Aurora-A Expression Is Independently Associated with Chromosomal Instability in Colorectal Cancer 1

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
Neoplasia (New York, N.Y.) (Impact Factor: 4.25). 06/2009; 11(5):418-25. DOI: 10.1593/neo.09154
Source: PubMed


AURKA (the official symbol for Aurora-A, STK15, or BTAK) regulates the function of centrosomes, spindles, and kinetochores for proper mitotic progression. AURKA overexpression is observed in various cancers including colon cancer, and a link between AURKA and chromosomal instability (CIN) has been proposed. However, no study has comprehensively examined AURKA expression in relation to CIN or prognosis using a large number of tumors. Using 517 colorectal cancers in two prospective cohort studies, we detected AURKA overexpression (by immunohistochemistry) in 98 tumors (19%). We assessed other molecular events including loss of heterozygosity (LOH) in 2p, 5q, 17q, and 18q, the CpG island methylation phenotype (CIMP), and microsatellite instability (MSI). Prognostic significance of AURKA was evaluated by Cox regression and Kaplan-Meier method. In both univariate and multivariate logistic regressions, AURKA overexpression was significantly associated with CIN (defined as the presence of LOH in any of the chromosomal segments; multivariate odds ratio, 2.97; 95% confidence interval, 1.40-6.29; P = .0045). In multivariate analysis, AURKA was associated with cyclin D1 expression (P = .010) and inversely with PIK3CA mutation (P=.014), fatty acid synthase expression (P=.028), and family history of colorectal cancer (P = .050), but not with sex, age, body mass index, tumor location, stage, CIMP, MSI, KRAS, BRAF, BMI, LINE-1 hypomethylation, p53, p21, beta-catenin, or cyclooxygenase 2. AURKA was not significantly associated with clinical outcome or survival. In conclusion, AURKA overexpression is independently associated with CIN in colorectal cancer, supporting a potential role of Aurora kinase-A in colorectal carcinogenesis through genomic instability (rather than epigenomic instability).

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    • "We show here that, in colorectal tumors, MAP9 is strongly underexpressed whereas AURKA and PLK1 are overexpressed. It was known that the two kinases AURKA and PLK1 were upregulated in a number of tumors including colorectal and breast cancer, as a result of perturbations in centrosome function and spindle assembly that could promote tumorigenesis by enhancing genome instability [25, 26, 31, 32]. Indeed, it has also been observed that overexpression of AURKA in breast, colorectal, and other cancers is associated with the amplification of the corresponding chromosomal region 20q13.2 "
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    ABSTRACT: Background: Colorectal and breast cancers are among the most common cancers worldwide. They result from a conjugated deficiency of gene maintenance and cell cycle control. Objective: We investigate the expression of the microtubule-associated protein MAP9/ASAP and its two partners AURKA and PLK1 in colorectal tumors as well as in ductal breast cancers. Materials and methods: 26 colorectal cancer samples and adjacent normal tissues and 77 ductal breast cancer samples from grade I to grade III were collected. Real-time quantitative PCR was used to analyse the expression of MAP9, AURKA, and PLK1. Results. Expression of MAP9 is downregulated in colorectal cancer compared to normal tissues (P > 10(-3)), whereas those of AURKA and PLK1 are upregulated (P > 10(-4)). In ductal breast cancer, we found a grade-dependent increase of AURKA expression (P > 10(-3)), while the variations of expression of MAP9 and PLK1 are not significant (P > 0.2). Conclusions: MAP9 downregulation is associated with colorectal malignancy and could be used as a disease marker and a new drug target, while AURKA and PLK1 are upregulated. In ductal breast cancer, AURKA overexpression is strongly associated with the tumor grade and is therefore of prognostic value for the progression of the disease.
    Full-text · Article · Apr 2014 · Disease markers
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    • "Early studies have demonstrated that Aurora-A is an oncogene situated on chromosome 20q13.2, a region constantly amplified in a number of human cancers [27]–[29]. Recent investigations have showed that regulated Aurora-A is pivotal for maintenance of chromosome integrity after DNA damage, and Aurora-A polymorphisms affect some important functions of Aurora-A protein [30]. Some investigations have demonstrated that Aurora-A gene SNPs may associate with the production of the Aurora-A protein on the process of carcinogenesis [31], [32]. "
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    ABSTRACT: The association between Aurora-A V57I (rs1047972, G>A) polymorphism and cancer susceptibility has been widely studied. However, the results are inconsistent. To obtain a more precise evaluation of the relationship, we performed a meta-analysis of 14 case-control studies involving a total of 11,245 cancer cases and 16,024 controls. Our results demonstrated that there was a borderline evidence of an association between the Aurora-A V57I polymorphism and the decreased risk of overall cancer in two genetic models: AA vs. GA+GG and AA vs. GG. In a stratified analysis by cancer type, significant association between Aurora-A V57I polymorphism and the decreased risk of breast cancer was identified in one genetic model: AA vs. GG. In a stratified analysis by ethnicity, in three genetic models, significant decreased cancer risk was observed among Caucasians (AA vs. GA+GG; AA vs. GG and A vs. G) instead of Asians. Furthermore, a stratified analysis by ethnicity in breast cancer subgroup, five genetic models (AA+GA vs. GG; AA vs. GA+GG; AA vs. GG; AA vs. GA and A vs. G), significant decreased cancer risk was observed among Caucasians, but not among Asians. A slight publication bias was observed in our meta-analysis, thus nonparametric "trim-and-fill" method was utilized to detect the stability of our results. The adjusted odds ratios and confidence intervals showed that Aurora-A V57I polymorphism might be a protective factor for cancer risk, suggesting the reliability of our findings. In summary, this meta-analysis suggests that Aurora-A V57I polymorphism may be a protective factor for cancer risk.
    Full-text · Article · Mar 2014 · PLoS ONE
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    • "Baba et. al. reported overexpression of Aurora A protein in 19% of CRC by immunohistochemistry [12]. High copy amplification of the Aurora A gene was found in colorectal tumors [13] and associated with chromosomal instability phenotypes [14]. "
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    ABSTRACT: Colorectal cancer is the third most commonly diagnosed cancer worldwide. Although surgery remains the best treatment for this disease, adjuvant chemotherapy and radiotherapy are also very important in clinical practice. However, the notorious refractory lack of responses to radiochemotherapy greatly limits the application of radiochemotherapy in the context of colorectal cancer. There is a growing interest in the role that Aurora B may play in colorectal cancer cell survival as well as other cancer subtypes. In the current study, we sought to ascertain whether blocking of Aurora B signaling machinery by a small molecule inhibitor, CCT137690, could synergize radiation-induced colorectal cancer cell death. Results showed that CCT137690 increases the sensitivity of SW620 cells to radiation. Mechanistic studies revealed that Aurora B-Survivin pathway may be involved in this synergistic effect. Taken together, our results for the first time show that Aurora B inhibition and radiation exert a synergistic effect, resulting in enhanced colorectal cancer cell death. This synergistic effect is clinically relevant as lower doses of radiation could be used for cancer treatment, and could provide significant clinical benefits in terms of colorectal cancer management, while reducing unwanted side-effects.
    Full-text · Article · Jan 2014 · Journal of Experimental & Clinical Cancer Research
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