Genetic and Methylation-Induced Loss of miR-181a2/181b2 within chr9q33.3 Facilitates Tumor Growth of Cervical Cancer through the PIK3R3/Akt/FoxO Signaling Pathway
Genetic and Methylation-Induced Loss of miR-181a2/181b2 within chr9q33.3 Facilitates Tumor Growth of Cervical Cancer through the PIK3R3/Akt/FoxO Signaling Pathway
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chr9q33.3 内遗传和甲基化诱导的 miR-181a2/181b2 丢失通过 PIK3R3/Akt/FoxO 信号通路促进宫颈癌肿瘤生长
DOI：
10.1158/1078-0432.ccr-16-0303
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发表时间：
2017-01-01
影响因子：
11.5
通讯作者：
Han, Weidong
中科院分区：
文献类型：
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作者：
Mei, Qian;Li, Xiang;Han, Weidong
目的：Chr9q31-33 丢失是宫颈癌最常见的染色体失衡之一，但其潜在机制尚未得到充分记录。实验设计：利用 26 个微卫星标记研究 Chr9q31-33 杂合性丢失 (LOH) 状态。我们通过 qRT-PCR 分析宫颈癌细胞系和 100 个配对肿瘤样本以及相应的邻近非肿瘤组织，检测了 miR-181a2/181b2 的表达。进行 Kaplan-Meier 和 Cox 比例风险回归分析以确定 miR-181a2/181b2 的预后价值。通过甲基化特异性 PCR 分析表达调节。在体外和体内测定了 miR-181a2/181b2 的肿瘤抑制作用。还确定了介导miR-181a2/181b2功能的靶基因和信号通路。结果：Chr9q33.3被确定为宫颈癌中缺失最多的区域之一。在 46% 的宫颈癌中检测到 miR-181a2/181b2 低表达，这是由 chr9q33.3 的 LOH 和启动子高甲基化诱导的。 miR-181a2/181b2 表达减弱预示着宫颈癌的不良预后表型和晚期临床分期。 miR-181a2/181b2 在体外显着抑制细胞周期进程、抑制细胞生长并促进肿瘤细胞凋亡。它们还有效地阻止体内肿瘤的形成和生长。 miR-181a2/181b2 通过抑制直接靶标 PIK3R3 (p55 gamma) 从而调节 PIK3R3/Akt/FoxO 信号通路来发挥肿瘤抑制能力。结论：我们证明了从 chr9q33.3 缺失（宫颈癌中常见的事件）到 miR-181a2/181b2 表达不足，导致宫颈癌的因果关系。 PI3K 通路的激活升高。临床癌症研究； 23(2)； 575-86。 (C) 2016 年 AACR。
Purpose: Loss of Chr9q31-33 is one of the most common chromosome imbalances of cervical cancer, but the underlying mechanism has not been well documented.Experimental Design: The loss ofheterozygosity (LOH) status of Chr9q31-33 was investigated utilizing 26 microsatellite markers. We detected the expression of miR-181a2/181b2 by qRT-PCR analysis of cervical cancer cell lines and 100 paired tumor samples and corresponding adjacent non-tumor tissues. Kaplan-Meier and Cox proportional hazard regression analyses were performed to identify the prognostic value of miR-181a2/181b2. Regulation of expression was analyzed by methylation-specific PCR. The tumorsuppressing effects of miR-181a2/181b2 were determined in vitro and in vivo. The target gene and signaling pathway thatmediated the function of miR-181a2/181b2 were also identified.Results: Chr9q33.3 was identified as one of the most deleted regions in cervical cancer. Underexpression of miR-181a2/181b2 was detected in 46% of cervical cancer and was induced by the LOH of chr9q33.3 and promoter hypermethylation. Attenuated miR-181a2/181b2 expression predicted a poor prognostic phenotype and advanced clinical stage of cervical cancer. miR-181a2/181b2 prominently dampened cell-cycle progression, suppressed cell growth, and promoted apoptosis of tumor cells in vitro. They also effectively impeded tumor formation and growth in vivo. miR-181a2/181b2 exert the tumor suppressor ability by depressing the direct target PIK3R3 (p55 gamma) and consequently modulating the PIK3R3/Akt/FoxO signaling pathway.Conclusions: We demonstrated a cause-and-effect event beginning from loss of chr9q33.3, a frequent event in cervical cancer, to the underexpression of miR-181a2/181b2, leading to the elevated activation of the PI3K pathway. Clin Cancer Res; 23(2); 575-86. (C) 2016 AACR.