Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer.
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 beta-catenin/Tcf signaling is a possible mechanism underlying claudin-1-dependent changes.
Dhawan
Punita
P
Surgical Oncology Research Laboratories, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA. punita.dhawan@vanderbilt.edu
Singh
Amar B
AB
Deane
Natasha G
NG
No
Yiran
Y
Shiou
Sheng-Ru
SR
Schmidt
Carl
C
Neff
John
J
Washington
M Kay
MK
Beauchamp
R Daniel
RD
D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D062445:Claudin-1; D003110:Colonic Neoplasms / Q000209:etiology* / Q000235:genetics / Q000473:pathology / Q000556:secondary; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000503:physiopathology; D009368:Neoplasm Transplantation; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014183:Transplantation, Heterologous; D051176:beta Catenin
C568108:CLDN1 protein, human; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D051176:beta Catenin