Brief Article
Copyright ©2014 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jan 7, 2014; 20(1): 250-257
Published online Jan 7, 2014. doi: 10.3748/wjg.v20.i1.250
Epithelial-mesenchymal transition in colorectal cancer tissue of patients with Lynch syndrome
Guo-Li Gu, Xiao-Quan Zhu, Xue-Ming Wei, Li Ren, De-Chang Li, Shi-Lin Wang
Guo-Li Gu, Xue-Ming Wei, Shi-Lin Wang, Department of General Surgery, the Air Force General Hospital PLA, Beijing 100142, China
Xiao-Quan Zhu, the Affiliated Hospital of Aviation Medical Institute, PLA Air Force, Beijing 100142, China
Li Ren, De-Chang Li, Department of Pathology, the Air Force General Hospital PLA, Beijing 100142, China
Author contributions: Gu GL and Wei XM designed the research; Gu GL, Ren L and Li DC performed the research; Gu GL, Zhu XQ and Ren L collected and analyzed the data; Gu GL wrote the paper; and Wei XM and Wang SL revised the paper.
Supported by Capital Citizen Health Cultivation Project, No. Z131100004013021; and General Projects of the Chinese PLA “Twelfth Five-Year” Logistics Research Subject, No. CWS11J193
Correspondence to: Xue-Ming Wei, Professor, Department of General Surgery, the Air Force General Hospital PLA, No.30, Fucheng Road, Haidian District, Beijing 100142, China. kzggl@163.com
Telephone: +86-10-66928302 Fax: +86-10-66928302
Received: September 9, 2013
Revised: October 29, 2013
Accepted: November 18, 2013
Published online: January 7, 2014
Processing time: 126 Days and 17.3 Hours
Abstract

AIM: To explore the epithelial-mesenchymal transition (EMT) in tissue from patients with Lynch syndrome, and to interpret biological behaviour of Lynch syndrome.

METHODS: Sixty-eight formalin-fixed and paraffin embedded tissue blocks were analyzed in this study, including tissues from Lynch syndrome (n = 30), sporadic colorectal carcinoma (CRC) (n = 30), and tumor-adjacent tissues (n = 8). Tissue sections were stained for human mutS homolog 2 (hMSH2), human mutL homolog 1 (hMLH1), transforming growth factor-β type II receptor (TGFβRII), E-cadherin, β-catenin, matrix metalloproteinase-7 (MMP-7) and tissue inhibitor of metalloproteinase-2 (TIMP-2) by immunohistochemical staining. Furthermore, clinical data such as age, gender and tumor-node-metastasis stage were also collected retrospectively.

RESULTS: The positive expression rates of hMSH2, hMLH1, TGFβRII, E-cadherin, β-catenin, MMP-7 and TIMP-2 were significantly related to the depth of invasion and lymph node metastasis, but not to sex or tumour size or location. The differences in the positive expression rates of hMSH2, hMLH1, TGFβRII, E-cadherin, cytomembrane β-catenin, cytoplasmic β-catenin, MMP-7 and TIMP-2 were significant between sporadic CRC and Lynch syndrome. The expression of hMSH2 had a positive correlation with that of hMLH1 in Lynch syndrome and sporadic CRC. The expression of TGFβRII had a positive correlation with that of hMSH2, hMLH1 and MMP-7, and a negative correlation with that of TIMP-2. The expression of MMP-7 had a negative correlation with that of TIMP-2 in Lynch syndrome and sporadic CRC. The expression of E-cadherin was positively correlated with that of cytomembrane β-catenin. However, the expression of cytomembrane β-catenin was negatively correlated with that of cytoplasmic β-catenin, and the expression of cytoplasmic β-catenin was positively correlated with that of MMP-7.

CONCLUSION: EMT may play an important role in the development and progression of Lynch syndrome. Lynch syndrome was caused by the mutations of mismatch repair genes, mainly hMSH2 and hMLH1, which also beget the mutational inactivation of TGFβRII. Therefore, the colorectal cancer of Lynch syndrome can escape the inhibitory effect of TGFβ1. However, TGFβ1 can up-regulate the expression of MMP-7 and down-regulate the expression of TIMP-2 in tumors by disassembling the E-cadherin/β-catenin complex in the cytomembrane.

Keywords: Lynch syndrome; Mutation; Epithelial-mesenchymal transition; β-catenin; Mismatch repair gene

Core tip: As a subgroup of colorectal carcinoma (CRC), Lynch syndrome presents better prognosis than sporadic CRC for less invasion and metastasis. Our study found epithelial-mesenchymal transition may play an important role in the development and progression of Lynch syndrome. Lynch syndrome was caused by the mutations of mismatch repair genes, which also beget the mutational inactivation of transforming growth factor-β type II receptor. Therefore, the colorectal cancer of Lynch syndrome can escape the inhibitory effect of transforming growth factor-β type 1 (TGFβ1). However TGFβ1 can up-regulate the expression of matrix metalloproteinase-7 and down-regulate the expression of tissue inhibitor of metalloproteinase-2 in tumors by disassembling the E-cadherin/β-catenin complex in the cytomembrane.