists & inhibitors)
• Cell Cycle
• Cell Line, Tumor
• Cell Proliferation
• Cell Transformation, Neoplastic
• DNA Damage
• Female
• Gene Silencing
• Genomic Instability
• Humans
• Ovarian Neoplasms (metabolism, pathology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, physiology)