Decreased Expression of the Polarity Regulatory PAR Complex Predicts Poor Prognosis of the Patients with Colorectal Adenocarcinoma

Partitioning defective (Par) proteins regulate cell polarity and differentiation. Par3, Par6 beta, and protein kinase C zeta(PKC zeta), which are PAR complex members, have been shown to be associated with oncogenesis and progression. Herein, we report the expression pattern and clinical relevance of Par3, Par6 beta, and PKC zeta in colorectal adenocarcinoma (CRAC). A total of 393 primary CRACs, 41 primary-metastatic CRAC pairs, 41 adenomas with low-grade dysplasia, and 41 nontumor colorectal tissue samples were examined by immunohistochemistry and Western blot assays for Par3, Par6 beta, and PKC zeta protein expressions. The association Par3, Par6 beta, and PKC zeta expressions and clinicopathologic factors, including patient survival, was evaluated. Primary CRACs and adenomas demonstrated higher levels of Par3, Par6 beta, and PKC zeta than in nontumor colorectal epithelia. The expressions of Par3, Par6 beta, and PKC zeta were higher in primary CRACs as compared to adenomas or in metastatic CRACs. Among primary CRACs, decreased Par3 expression was found to correlate with a high proliferation rate and poor histologic differentiation, decreased PKC zeta expression was correlated with pathologic TNM stage (I-II vs III-IV) and lymph node metastasis, and decreased Par6 beta and PKC zeta expressions were correlated with shortened overall survivals. In metastatic CRACs, decreased PKC zeta expression was correlated with a shortened metastasis-free survival. While increased Par3, Par6 beta, and PKC zeta expressions were implicated in tumorigenesis, decreased expressions of Par3, Par6 beta, and PKC zeta were found to be associated with worse clinicopathologic factors in CRAC. In particular, the results of our study suggest that PKC zeta down-expression is an independent poor prognostic and metastatic factor for CRAC.