Decreased NHE3 expression in colon cancer is associated with DNA damage, increased inflammation and tumor growth
Abstract 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 pre...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-19091-x |
| _version_ | 1817994055094632448 |
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| author | Daniel Laubitz Michael A. Gurney Monica Midura-Kiela Christy Clutter David G. Besselsen Hao Chen Fayez K. Ghishan Pawel R. Kiela |
| author_facet | Daniel Laubitz Michael A. Gurney Monica Midura-Kiela Christy Clutter David G. Besselsen Hao Chen Fayez K. Ghishan Pawel R. Kiela |
| author_sort | Daniel Laubitz |
| collection | DOAJ |
| description | Abstract 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 ApcMin 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. |
| first_indexed | 2024-04-14T01:47:04Z |
| format | Article |
| id | doaj.art-8131be6d7bd141758894732769fe97c6 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-14T01:47:04Z |
| publishDate | 2022-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-8131be6d7bd141758894732769fe97c62022-12-22T02:19:29ZengNature PortfolioScientific Reports2045-23222022-08-0112111710.1038/s41598-022-19091-xDecreased NHE3 expression in colon cancer is associated with DNA damage, increased inflammation and tumor growthDaniel Laubitz0Michael A. Gurney1Monica Midura-Kiela2Christy Clutter3David G. Besselsen4Hao Chen5Fayez K. Ghishan6Pawel R. Kiela7Department of Pediatrics, Steele Children’s Research Center, University of Arizona College of MedicineDepartment of Pediatrics, Steele Children’s Research Center, University of Arizona College of MedicineDepartment of Pediatrics, Steele Children’s Research Center, University of Arizona College of MedicineDepartment of Pediatrics, Steele Children’s Research Center, University of Arizona College of MedicineUniversity Animal Care, University of ArizonaDepartment of Pathology, University of Texas Southwestern Medical CenterDepartment of Pediatrics, Steele Children’s Research Center, University of Arizona College of MedicineDepartment of Pediatrics, Steele Children’s Research Center, University of Arizona College of MedicineAbstract 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 ApcMin 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.https://doi.org/10.1038/s41598-022-19091-x |
| spellingShingle | Daniel Laubitz Michael A. Gurney Monica Midura-Kiela Christy Clutter David G. Besselsen Hao Chen Fayez K. Ghishan Pawel R. Kiela Decreased NHE3 expression in colon cancer is associated with DNA damage, increased inflammation and tumor growth Scientific Reports |
| title | Decreased NHE3 expression in colon cancer is associated with DNA damage, increased inflammation and tumor growth |
| title_full | Decreased NHE3 expression in colon cancer is associated with DNA damage, increased inflammation and tumor growth |
| title_fullStr | Decreased NHE3 expression in colon cancer is associated with DNA damage, increased inflammation and tumor growth |
| title_full_unstemmed | Decreased NHE3 expression in colon cancer is associated with DNA damage, increased inflammation and tumor growth |
| title_short | Decreased NHE3 expression in colon cancer is associated with DNA damage, increased inflammation and tumor growth |
| title_sort | decreased nhe3 expression in colon cancer is associated with dna damage increased inflammation and tumor growth |
| url | https://doi.org/10.1038/s41598-022-19091-x |
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