Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
Xinhua Hospital Affiliated to Shanghai Jiaotong University, Shanghai, China.
Clin Cancer Res. 2018 Apr 15;24(8):2015-2025. doi: 10.1158/1078-0432.CCR-17-2986. Epub 2018 Feb 6.
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 REGγ and NF-kappaB (NF-κB) 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. Here, we used REGγ-deficient colon cancer cell lines, REGγ knockout mice, and human colorectal cancer samples to identify the novel molecular mechanism by which REGγ functions as an oncoprotein in the development of colorectal cancer. REGγ can directly interact with Lats1 and promote its degradation, which facilitates Yes-associated protein (YAP) activation in colon cancer cells. REGγ deficiency significantly attenuated colon cancer growth, associated with decreased YAP activity. Suppression of tumor growth due to REGγ depletion was overcome by constitutively active YAP. Surprisingly, reciprocal activation of the YAP and NF-κB pathways was observed in human colon cancer cells. REGγ 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 REGγ, YAP, and p-p65. REGγ could be a master regulator during colorectal cancer development to promote YAP signaling and reinforce cross-talks between inflammation and growth pathways, and REGγ might be a new marker for prognosis of colorectal cancer patients. .
结直肠癌是最常见的癌症之一，与炎症和过度生长密切相关。我们之前在结肠炎症中证明了蛋白酶体激活剂 REGγ 和 NF-κB（NF-κB）之间的调节回路，这在结肠炎相关癌症以及散发性结直肠癌的发展中很重要。炎症微环境如何在结直肠癌发展过程中影响 Hippo 通路在很大程度上尚不清楚。在这里，我们使用 REGγ 缺陷结肠癌细胞系、REGγ 敲除小鼠和人结直肠癌样本，确定了 REGγ 在结直肠癌发展中作为癌蛋白的新分子机制。REGγ 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 Yes 相关蛋白 (YAP) 的激活。REGγ 缺陷显着减弱了结肠癌的生长，与 YAP 活性降低有关。由于 REGγ 耗竭导致的肿瘤生长抑制被组成型激活的 YAP 克服。令人惊讶的是，在人结肠癌细胞中观察到 YAP 和 NF-κB 通路的相互激活。在 172 例结直肠癌标本中，超过 60%的标本发现 REGγ 过表达，与 YAP 和 p65 的升高高度相关。术后随访显示，同时高表达 REGγ、YAP 和 p-p65 的患者生存率显着降低。REGγ 可能是结直肠癌发展过程中的主要调节因子，可促进 YAP 信号转导并加强炎症和生长途径之间的交叉对话，并且 REGγ 可能是结直肠癌患者预后的新标志物。
