Li Bowen, Wang Weizhi, Li Zheng, Chen Zheng, Zhi Xiaofei, Xu Jianghao, Li Qing, Wang Lu, Huang Xiaoxu, Wang Linjun, Wei Song, Sun Guangli, Zhang Xuan, He Zhongyuan, Zhang Lu, Zhang Diancai, Xu Hao, El-Rifai Wael, Xu Zekuan
Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu province, China.
Department of Surgery and Cancer Biology, Vanderbilt University Medical Center, Nashville, 37232, TN, USA.
Cancer Lett. 2017 Dec 1;410:212-227. doi: 10.1016/j.canlet.2017.09.035. Epub 2017 Sep 28.
Cisplatin (CDDP) resistance is a major clinical problem associated with poor prognosis in gastric cancer (GC) patients. In this study, we performed integrated analysis of TCGA data from microRNAs (miRNAs) expression matrix of GC patients who received CDDP-based chemotherapy with GEO dataset which contains differential miRNAs expression profiles in CDDP-resistant and -sensitive cell lines. We identified miR-148a-3p downregulation as a key step involved in CDDP resistance. Using a cohort consisting 105 GC patients who received CDDP-based therapy, we found that miR-148a-3p downregulation was associated with a decrease in patients' disease-free survival (DFS, P = 0.0077). A series of experiment data demonstrated that: 1) miR-148a-3p was downregulated in CDDP-resistant GC cell lines; 2) miR-148a-3p reconstitution sensitized CDDP-resistant cells to CDDP treatment through promoting mitochondrial fission and decreasing AKAP1 expression level; 3) AKAP1 played a novel role in CDDP resistance by inhibiting P53-mediated DRP1 dephosphorylation; 4) miR-148a-3p reconstitution in CDDP-resistant cells inhibits the cyto-protective autophagy by suppressing RAB12 expression and mTOR1 activation. Taken together, our study demonstrates that miR-148a-3p could be a promising prognostic marker or therapeutic candidate for overcoming CDDP resistance in GC.
顺铂（CDDP）耐药是胃癌（GC）患者预后不良的一个主要临床问题。在本研究中，我们对接受基于顺铂化疗的GC患者的微小RNA（miRNA）表达矩阵的TCGA数据与包含顺铂耐药和敏感细胞系中差异miRNA表达谱的GEO数据集进行了综合分析。我们确定miR-148a-3p下调是顺铂耐药所涉及的关键步骤。使用一个由105名接受基于顺铂治疗的GC患者组成的队列，我们发现miR-148a-3p下调与患者无病生存期（DFS）降低相关（P = 0.0077）。一系列实验数据表明：1）miR-148a-3p在顺铂耐药的GC细胞系中下调；2）miR-148a-3p的恢复通过促进线粒体分裂和降低AKAP1表达水平使顺铂耐药细胞对顺铂治疗敏感；3）AKAP1通过抑制P53介导的DRP1去磷酸化在顺铂耐药中发挥新作用；4）顺铂耐药细胞中miR-148a-3p的恢复通过抑制RAB12表达和mTOR1激活来抑制细胞保护性自噬。综上所述，我们的研究表明miR-148a-3p可能是克服GC中顺铂耐药的一个有前景的预后标志物或治疗候选物。
