miR-200b induces cell cycle arrest and represses cell growth in esophageal squamous cell carcinoma
miR-200b induces cell cycle arrest and represses cell growth in esophageal squamous cell carcinoma
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miR-200b 诱导食管鳞状细胞癌细胞周期停滞并抑制细胞生长
DOI：
10.1093/carcin/bgw079
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发表时间：
2016-09-01
期刊：
影响因子：
4.7
通讯作者：
Li, En-Min
中科院分区：
文献类型：
--
作者：
Zhang, Hai-Feng;Alshareef, Abdulraheem;Li, En-Min
miR-200 b是一种在癌症进展中发挥多效性作用的microRNA，代表了一个有吸引力的治疗靶点。我们以前确定miR-200 b作为食管鳞状细胞癌（ESCC）的侵袭性抑制因子，而进一步的理解是有必要建立它作为一个治疗靶点。在这里，我们发现miR-200 b通过诱导G2期细胞周期停滞和凋亡来减轻ESCC细胞的生长。miR-200 B调控多种关键细胞周期调节因子如CDK 1、CDK 2、CDK 4和Cyclin B的表达/激活以及Wnt/β-连环蛋白信号传导。我们确定了CDK 2和PAF（PCNA相关因子），两个重要的肿瘤促进因子，作为ESCC中miR-200 b的直接靶点。与ESCC中miR-200 b的频繁丢失相关，与病例匹配的正常组织相比，ESCC肿瘤中CDK 2和PAF水平均显著升高（n = 119，均P < 0.0001），并与显著降低的生存率相关（分别为P = 0.007和P = 0.041）。此外，CDK 2和PAF也与乳腺癌（n = 1802）和胃癌（n = 233）的某些亚型的不良预后相关。虽然CDK 2不能显著介导miR-200 b的生物学功能，但PAF siRNA敲除表型复制，同时恢复PAF表达，消除了miR-200 b对ESCC细胞的生物学效应。此外，PAF被揭示介导miR-200 b对Wnt/beta-Catenin信号传导的抑制作用。总的来说，miR-200 b在ESCC中的多效性作用突出了其在这种侵袭性疾病中的治疗干预潜力。
miR-200b is a pleiotropically acting microRNA in cancer progression, representing an attractive therapeutic target. We previously identified miR-200b as an invasiveness repressor in esophageal squamous cell carcinoma (ESCC), whereas further understanding is warranted to establish it as a therapeutic target. Here, we show that miR-200b mitigates ESCC cell growth by inducing G2-phase cell cycle arrest and apoptosis. The expression/activation of multiple key cell cycle regulators such as CDK1, CDK2, CDK4 and Cyclin B, and the Wnt/beta-Catenin signaling are modulated by miR-200b. We identified CDK2 and PAF (PCNA-associated factor), two important tumor-promoting factors, as direct miR-200b targets in ESCC. Correlating with the frequent loss of miR-200b in ESCC, both CDK2 and PAF levels are significantly increased in ESCC tumors compared to case-matched normal tissues (n = 119, both P < 0.0001), and correlate with markedly reduced survival (P = 0.007 and P = 0.041, respectively). Furthermore, CDK2 and PAF are also associated with poor prognosis in certain subtypes of breast cancer (n = 1802) and gastric cancer (n = 233). Although CDK2 could not significantly mediate the biological function of miR-200b, PAF siRNA knockdown phenocopied while restored expression of PAF abrogated the biological effects of miR-200b on ESCC cells. Moreover, PAF was revealed to mediate the inhibitory effects of miR-200b on Wnt/beta-Catenin signaling. Collectively, the pleiotropic effects of miR-200b in ESCC highlight its potential for therapeutic intervention in this aggressive disease.