Department of Urology Surgery, The Fourth Hospital of Harbin Medical University, 37 Yiyuan Road, Harbin, 150000, Heilongjiang, China.
Department of Pharmacology and Toxicology, Boonshoft School of Medicine, Wright State University, Fairborn, OH, 45345, USA.
Clin Transl Oncol. 2018 Nov;20(11):1400-1407. doi: 10.1007/s12094-018-1871-y. Epub 2018 Apr 9.
Her-2 is an epidermal growth factor receptor expressed in some prostate cancers (PC) associated with outgrowth of the tumor. Dysregulation of some microRNAs is involved in the regulation of PC pathogenesis, whereas the role of miR-4319 in PC is unknown and addressed in the current study.
The levels of miR-4319 in PC tissues were determined by RT-qPCR and their association with patient survival was studied by Kaplan-Meier analysis. Targeted genes for miR-4319 were predicted by a bioinformatics algorithm and confirmed by a dual-luciferase reporter assay. Growth of cells of overexpression or inhibition of miR-4319 or Her-2 was analyzed by an MTT assay. Cell survival in response to a chemotherapeutic drug, estramustine (EM), was analyzed by CCK-8 assay. Cell apoptosis was evaluated by TUNEL assay and Western blotting for apoptosis-associated proteins.
MiR-4319 levels were decreased in PC specimens, compared to corresponding normal prostate tissue. Lower levels of miR-4319 were correlated with poorer overall patients' survival. In vitro, the cell survival mediated with Her-2 against chemotherapy was inhibited by overexpression of miR-4319 and was enhanced by depletion of miR-4319. Depletion of miR-4319 in primary prostate epithelial cells increased Her-2-dependent cell growth, while re-expression of miR-4319 in PC cells inhibited Her-2-dependent cell growth and Her-2-dependent resistance to EM-induced apoptosis.
The growth and chemo-resistance of PC cells may be suppressed via re-expression of miR-4319 that inhibits Her-2 signaling.
Her-2 是一种在某些与肿瘤生长相关的前列腺癌（PC）中表达的表皮生长因子受体。一些 microRNA 的失调参与了 PC 发病机制的调节，而 miR-4319 在 PC 中的作用尚不清楚，本研究对此进行了探讨。
通过 RT-qPCR 测定 PC 组织中 miR-4319 的水平，并通过 Kaplan-Meier 分析研究其与患者生存的关系。通过生物信息学算法预测 miR-4319 的靶基因，并通过双荧光素酶报告基因实验进行验证。通过 MTT 分析测定过表达或抑制 miR-4319 或 Her-2 的细胞生长情况。通过 CCK-8 分析测定细胞对化疗药物雌莫司汀（EM）的存活情况。通过 TUNEL 分析和凋亡相关蛋白的 Western blot 评估细胞凋亡。
与相应的正常前列腺组织相比，PC 标本中 miR-4319 的水平降低。较低水平的 miR-4319与较差的总患者生存相关。在体外，过表达 miR-4319可抑制 Her-2介导的化疗耐药细胞的存活，而抑制 miR-4319 可增强其活性。在原代前列腺上皮细胞中，miR-4319 的耗竭增加了 Her-2 依赖性细胞生长，而在 PC 细胞中重新表达 miR-4319抑制了 Her-2 依赖性细胞生长和 Her-2 依赖性对 EM 诱导的细胞凋亡的抵抗。
通过抑制 Her-2 信号转导，重新表达 miR-4319 可能抑制 PC 细胞的生长和化疗耐药性。
