Role of Claudin-1 in cancer metastasis of lung adenocarcinoma

博士 === 國防醫學院 === 生命科學研究所 === 97 === Tight junctions (TJs) are essential intercellular junctions, because their barrier and fence functions are indispensable for the establishment of compositionally distinct compartments in multicellular organisms. Due to TJs function in an adhesive manner and can pr...

Full description

Bibliographic Details
Main Authors: Yu-Chih Chao, 趙育志
Other Authors: Pan-Chyr Yang
Format: Others
Language:en_US
Published: 2008
Online Access:http://ndltd.ncl.edu.tw/handle/30880905196233249534
Description
Summary:博士 === 國防醫學院 === 生命科學研究所 === 97 === Tight junctions (TJs) are essential intercellular junctions, because their barrier and fence functions are indispensable for the establishment of compositionally distinct compartments in multicellular organisms. Due to TJs function in an adhesive manner and can prevent cell dissociation, the loss of functional TJs in carcinomas has been regarded as an important step that cancer cells must overcome in order to metastasise. Claudin-1(CLDN1), a key component of tight junction complexes, was down-regulated in human lung adenocarcinomas. The role of CLDN1 in cancer progression of lung adenocarcinoma is unknown. We hypothesized that CLDN1 may play a role in invasion and metastasis of lung adenocarcinoma. In this study, we investigated the clinical significance of CLDN1 expression in lung adenocarcinoma patients and characterize its role in cancer invasion and metastasis. We examined the CLDN1 mRNA expression in tumor specimens from 64 lung adenocarcinoma patients and protein expression by immunohistochemistry in an independent cohort of 67 lung adenocarcinoma patients. CLDN1 functions in cancer cell migration, invasion, and metastatic colonization were studied by overexpression and knockdown of CLDN1. Affymetrix microarrays were performed to identify gene expression changes associated with CLDN1 overexpression. We found that low CLDN1 mRNA expression had shorter overall survival (p = 0.027, log-rank test) in 64 lung adenocarcinoma patients. We further confirmed by immunohistochemistry that CLDN1 protein expression correlated with overall survival in an independent cohort of 67 lung adenocarcinoma patients (p = 0.024, log-rank test). Overexpression of CLDN1 inhibited cancer cell dissociation in time-lapse imaging of wound healing, suppressed cancer cell migration, invasion, and in vivo metastasis. Knockdown of the exogenous/endogenous CLDN1 expression increased cancer cell invasive and metastatic abilities. Using Affymetrix microarrays, we identified a panel of genes altered by CLDN1 overexpression. CLDN1 increased expressions of cancer invasion/metastasis suppressors (e.g., CTGF, THBS1, DLC1, OCLN, ZO-1) and suppressed expressions of invasion/metastasis enhancers (e.g., SPP1, CUTL1, TGF-α, SLC2A3, PGF), supporting a role for CLDN1 as an invasion and metastasis suppressor. In summary, CLDN1 is a cancer invasion/metastasis suppressor. CLDN1 is also a useful prognostic predictor and potential drug treatment target for lung adenocarcinoma patients.