Format

Send to

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

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

Author information

1
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;
2
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;
3
Department of Computer Science, Dartmouth College, Hanover, New Hampshire;
4
Winship Cancer Institute, Emory University, Atlanta, Georgia; and Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia.
5
Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia;
6
Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; Winship Cancer Institute, Emory University, Atlanta, Georgia; and ccyun@emory.edu.

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.

KEYWORDS:

CD24; NHERF2; Stat3; colorectal cancer

PMID:
26867566
PMCID:
PMC4836134
DOI:
10.1152/ajpgi.00419.2015
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center