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Claudin-1 Is a Metastasis Suppressor and Correlates with Clinical Outcome in Lung Adenocarcinoma

¹ Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan; ² Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan; ³ Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine; ⁴ Graduate Institute of Molecular Medicine, College of Medicine; ⁵ Department of Pathology and Graduate Institute of Pathology, ⁸ National Taiwan University Center of Genomic Medicine, Taipei, Taiwan, ⁷ Department of Surgery; ¹⁰ Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; ⁶ Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; ⁹ Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan

^* Correspondence and requests for reprints should be addressed to Pan-Chyr Yang, M.D., Ph.D., Department of Internal Medicine, National Taiwan University College of Medicine, No. 7, Chung Shan South Road, Taipei, Taiwan. E-mail: pcyang{at}ntu.edu.tw

Rationale: Claudin (CLDN)-1, a key component of tight junction complexes, was down-regulated in human lung adenocarcinomas.

Objectives: To investigate the clinical significance of CLDN1 expression in patients with lung adenocarcinoma and its role in cancer invasion and metastasis.

Methods: We examined the CLDN1 mRNA expression in tumor specimens from 64 patients with lung adenocarcinoma and protein expression by immunohistochemistry in an independent cohort of 67 patients with lung adenocarcinoma. 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.

Measurements and Main Results: We found that low-CLDN1 mRNA expression had shorter overall survival (P = 0.027, log-rank test) in 64 patients with lung adenocarcinoma, and we confirmed by immunohistochemistry that low CLDN1 expression had shorter overall survival (P = 0.024, log-rank test) in an independent cohort of 67 patients with lung adenocarcinoma. Overexpression of CLDN1 inhibited cancer cell dissociation in time-lapse imaging of wound healing, and suppressed cancer cell migration, invasion, and metastasis. Knockdown CLDN1 expression increased cancer cell invasive and metastatic abilities. Affymetrix microarrays identified a panel of genes altered by CLDN1 overexpression. CLDN1 increased expressions of cancer invasion/metastasis suppressors (e.g., connective tissue growth factor [CTGF], thrombospondin 1 [THBS1], deleted in liver cancer 1 [DLC1], occludin [OCLN], zona occludens 1 [ZO-1]) and suppressed expressions of invasion/metastasis enhancers (e.g., secreted phosphoprotein 1 [SPP1], cut-like homeobox 1 [CUTL1], transforming growth factor alpha [TGF-], solute carrier family 2 [faciliated glucose transporter] member 3 [SLC2A3], placental growth factor [PGF]), supporting a role for CLDN1 as an invasion and metastasis suppressor.

Conclusions: CLDN1 is a cancer invasion/metastasis suppressor. CLDN1 is also a useful prognostic predictor and potential drug treatment target for patients with lung adenocarcinoma.

Key Words: tight junctions • cell–cell adhesion • invasion

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Loss of tight junction function may lead to loss of cell–cell adhesion and promote tumor metastasis. Claudin-1 (CLDN1), a key component of tight junctions, is down-regulated in lung adenocarcinoma, but its role in cancer progression of lung adenocarcinoma is unknown. What This Study Adds to the Field CLDN1 inhibits lung adenocarcinoma cells from dissociating from each other and regulates cancer cell migration, invasion and metastasis. CLDN1 may be an invasion/metastasis suppressor as well as a useful prognostic biomarker and potential therapeutic target.