REGγ Controls Hippo Signaling and Reciprocal NF-κB-YAP Regulation to Promote Colon Cancer
REGγ Controls Hippo Signaling and Reciprocal NF-κB-YAP Regulation to Promote Colon Cancer
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REG gamma 控制 Hippo 信号传导和 NF-kappa B-YAP 相互调节促进结肠癌
DOI：
10.1158/1078-0432.ccr-17-2986
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发表时间：
2018-04-15
影响因子：
11.5
通讯作者：
Li, Xiaotao
中科院分区：
文献类型：
--
作者：
Wang, Qingwei;Gao, Xiao;Li, Xiaotao
目的：结直肠癌是最常见的与炎症和过度生长密切相关的癌症之一。我们先前展示了蛋白酶体激活物REG伽马和核因子-kappaB(NF-kappaB)在结肠炎期间的调节电路，已知在结肠炎相关癌症以及散发性结直肠癌的发展中起重要作用。在结直肠癌的发生发展过程中，炎性微环境如何影响河马通路尚不清楚。实验设计：我们利用REG-伽玛基因缺陷的结肠癌细胞系、REG-伽玛基因敲除小鼠和人类结直肠癌样本来确定REG-伽马在结直肠癌发生发展中作为癌蛋白发挥作用的新的分子机制。结果：REG-伽马可以直接与Lats1相互作用并促进其降解，从而促进结肠癌细胞中YAP的激活。REGγ缺乏显著抑制结肠癌的生长，这与YAP活性降低有关。由于REGγ耗尽而导致的肿瘤生长抑制可被结构性活性的YAP克服。令人惊讶的是，在人类结肠癌细胞中观察到了YAP和NF-kappa B通路的相互激活。在172例结直肠癌标本中，超过60%的组织中存在REG-Gamma过表达，且与YAP和P65的升高高度相关。术后随访发现，同时伴有REG-γ、YAP和p-p65高表达的患者生存率显著降低。结论：REG-γ可能是结直肠癌发生发展过程中的主要调节因子，促进YAP信号转导，加强炎症和生长途径之间的相互作用，REG-γ可能成为判断结直肠癌患者预后的新指标。(C)2018年AACR。
Purpose: Colorectal cancer is one of the most commonly diagnosed cancers closely associated with inflammation and hyperactive growth. We previously demonstrated a regulatory circuit between the proteasome activator REG gamma and NF-kappaB (NF-kappa B) during colon inflammation, known to be important in the development of colitis-associated cancer as well as sporadic colorectal cancer. How the inflammatory microenvironment affects the Hippo pathway during colorectal cancer development is largely unknown.Experimental Design: Here, we used REG gamma-deficient colon cancer cell lines, REG gamma knockout mice, and human colorectal cancer samples to identify the novel molecular mechanism by which REG gamma functions as an oncoprotein in the development of colorectal cancer.Results: REG gamma can directly interact with Lats1 and promote its degradation, which facilitates Yes-associated protein (YAP) activation in colon cancer cells. REG gamma deficiency significantly attenuated colon cancer growth, associated with decreased YAP activity. Suppression of tumor growth due to REG gamma depletion was overcome by constitutively active YAP. Surprisingly, reciprocal activation of the YAP and NF-kappa B pathways was observed in human colon cancer cells. REG gamma overexpression was found in over 60% of 172 colorectal cancer specimens, highly correlating with the elevation of YAP and p65. Postoperative follow-up revealed a significantly lower survival rate in patients with concomitantly high expression of REG gamma, YAP, and p-p65.Conclusions: REG gamma could be a master regulator during colorectal cancer development to promote YAP signaling and reinforce cross-talks between inflammation and growth pathways, and REG gamma might be a new marker for prognosis of colorectal cancer patients. (C) 2018 AACR.