Decreased NHE3 expression in colon cancer is associated with DNA damage, increased inflammation and tumor growth.

Autor: Laubitz D; Department of Pediatrics, Steele Children's Research Center, University of Arizona College of Medicine, 1501 N. Campbell Ave, Tucson, AZ, 85724, USA., Gurney MA; Department of Pediatrics, Steele Children's Research Center, University of Arizona College of Medicine, 1501 N. Campbell Ave, Tucson, AZ, 85724, USA., Midura-Kiela M; Department of Pediatrics, Steele Children's Research Center, University of Arizona College of Medicine, 1501 N. Campbell Ave, Tucson, AZ, 85724, USA., Clutter C; Department of Pediatrics, Steele Children's Research Center, University of Arizona College of Medicine, 1501 N. Campbell Ave, Tucson, AZ, 85724, USA., Besselsen DG; University Animal Care, University of Arizona, Tucson, AZ, USA., Chen H; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA., Ghishan FK; Department of Pediatrics, Steele Children's Research Center, University of Arizona College of Medicine, 1501 N. Campbell Ave, Tucson, AZ, 85724, USA., Kiela PR; Department of Pediatrics, Steele Children's Research Center, University of Arizona College of Medicine, 1501 N. Campbell Ave, Tucson, AZ, 85724, USA. pkiela@peds.arizona.edu.; Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ, USA. pkiela@peds.arizona.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2022 Aug 30; Vol. 12 (1), pp. 14725. Date of Electronic Publication: 2022 Aug 30.
DOI: 10.1038/s41598-022-19091-x
Abstrakt: Dysregulation of intra- and extracellular pH in cancer contributes to extracellular matrix remodeling, favors cell migration, proliferation, and metastasis. Although the primary attention has been focused on the role of the ubiquitous Na + /H + exchanger isoform NHE1, the role of NHE3, the predominant apical isoform in colonic surface epithelium in the pathogenesis of colon cancer has not been investigated. Here, we show that NHE3 mRNA expression is significantly reduced in colorectal cancer patients and that low NHE3 expression is associated with poorer survival. Deletion of NHE3 in Apc Min mice evaluated at 15 weeks of age (significant mortality was observed beyond this time) led to lower body weights, increased mucosal inflammation, increased colonic tumor numbers, evidence of enhanced DNA damage in tumor surface epithelium, and to significant alteration in the gut microbiota. In the absence of the inflammatory and microbial pressors, ca. 70% knockdown of NHE3 expression in SK-CO15 cells led to reduced intracellular pH, elevated apical pH, dramatic differences in their transcriptomic profile, increased susceptibility to DNA damage, increased proliferation, decreased apoptosis and reduced adhesion to extracellular matrix proteins. Our findings suggest that loss of NHE3 in the surface epithelium of colonic tumors has profound consequences for cancer progression and behavior.
(© 2022. The Author(s).)
Databáze: MEDLINE
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