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Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer
Punita Dhawan, … , M. Kay Washington, R. Daniel Beauchamp
Punita Dhawan, … , M. Kay Washington, R. Daniel Beauchamp
Published July 1, 2005
Citation Information: J Clin Invest. 2005;115(7):1765-1776. https://doi.org/10.1172/JCI24543.
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Research Article Oncology Article has an altmetric score of 4

Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer

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Abstract

Disruption of the cell-cell junction with concomitant changes in the expression of junctional proteins is a hallmark of cancer cell invasion and metastasis. The role of adherent junction proteins has been studied extensively in cancer, but the roles of tight junction (TJ) proteins are less well understood. Claudins are recently identified members of the tetraspanin family of proteins, which are integral to the structure and function of TJs. Recent studies show changes in expression/cellular localization of claudins during tumorigenesis; however, a causal relationship between claudin expression/localization and cancer has not been established. Here, we report an increased expression of claudin-1 in human primary colon carcinoma and metastasis and in cell lines derived from primary and metastatic tumors. We also report frequent nuclear localization of claudin-1 in these samples. Genetic manipulations of claudin-1 expression in colon cancer cell lines induced changes in cellular phenotype, with structural and functional changes in markers of epithelial-mesenchymal transition. Furthermore, we demonstrate that changes in claudin-1 expression have significant effects on growth of xenografted tumors and metastasis in athymic mice. We further provide data suggesting that the regulation of E-cadherin expression and β-catenin/Tcf signaling is a possible mechanism underlying claudin-1–dependent changes.

Authors

Punita Dhawan, Amar B. Singh, Natasha G. Deane, YiRan No, Sheng-Ru Shiou, Carl Schmidt, John Neff, M. Kay Washington, R. Daniel Beauchamp

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Figure 1

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Claudin-1 expression increases in colon carcinoma and metastasis. (A–I) ...
Claudin-1 expression increases in colon carcinoma and metastasis. (A–I) Paraffin-embedded sections of matched normal, colonic tumor, and metastatic tissues samples from the same patients were examined for claudin-1 expression and subcellular localization by immunohistochemistry using a polyclonal rabbit anti–claudin-1 antibody. (A and B) Representative normal colon tissue. Arrows indicate membranous staining. (C–E) Primary human colon adenocarcinoma tissues. Claudin-1 immunoreactivity was visible in the cytoplasm and cell nucleus (arrows). (F and G) Colon adenocarcinoma metastatic to the liver. Claudin-1 nuclear localization is shown by the arrows. (H) Tumor showing no immunoreactivity for claudin-1. (I) No staining was observed in a control experiment without primary antibody. (J) Claudin-1 expression in cell lines and human tissue samples. Equal amounts of total protein (25 μg) from various cell lines (upper panel) or tissues extracts (matched normal primary and metastasis samples; lower panel) were immunoblotted with claudin-1, claudin-7, or actin antibody. (K–P) Immunofluorescence localization of claudin-1, claudin-4, and E-cadherin in metastatic SW620 cells. (K–M) Claudin-1 (red) was predominantly localized in cell nucleus (arrows), whereas claudin-4 was largely localized on cell membrane (green; arrows). (N–P) Colocalization of claudin-1 (red) with DAPI (blue) is confirmed by overlay (purple). (Q) Cytoplasmic, nuclear, and membrane-specific fractions were prepared as described in Methods. Equal amounts of protein from all fractions were subjected to Western blot analysis using claudin-1 antibody. (R–U) Claudin-1 expression in intestinal epithelium and adenoma in ApcMin/+ mice. By immunohistochemical analysis, claudin-1 is detected in the mucosa primarily in the membrane (arrows) and in the adenoma mainly in the cytoplasm and nucleus (S–U) in ApcMin/+ mice.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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