title: STAT3 in epithelial cells regulates inflammation and tumor progression to malignant state in colon.
abstract: Chronic inflammation is an important risk factor for the development of colorectal cancer; however, the mechanism of tumorigenesis especially tumor progression to malignancy in the inflamed colon is still unclear. Our study shows that epithelial signal transducer and activator of transcription 3 (STAT3), persistently activated in inflamed colon, is not required for inflammation-induced epithelial overproliferation and the development of early-stage tumors; however, it is essential for tumor progression to advanced malignancy. We found that one of the mechanisms that epithelial STAT3 regulates in tumor progression might be to modify leukocytic infiltration in the large intestine. Activation of epithelial STAT3 promotes the infiltration of the CD8+ lymphocyte population but inhibits the recruitment of regulatory T (Treg) lymphocytes. The loss of Stat3 in epithelial cells promoted the expression of cytokines/chemokines including CCL19, CCL28, and RANTES, which are known to be able to recruit Treg lymphocytes. Linked to these changes was the pathway mediated by sphingosine 1-phosphate receptor 1 and sphingosine 1-phosphate kinases, which is activated in colonic epithelial cells in inflamed colon with functional STAT3 but not in epithelial cells deleted of STAT3. Our data suggest that epithelial STAT3 plays a critical role in inflammation-induced tumor progression through regulation of leukocytic recruitment especially the infiltration of Treg cells in the large intestine.
authors.affiliation: Department of Biological Sciences and Geology, Queensborough-The City University of New York, Bayside, NY.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Nguyen
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Wu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Donghai
authors.initials: D
authors.lastname: Wang
authors.forename: Stephanie
authors.initials: S
authors.lastname: Nguyen
authors.forename: Ricky
authors.initials: R
authors.lastname: Loh
authors.forename: Joey
authors.initials: J
authors.lastname: Pang
authors.forename: Kenneth
authors.initials: K
authors.lastname: Friedman
authors.forename: Amos
authors.initials: A
authors.lastname: Orlofsky
authors.forename: Leonard
authors.initials: L
authors.lastname: Augenlicht
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Pollard
authors.forename: Elaine Y
authors.initials: EY
authors.lastname: Lin
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism; D000368:Aged; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D054415:Chemokine CCL19 / Q000096:biosynthesis; D018946:Chemokine CCL5 / Q000096:biosynthesis; D019742:Chemokines, CC / Q000096:biosynthesis; D003093:Colitis, Ulcerative / Q000378:metabolism*; D003106:Colon / Q000276:immunology / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007413:Intestinal Mucosa / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C515460:CCL19 protein, human; C414047:CCL28 protein, human; C483024:CCL5 protein, human; D054415:Chemokine CCL19; D018946:Chemokine CCL5; D019742:Chemokines, CC; D049349:Receptors, Lysosphingolipid; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
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