Effects Of Altered Distribution Of β-catenin And Related Influence Factors On Progression Of Colorectal Cancer In Chinese

The deregulation of the Wnt signaling pathway is a key event in the initiation and development of colorectal cancer(CRC),among which the cytoplasmic stabilization and nuclear translocation ofβ-catenin contributes to the CRC progression.The altered distribution ofβ-catenin plays central role in Wnt activation and may be of significance in colorectal carcinogenesis.However,the mechanisms underlying the altered distribution ofβ-catenin are still elusive.This event may be attributed to the overexpression of cyclooxygenase-2(COX-2),the inability of APC to enhance the association of axin andβ-catenin,mutations in the phosphorylation sites on CTNNB1,or reduced membranous expression of E-cadherin.In the present study,we detected the expression ofβ-catenin,APC,COX-2 and E-cadherin in 206 tissue samples including normal colonic mucosae,adnomas and carcinomas to study the prognostic roles of altered distribution ofβ-catenin and related influence factors' aberrant expression;The correlation betweenβ-catenin and APC,COX-2 or E-cadherin were analyzed.We also screened APC gene mutations and promoter region hypermethylation by systematic screening and methylation-specific PCR in Chinese FAP patients to speculate the mutation features in the early stage of CRC in Chinese,providing the basis of personized usage of COX-2 inhibitors.The results showed that:(1)Altered distribution ofβ-catenin was significantly correlated with early stage of CRC progression,as well as Dukes' stages,histological differentiation,lymph node metastasis and 5-year survival rates of CRC(P＜0.05);Reduced expression of E-cadherin was significantly correlated with later stage of CRC progression, as well as Dukes' stages,lymph node metastasis and 5-year survival rates of CRC(P＜0.05). (2)There were significantly correlations of altered distribution ofβ-catenin and COX-2 overexpression or loss of APC,among which the correlation of COX-2 overexpression and altered distribution ofβ-catenin was significant only in the subgroup of APC negative expression(Spearman's correlation=0.233,P=0.013).(3)There types of mutations of APC gene were identified in FAP patients as c.3184₃187 delCAAA;c.1999C＞T and c.5432C＞T. One of FAP patients carried somatic loss of wild-type allele and 2 patients had promoter region hypermethylation,corresponding to the severity of their syndrome.In addition, mutation in exon 3 of CTNNB1 gene was not detected in CRC tissues.The results suggested that altered distribution ofβ-catenin may serve as an additional marker for the progression and prognosis of colorectal cancer;Moreover,the altered distribution ofβ-catenin was connected with COX-2 overexpression,which was dependent on the APC expression status.However,loss of E-cadherin and the exon 3 mutation of CTNNB1 did not appear contributive to the altered distribution ofβ-catenin in Chinese CRC. From Chinese FAP patients,we reported two novel germline mutations c.1999C＞T and c.5432C＞T,and one with somatic LOH showed specific relation of germline mutation site and somatic mutation.It implied there were ethnic-specific APC mutations in Chinese FAP patients.The results potentially provided a framework for further study of the mechanisms of altered distribution ofβ-catenin and the rational use of COX-2 inhibitors in the therapy of Chinese colon cancer.