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

Gong Yang, Bin Chang, Fan Yang, Xiaoqing Guo, Kathy Qi Cai, Xue Xiao, Huamin Wang, Subrata Sen, Mien Chie Hung, Gordon Mills, Sandy Chang, Asha S. Multani, Imelda Mercado-Uribe, Jinsong Liu

Research output: Contribution to journalArticle

65 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3171-3181
Number of pages11
JournalClinical Cancer Research
Volume16
Issue number12
DOIs
StatePublished - Jun 15 2010
Externally publishedYes

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Aurora Kinase A
Cell Cycle
Carcinogenesis
Ovarian Neoplasms
Genomic Instability
Centrosome
Pancreatic Neoplasms
DNA Damage
Disease-Free Survival
Neoplasms
Apoptosis
Breast Neoplasms
Carcinoma
Spindle Apparatus
Cytogenetic Analysis
Retroviridae
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Aurora kinase A promotes ovarian tumorigenesis through dysregulation of the cell cycle and suppression of BRCA2. / Yang, Gong; Chang, Bin; Yang, Fan; Guo, Xiaoqing; Cai, Kathy Qi; Xiao, Xue; Wang, Huamin; Sen, Subrata; Hung, Mien Chie; Mills, Gordon; Chang, Sandy; Multani, Asha S.; Mercado-Uribe, Imelda; Liu, Jinsong.

In: Clinical Cancer Research, Vol. 16, No. 12, 15.06.2010, p. 3171-3181.

Research output: Contribution to journalArticle

Yang, G, Chang, B, Yang, F, Guo, X, Cai, KQ, Xiao, X, Wang, H, Sen, S, Hung, MC, Mills, G, Chang, S, Multani, AS, Mercado-Uribe, I & Liu, J 2010, 'Aurora kinase A promotes ovarian tumorigenesis through dysregulation of the cell cycle and suppression of BRCA2', Clinical Cancer Research, vol. 16, no. 12, pp. 3171-3181. https://doi.org/10.1158/1078-0432.CCR-09-3171
Yang, Gong ; Chang, Bin ; Yang, Fan ; Guo, Xiaoqing ; Cai, Kathy Qi ; Xiao, Xue ; Wang, Huamin ; Sen, Subrata ; Hung, Mien Chie ; Mills, Gordon ; Chang, Sandy ; Multani, Asha S. ; Mercado-Uribe, Imelda ; Liu, Jinsong. / Aurora kinase A promotes ovarian tumorigenesis through dysregulation of the cell cycle and suppression of BRCA2. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 12. pp. 3171-3181.
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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.",
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AU - Yang, Gong

AU - Chang, Bin

AU - Yang, Fan

AU - Guo, Xiaoqing

AU - Cai, Kathy Qi

AU - Xiao, Xue

AU - Wang, Huamin

AU - Sen, Subrata

AU - Hung, Mien Chie

AU - Mills, Gordon

AU - Chang, Sandy

AU - Multani, Asha S.

AU - Mercado-Uribe, Imelda

AU - Liu, Jinsong

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