Published online Jan 7, 2014. doi: 10.3748/wjg.v20.i1.250
Revised: October 29, 2013
Accepted: November 18, 2013
Published online: January 7, 2014
Processing time: 126 Days and 17.3 Hours
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.
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.