title: Deletion of Na+/H+ exchanger regulatory factor 2 represses colon cancer progress by suppression of Stat3 and CD24.
abstract: The Na(+)/H(+) exchanger regulatory factor (NHERF) family of proteins is scaffolds that orchestrate interaction of receptors and cellular proteins. Previous studies have shown that NHERF1 functions as a tumor suppressor. The goal of this study is to determine whether the loss of NHERF2 alters colorectal cancer (CRC) progress. We found that NHERF2 expression is elevated in advanced-stage CRC. Knockdown of NHERF2 decreased cancer cell proliferation in vitro and in a mouse xenograft tumor model. In addition, deletion of NHERF2 in Apc(Min/+) mice resulted in decreased tumor growth in Apc(Min/+) mice and increased lifespan. Blocking NHERF2 interaction with a small peptide designed to bind the second PDZ domain of NHERF2 attenuated cancer cell proliferation. Although NHERF2 is known to facilitate the effects of lysophosphatidic acid receptor 2 (LPA2), transcriptome analysis of xenograft tumors revealed that NHERF2-dependent genes largely differ from LPA2-regulated genes. Activation of β-catenin and ERK1/2 was mitigated in Apc(Min/+);Nherf2(-/-) adenomas. Moreover, Stat3 phosphorylation and CD24 expression levels were suppressed in Apc(Min/+);Nherf2(-/-) adenomas. Consistently, NHERF2 knockdown attenuated Stat3 activation and CD24 expression in colon cancer cells. Interestingly, CD24 was important in the maintenance of Stat3 phosphorylation, whereas NHERF2-dependent increase in CD24 expression was blocked by inhibition of Stat3, suggesting that NHERF2 regulates Stat3 phosphorylation through a positive feedback mechanism between Stat3 and CD24. In summary, this study identifies NHERF2 as a novel oncogenic protein and a potential target for cancer treatment. NHERF2 potentiates the oncogenic effects in part by regulation of Stat3 and CD24.
authors: Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan;
authors: Michihiro
authors: M
authors: Yoshida
authors: Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Division of Gastroenterology, Department of Medicine, Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University, Beijing, China;
authors: Luqing
authors: L
authors: Zhao
authors: Department of Computer Science, Dartmouth College, Hanover, New Hampshire;
authors: Gevorg
authors: G
authors: Grigoryan
authors: Winship Cancer Institute, Emory University, Atlanta, Georgia; and Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia.
authors: Hyunsuk
authors: H
authors: Shim
authors: Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia;
authors: Peijian
authors: P
authors: He
authors: Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Winship Cancer Institute, Emory University, Atlanta, Georgia; and ccyun@emory.edu.
authors: C Chris
authors: CC
authors: Yun
mesh_terms: D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025461:Feedback, Physiological; D005260:Female; D017353:Gene Deletion; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051927:CD24 Antigen; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor; D017923:Sodium-Hydrogen Exchangers; C000613192:adenomatous polyposis coli protein, mouse; C093376:sodium-hydrogen exchanger regulatory factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: CD24; NHERF2; Stat3; colorectal cancer