Shi Yanlong, Zou Yuwei, Guo Yu, Liu Yulin, Wang Qiang
Department of Oncology, 960th Hospital of PLA Jinan 250031, Shandong, China.
Department of Pathology, Affiliated Hospital of Medical College, Qingdao University Qingdao 266003, Shandong, China.
Am J Cancer Res. 2023 May 15;13(5):1999-2012. eCollection 2023.
The RNA polymerase II mediator complex subunit 12 (MED12) is an important factor for chemotherapy sensitivity. We explored the roles of exosomal transfer of carcinogenic microRNAs (miRNAs) in MED12 regulation and cisplatin resistance of ovarian cancer cells. In this study, the correlation between MED12 expression and cisplatin resistance was analyzed in ovarian cancer cells. The molecular regulation of MED12 by exosomal miR-548aq-3p was investigated by bioinformatics analysis and luciferase reporter assays. Further clinical significance of miR-548aq was assessed with TCGA data. We identified decreased MED12 expression in cisplatin-resistance of ovarian cancer cells. More importantly, coculture with cisplatin-resistant cells attenuated cisplatin sensitivity of parental ovarian cancer cells, as well as reduced MED12 expression to a large extent. Further bioinformatic analysis identified that exosomal miR-548aq-3p was correlated with MED12 transcriptional regulation in ovarian cancer cells. Luciferase reporter assays demonstrated that miR-548aq-3p down-regulated MED12 expression. miR-548aq-3p overexpression enhanced cell survival and proliferation of ovarian cancer cells with cisplatin treatment, while miR-548aq-3p inhibition induced cell apoptosis of cisplatin-resistant cells. Further clinical analysis indicated that miR-548aq was correlated with lower MED12 expression. More importantly, miR-548aq expression was a detrimental factor in the disease progression of ovarian cancer patients. In conclusion, we found that miR-548aq-3p contributed to cisplatin chemotherapy resistance of ovarian cancer cells through MED12 downregulation. Our study supported miR-548aq-3p as a promising therapeutic target for improving chemotherapy sensitivity of ovarian cancer.
RNA聚合酶II中介体复合物亚基12（MED12）是化疗敏感性的重要因素。我们探讨了致癌性微小RNA（miRNA）的外泌体转移在MED12调控及卵巢癌细胞顺铂耐药中的作用。在本研究中，分析了卵巢癌细胞中MED12表达与顺铂耐药性之间的相关性。通过生物信息学分析和荧光素酶报告基因检测研究了外泌体miR-548aq-3p对MED12的分子调控。利用TCGA数据评估了miR-548aq的进一步临床意义。我们发现卵巢癌细胞顺铂耐药时MED12表达降低。更重要的是，与顺铂耐药细胞共培养会减弱亲本卵巢癌细胞的顺铂敏感性，同时也会在很大程度上降低MED12的表达。进一步的生物信息学分析表明，外泌体miR-548aq-3p与卵巢癌细胞中MED12的转录调控相关。荧光素酶报告基因检测表明miR-548aq-3p下调MED12表达。miR-548aq-3p过表达可增强顺铂处理的卵巢癌细胞的存活和增殖能力，而抑制miR-548aq-3p可诱导顺铂耐药细胞凋亡。进一步的临床分析表明，miR-548aq与较低的MED12表达相关。更重要的是，miR-548aq表达是卵巢癌患者疾病进展的有害因素。总之，我们发现miR-548aq-3p通过下调MED12导致卵巢癌细胞对顺铂化疗耐药。我们的研究支持miR-548aq-3p作为提高卵巢癌化疗敏感性的有前景的治疗靶点。
