Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 310, Issue 8, Pages G586-G598Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00419.2015
Keywords
colorectal cancer; NHERF2; Stat3; CD24
Categories
Funding
- National Institutions of Health [DK071597]
- Emory University Institutional fund
- KAKENHI [25860552]
- Grants-in-Aid for Scientific Research [25860552] Funding Source: KAKEN
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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 (LPA(2)), transcriptome analysis of xenograft tumors revealed that NHERF2-dependent genes largely differ from LPA(2)-regulated genes. Activation of beta-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.
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