Deletion of Na+/H+ exchanger regulatory factor 2 represses colon cancer progress by suppression of Stat3 and CD24

Am J Physiol Gastrointest Liver Physiol. 2016 Apr 15;310(8):G586-98. doi: 10.1152/ajpgi.00419.2015. Epub 2016 Feb 11.


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.

Keywords: CD24; NHERF2; Stat3; colorectal cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenoma / genetics
  • Adenoma / metabolism*
  • Adenoma / pathology
  • Adenomatous Polyposis Coli Protein / genetics
  • Animals
  • CD24 Antigen / genetics
  • CD24 Antigen / metabolism*
  • Cell Proliferation
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Feedback, Physiological
  • Female
  • Gene Deletion*
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Nude
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism*
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / metabolism*
  • Transcriptome


  • Adenomatous Polyposis Coli Protein
  • CD24 Antigen
  • Phosphoproteins
  • STAT3 Transcription Factor
  • Sodium-Hydrogen Exchangers
  • adenomatous polyposis coli protein, mouse
  • sodium-hydrogen exchanger regulatory factor
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3