Abstract
Mitosis dysregulation is common in cancers. This study explored the nuclear expression patterns and prognostic significance of mitotic regulatory proteins, including Aurora kinases, survivin, and p53, in biliary tract cancer (BTC). Archival tumor samples from 161 BTC patients who underwent surgery were tested for the expression of Aurora-A, Aurora-B, survivin, and p53 by immunohistochemistry. The potential endogeneity among the clinicopathologic variables and survival outcome was assessed by a generalized simultaneous equations model. Nuclear overexpression of Aurora-A, Aurora-B, survivin, and p53 was found in 79 (49.1%), 45 (28.0%), 55 (34.2%), and 55 (34.2%) patients, respectively. Intrahepatic cholangiocarcinoma, compared with the other two subtypes, had significantly higher proportions of nuclear overexpression of Aurora-B and survivin (37.8% and 47.3%, respectively). Simultaneous overexpression of Aurora-A and Aurora-B was correlated with that of p53. Overexpression of Aurora-B was also correlated with that of survivin and tumor grade. Our data indicate that simultaneous overexpression of Aurora-A and Aurora-B, suggesting dysregulated mitosis is associated with worse survival in patients with BTC. Independent prognostic factors for poor overall survival included simultaneous overexpression of Aurora-A and Aurora-B (hazard ratio, 1.997; 95% confidence interval, 1.239-3.219; P = 0.0045) and tumor grade (hazard ratio, 2.117; 95% confidence interval, 1.339-3.348; P = 0.0013) assessed by a multivariate analysis stratified by American Joint Committee on Cancer stage and p53 overexpression. Endogeneity testing suggested that nuclear overexpression of p53 and tumor type may influence patient survival through their interactions with Aurora-A/Aurora-B expression and tumor grade.
Highlights
Biliary tract cancer (BTC) accounts for f10% of the primary cancers occurring in the hepatobiliary system
A stratified analysis was done and the results indicated that overexpression of survivin was associated with poorer survival in patients with stage I/II disease, well or moderately differentiated tumors, and intrahepatic cholangiocarcinoma
This study showed the patterns of nuclear overexpression of several key mitotic regulatory proteins, including Aurora-A, Aurora-B, survivin, and p53, and their clinicopathologic correlations in patients with BTC
Summary
Biliary tract cancer (BTC) accounts for f10% of the primary cancers occurring in the hepatobiliary system. A general phenomenon in cancer cells, has been found to be an important avenue for the development of anticancer drugs. Clarification of the difference in the expression patterns of these regulatory proteins between cancer cells and normal cells will help us understand the pathogenesis of BTC and identify more novel targets for developing anticancer drugs. The agents targeting cyclin-dependent kinases and their related proteins and mitotic regulatory kinases have entered early-phase clinical trials [5, 6]. These agents may provide new treatment options for this difficult disease
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