Deletion of Na+/H+ exchanger regulatory factor 2 represses colon cancer progress by suppression of Stat3 and CD24.
Deletion of Na+/H+ exchanger regulatory factor 2 represses colon cancer progress by suppression of Stat3 and CD24.
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DOI：
10.1152/ajpgi.00419.2015
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发表时间：
2016-04
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影响因子：
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通讯作者：
Michihiro Yoshida;M. Yoshida;Luqing Zhao;Luqing Zhao;G. Grigoryan;H. Shim;Peijian He;C. Yun
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文献类型：
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作者：
Michihiro Yoshida;M. Yoshida;Luqing Zhao;Luqing Zhao;G. Grigoryan;H. Shim;Peijian He;C. Yun
Na（+）/H（+）交换调节因子（NHERF）蛋白质家族是协调受体和细胞蛋白质相互作用的支架。先前的研究表明NHERF 1具有肿瘤抑制剂的功能。这项研究的目的是确定NHERF 2的缺失是否会改变结直肠癌（CRC）的进展。我们发现NHERF 2的表达在晚期CRC中升高。在体外和小鼠异种移植肿瘤模型中，NHERF 2的敲低降低了癌细胞增殖。此外，Apc（Min/+）小鼠中NHERF 2的缺失导致Apc（Min/+）小鼠的肿瘤生长减少并延长寿命。用设计用于结合NHERF 2的第二PDZ结构域的小肽阻断NHERF 2相互作用可减弱癌细胞增殖。尽管已知NHERF 2促进溶血磷脂酸受体2（LPA 2）的作用，但异种移植肿瘤的转录组分析显示，NHERF 2依赖性基因与LPA 2调节的基因有很大不同。β-catenin和ERK 1/2的激活在Apc（Min/+）; Nherf 2（-/-）腺瘤中减轻。此外，Stat 3磷酸化和CD 24表达水平在Apc（Min/+）; Nherf 2（-/-）腺瘤中受到抑制。因此，NHERF 2敲低减弱了结肠癌细胞中Stat 3的活化和CD 24的表达。有趣的是，CD 24在维持Stat 3磷酸化中很重要，而NHERF 2依赖性的CD 24表达增加被Stat 3抑制所阻断，表明NHERF 2通过Stat 3和CD 24之间的正反馈机制调节Stat 3磷酸化。总之，这项研究确定NHERF 2作为一种新的致癌蛋白和癌症治疗的潜在靶点。NHERF 2部分通过调节Stat 3和CD 24增强致癌作用。
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.