Dai Weiyu, Liu Side, Zhang Jieming, Pei Miaomiao, Xiao Yizhi, Li Jiaying, Hong Linjie, Lin Jianjiao, Wang Jing, Wu Xiaosheng, Liu Guangnan, Chen Yaying, Wang Yusi, Lin Zhizhao, Yang Qiong, Zhi Fachao, Li Guoxin, Tang Weimei, Li Aimin, Xiang Li, Wang Jide
Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; Department of Gastroenterology, Longgang District People's Hospital, Shenzhen, 518172, China.
Cancer Lett. 2021 Sep 3;521:196-209. doi: 10.1016/j.canlet.2021.09.001.
Previous reports have shown that histone deacetylase inhibitors (HDACi) can alter miRNA expression in a range of cancers. Both the 5p-arm and 3p-arm of mature miRNAs can be expressed from the same precursor and involved in cancer progress. Nevertheless, the detailed mechanism by which vorinostat (SAHA), a HDACi, triggers miR-769-5p/miR-769-3p-mediated suppression of proliferation and induces apoptosis in gastric cancer (GC) cells remains elusive. Here, we showed that the miRNA-seq analysis of GC cells treated with SAHA identified seven differentially expressed miRNAs with both strands of the miRNA duplex. miR-769-5p/miR-769-3p expression was downregulated in GC tissues compared with normal tissues. Functionally, high expression of miR-769-5p/miR-769-3p blocked the malignant abilities of GC cells. Mechanistically, miR-769-5p/miR-769-3p targeted IGF1R and IGF1R overexpression rescued the effects of miR-769-5p/miR-769-3p on GC cells growth and metastasis. Moreover, STAT3 bound to the promoter of miR-769. Furthermore, miR-769-5p/miR-769-3p expression was negatively regulated by the STAT3-IGF1R-HDAC3 complex. Besides, miR-769-5p/miR-769-3p synergized with SAHA to promote GC cells apoptosis. Our studies suggest that miR-769-5p/miR-769-3p acts as a tumor suppressor by the STAT3-IGF1R-HDAC3 complex. Moreover, SAHA triggers miR-769-5p/miR-769-3p-mediated inhibition of proliferation and induces apoptosis in GC cells.
先前的报道表明，组蛋白去乙酰化酶抑制剂（HDACi）可改变多种癌症中的miRNA表达。成熟miRNA的5p臂和3p臂均可从同一前体表达，并参与癌症进展。然而，HDACi伏立诺他（SAHA）触发miR-769-5p/miR-769-3p介导的胃癌（GC）细胞增殖抑制和诱导凋亡的详细机制仍不清楚。在此，我们表明，对用SAHA处理的GC细胞进行miRNA测序分析，鉴定出miRNA双链体两条链上有7种差异表达的miRNA。与正常组织相比，miR-769-5p/miR-769-3p在GC组织中的表达下调。在功能上，miR-769-5p/miR-769-3p的高表达阻断了GC细胞的恶性能力。机制上，miR-769-5p/miR-769-3p靶向IGF1R，IGF1R的过表达挽救了miR-769-5p/miR-769-3p对GC细胞生长和转移的影响。此外，STAT3与miR-769的启动子结合。此外，miR-769-5p/miR-769-3p的表达受STAT3-IGF1R-HDAC3复合物的负调控。此外，miR-769-5p/miR-769-3p与SAHA协同促进GC细胞凋亡。我们的研究表明，miR-769-5p/miR-769-3p通过STAT3-IGF1R-HDAC3复合物发挥肿瘤抑制作用。此外，SAHA触发miR-769-5p/miR-769-3p介导的增殖抑制并诱导GC细胞凋亡。
