Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education and School of Diagnostic Medicine, Chongqing Medical University, Chongqing, PR China.
Oncol Rep. 2013 Aug;30(2):877-89. doi: 10.3892/or.2013.2532. Epub 2013 Jun 11.
Chemotherapy is an important option for the treatment of advanced breast cancer, but multidrug resistance is one of the major obstacles in the clinical control of breast cancer. The present study investigated the effects of the miR‑195-led gene pathway in the sensitization of breast cancer cells to treatment with the chemotherapeutic drug Adriamycin. Breast cancer cell lines and tissue specimens (obtained from chemotherapy-sensitive or resistant patients) as well as a normal breast cell line were used to assess expression of miR-195, Raf-1, Bcl-2 and P-glycoprotein mRNA and/or mRNA. miR-195 mimics, inhibitor and Raf-1 siRNA were used to transfect breast cancer MCF-7 and MCF-7/ADR cells (an Adriamycin-resistant MCF-7 subline) for cell viability, apoptosis and gene expression analysis. The data showed that miR-195 expression was low in breast cancer cells and multidrug-resistant breast cancer tissues, which was associated with reduced Raf-1 expression in vitro and ex vivo. Induction of miR-195 expression promoted tumor cell apoptosis and inhibited breast cancer cell viability, but induced the sensitivity of breast cancer cells to Adriamycin treatment and was associated with inhibition of Raf-1 expression in breast cancer cells. Moreover, knockdown of Raf-1 expression had similar effects of miR-195 mimics on breast cancer cells, both of which were able to suppress Bcl-2 and P-glycoprotein expression in breast cancer cells. The data from the current study demonstrated that expression of miR-195 was inversely associated with Raf-1 expression in breast cancer cell lines and tissue specimens, and that Raf-1 is the target gene of miR-195. Thus, expression of miR-195 or knockdown of Raf-1 can similarly reduce tumor cell survival but increase apoptosis through downregulation of Raf-1 and Bcl-2 and P-glycoprotein expression. In conclusion, this gene pathway mediated the sensitivity of breast cancer cells to Adriamycin treatment.
化疗是治疗晚期乳腺癌的重要选择，但多药耐药性是乳腺癌临床控制的主要障碍之一。本研究探讨了 miR-195 介导的基因通路在增强乳腺癌细胞对阿霉素化疗药物敏感性中的作用。使用乳腺癌细胞系和组织标本（来自化疗敏感或耐药患者）以及正常乳腺细胞系来评估 miR-195、Raf-1、Bcl-2 和 P-糖蛋白 mRNA 和/或 mRNA 的表达。使用 miR-195 模拟物、抑制剂和 Raf-1 siRNA 转染乳腺癌 MCF-7 和 MCF-7/ADR 细胞（阿霉素耐药 MCF-7 亚系），进行细胞活力、细胞凋亡和基因表达分析。结果显示，miR-195 在乳腺癌细胞和多药耐药性乳腺癌组织中的表达较低，这与体外和体内 Raf-1 表达降低有关。诱导 miR-195 表达可促进肿瘤细胞凋亡并抑制乳腺癌细胞活力，但可诱导乳腺癌细胞对阿霉素治疗的敏感性，并与乳腺癌细胞中 Raf-1 表达的抑制有关。此外，下调 Raf-1 表达具有与 miR-195 模拟物对乳腺癌细胞相似的作用，两者均能抑制乳腺癌细胞中 Bcl-2 和 P-糖蛋白的表达。本研究的数据表明，miR-195 在乳腺癌细胞系和组织标本中的表达与 Raf-1 的表达呈负相关，Raf-1 是 miR-195 的靶基因。因此，miR-195 的表达或 Raf-1 的下调均可通过下调 Raf-1 和 Bcl-2 以及 P-糖蛋白的表达，相似地减少肿瘤细胞的存活并增加细胞凋亡。总之，该基因通路介导了乳腺癌细胞对阿霉素治疗的敏感性。
