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

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

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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Effect of modulation of claudin-1 expression on tumor xenograft and live...
Effect of modulation of claudin-1 expression on tumor xenograft and liver metastasis in vivo. (A) Flank tumor xenografts after subcutaneous injection (n = 5 mice per group) were monitored for SW480control or 2 individual SW480claudin-1 clones in nude mice (*P < 0.005 and P = 0.063 for each clone compared with the control group). Conversely, cells expressing either SW620control or 2 individual SW620siRNA clones in nude mice were used (P = 0.27 and P = 0.26). The P value was determined using unpaired Student’s t test. (B–G) Liver metastasis. Representative metastatic tumors in livers from SW480control (B) and SW480claudin-1 cells (C–E) from experiments on nude mice, with corresponding H&E sections indicating intrahepatic tumors (F and G), are shown. (F) Microscopic examination of the liver tumors confirmed that they represented metastases. (G) Intrahepatic vascular spread was noted. (H–K) SW620 parental or SW620control cells or 3 individual SW620siRNA clones were injected in nude mice. Seven weeks after inoculation, metastatic tumors were detected in the livers of nude mice by microPET (H and I) and upon necroscopy (J and K). MicroPET imaging was used to screen for nonpalpable lesions in the liver, using 100–150 μCi of 18F-deoxyglucose (18FDG) injected i.p to detect metabolically active foci in the abdomen. The arrows point to the metastatic nodules in the liver. The P value was determined using 2-sided test of proportion.