title: Claudin-1 promotes TNF-α-induced epithelial-mesenchymal transition and migration in colorectal adenocarcinoma cells.
abstract: Epithelial-mesenchymal transition (EMT) is an important mechanism in cancer progression and malignancy including colorectal cancer (CRC). Importantly, inflammatory mediators are critical constituents of the local tumor environment and an intimate link between CRC progression and inflammation is now validated. We and others have reported key role of the deregulated claudin-1 expression in colon carcinogenesis including colitis-associated colon cancer (CAC). However, the causal association between claudin-1 expression and inflammation-induced colon cancer progression remains unclear. Here we demonstrate, TNF-α, a pro-inflammatory cytokine, regulates claudin-1 to modulate epithelial to mesenchymal transition (EMT) and migration in colon adenocarcinoma cells. Importantly, colon cancer cells cultured in the presence of TNF-α (10ng/ml), demonstrated a sharp decrease in E-cadherin expression and an increase in vimentin expression (versus control cells). Interestingly, TNF-α treatment also upregulated (and delocalized) claudin-1 expression in a time-dependent manner accompanied by increase in proliferation and wound healing. Furthermore, similar to our previous observation that claudin-1 overexpression in CRC cells induces ERK1/2 and Src- activation, signaling associated with colon cancer cell survival and transformation, TNF-α-treatment induced upregulation of phospho-ERK1/2 and -Src expression. The shRNA-mediated inhibition of claudin-1 expression largely abrogated the TNF-α-induced changes in EMT, proliferation, migration, p-Erk and p-Src expression. Taken together, our data demonstrate TNF-α mediated regulation of claudin-1 and tumorigenic abilities of colon cancer cells and highlights a key role of deregulated claudin-1 expression in inflammation-induced colorectal cancer growth and progression, through the regulation of the ERK and Src-signaling.
authors.affiliation: Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, United States.
authors.forename: Ajaz A
authors.initials: AA
authors.lastname: Bhat
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68022, United States.
authors.forename: Rizwan
authors.initials: R
authors.lastname: Ahmad
authors.affiliation: Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68022, United States.
authors.forename: SrijayaPrakash B
authors.initials: SB
authors.lastname: Uppada
authors.affiliation: From the Department of Veterans Affairs, University of Nebraska Medical Center, Omaha, NE 68022, United States; Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68022, United States; Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68022, United States.
authors.forename: Amar B
authors.initials: AB
authors.lastname: Singh
authors.affiliation: From the Department of Veterans Affairs, University of Nebraska Medical Center, Omaha, NE 68022, United States; Departments of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68022, United States; Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE 68022, United States. Electronic address: punita.dhawan@unmc.edu.
authors.forename: Punita
authors.initials: P
authors.lastname: Dhawan
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D062445:Claudin-1 / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D019073:HT29 Cells; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D062445:Claudin-1; D014409:Tumor Necrosis Factor-alpha; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Claudin-1; EMT; Migration; TNF-alpha