CRHR2/Ucn2 signaling is a novel regulator of miR-7/YY1/Fas circuitry contributing to reversal of colorectal cancer cell resistance to Fas-mediated apoptosis.
CRHR2/Ucn2 signaling is a novel regulator of miR-7/YY1/Fas circuitry contributing to reversal of colorectal cancer cell resistance to Fas-mediated apoptosis.
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DOI：
10.1002/ijc.31064
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发表时间：
2018-01-15
影响因子：
6.4
通讯作者：
Baritaki S
中科院分区：
文献类型：
--
作者：
Pothoulakis C;Torre-Rojas M;Duran-Padilla MA;Gevorkian J;Zoras O;Chrysos E;Chalkiadakis G;Baritaki S
结直肠癌（CRC）对免疫介导的细胞毒性反应较差。促肾上腺皮质激素释放激素受体-2 （CRHR2）在结直肠癌中的低表达促进肿瘤存活、生长和上皮向间充质转化（EMT），无论在体内还是体外。我们探讨了CRHR2下调在结直肠癌细胞抵抗Fas/ fasl介导的凋亡中的作用及其潜在的分子机制。比较了Urocortin-2 （Ucn2）刺激的亲代和过表达CRHR2的CRC细胞系对ch11诱导的CRC细胞凋亡的敏感性，并通过体外和离体分析确定了CRHR2/Ucn2信号通路的靶点。SW620和DLD1细胞中诱导的CRHR2/Ucn2信号通过Fas mRNA和蛋白上调特异性地增加了它们对ch11介导的凋亡的敏感性。与对照组织相比，结直肠癌的Fas表达减少，这与CRHR2 mRNA缺失、肿瘤分化差和远处转移的高风险相关。YY1沉默增加了SW620中Fas启动子的活性，使其对ch11 -凋亡重新敏感；这表明YY1可能是结直肠癌中Fas的转录抑制因子。在结直肠癌组织阵列中，Fas和YY1的表达呈负相关，而YY1 mRNA的升高与结直肠癌的晚期分级和远处转移的高风险相关。CRHR2/Ucn2信号通过miR-7的升高特异性下调YY1的表达，而miR-7在miR-7高的SW620-CRHR2+和mir - 7低的HCT116细胞中的调节，对YY1和Fas的表达以及细胞对ch11杀伤的敏感性有相反的影响。通过靶向miR-7/YY1/Fas通路，CRHR2/Ucn2信号通路是CRC细胞对Fas/ fasl凋亡抗性的负调控因子。CRHR2修复可能在控制CRC对免疫介导的凋亡刺激的反应中被证明是有效的。
Colorectal cancer (CRC) responds poorly to immuno-mediated cytotoxicity. Underexpression of Corticotropin-releasing-hormone-receptor-2 (CRHR2) in CRC, promotes tumor survival, growth and Epithelial to Mesenchymal Transition (EMT), in vitro and in vivo. We explored the role of CRHR2 downregulation in CRC cell resistance to Fas/FasL-mediated apoptosis and the underlying molecular mechanism. CRC cell sensitivity to CH11-induced apoptosis was compared between Urocortin-2 (Ucn2)-stimulated parental and CRHR2-overexpressing CRC cell lines and targets of CRHR2/Ucn2 signaling were identified through in vitro and ex vivo analyses. Induced CRHR2/Ucn2 signaling in SW620 and DLD1 cells increased specifically their sensitivity to CH11-mediated apoptosis, via Fas mRNA and protein upregulation. CRC compared to control tissues had reduced Fas expression that was associated with lost CRHR2 mRNA, poor tumor differentiation and high risk for distant metastasis. YY1 silencing increased Fas promoter activity in SW620 and re-sensitized them to CH11-apoptosis; suggesting YY1 as a putative transcriptional repressor of Fas in CRC. An inverse correlation between Fas and YY1 expression was confirmed in CRC tissue arrays, while elevated YY1 mRNA was clinically relevant with advanced CRC grade and higher risk for distant metastasis. CRHR2/Ucn2 signaling downregulated specifically YY1 expression through miR-7 elevation, while miR-7 modulation in miR-7high SW620-CRHR2+ and miR-7low HCT116 cells, had opposite effects on YY1 and Fas expressions and cell sensitivity to CH11-killing. CRHR2/Ucn2 signaling is a negative regulator of CRC cell resistance to Fas/FasL-apoptosis via targeting the miR-7/YY1/Fas circuitry. CRHR2 restoration might prove effective in managing CRC response to immune-mediated apoptotic stimuli.
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