MiR-186 bidirectionally regulates cisplatin sensitivity of ovarian cancer cells via suppressing targets PIK3R3 and PTEN and upregulating APAF1 expression
MiR-186 bidirectionally regulates cisplatin sensitivity of ovarian cancer cells via suppressing targets PIK3R3 and PTEN and upregulating APAF1 expression
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MiR-186通过抑制靶标PIK3R3和PTEN并上调APAF1表达来双向调节卵巢癌细胞的顺铂敏感性。
DOI：
10.7150/jca.41135
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发表时间：
2020-01-01
影响因子：
3.9
通讯作者：
Xin, Hong-Wu
中科院分区：
文献类型：
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作者：
Xiang, Ying;Chen, Ya-Jun;Xin, Hong-Wu
卵巢癌是女性生殖系统中一种高度致命的恶性肿瘤。以顺铂为代表的铂类药物是治疗包括卵巢癌在内的多种恶性肿瘤的一线化疗药物，但耐药性导致化疗失败。 MicroRNA 成为逆转顺铂耐药性的有前途的分子。据报道，miR-186 在顺铂耐药卵巢细胞系中下调，并且 miR-186 表达增加了顺铂敏感性。然而，我们首次发现miR-186对顺铂敏感性的双向调节作用，低浓度的miR-186过表达增加了卵巢癌细胞A2780/DDP的顺铂敏感性，而高浓度的miR-186则降低了顺铂敏感性。其他类型癌细胞系的存活测定验证了 miR-186 以剂量和细胞类型依赖性方式对顺铂敏感性的双向调节功能。 MiR-186 剂量依赖性地抑制 PTEN 和 PIK3R3 的蛋白水平，它们是致癌 AKT 通路的相反调节分子。 MiR-186 还可以剂量依赖性地增强凋亡基因 APAF1 的蛋白水平。我们提出当miR-186在低浓度时，PTEN和APAF1的最终作用超过PIK3R3，从而增加卵巢癌细胞的顺铂敏感性；而当miR-186在高浓度时，PIK3R3的最终作用超过PTEN和APAF1，从而降低顺铂敏感性。我们得出的结论是，这些相反功能分子的调节结果促成了 miR-186 对卵巢癌顺铂敏感性的双向调节作用。在开发基于双向功能miRNA的治疗策略时值得更多关注。
Ovarian cancer is a highly lethal malignancy in the female reproductive system. Platinum drugs, represented by cisplatin, are the first-line chemotherapeutic agents for treatment of various malignancies including ovarian cancer, but drug resistance leads to chemotherapy failure. MicroRNAs emerged as promising molecules in reversal of cisplatin resistance. MiR-186 was reported to be downregulated in the cisplatin-resistant ovarian cell lines and miR-186 expression increased cisplatin sensitivity. However, we found the bidirectional regulatory effects of miR-186 on cisplatin sensitivity for the first time that overexpression of miR-186 at low concentration increased the cisplatin sensitivity of ovarian cancer cells A2780/DDP, while high concentration of miR-186 decreased the cisplatin sensitivity. The survival assay in other types of cancer cell lines verified the bidirectional regulatory function of miR-186 on cisplatin sensitivity in dose and cell type dependent manners. MiR-186 suppressed the protein levels of PTEN and PIK3R3 dose-dependently, which are opposite regulatory molecules of the oncogenic AKT pathway. MiR-186 also enhanced the protein levels of apoptotic gene APAF1 dose-dependently. We proposed the final effects of PTEN and APAF1 outweighed PIK3R3 when miR-186 at low concentration so as to increase the cisplatin sensitivity of ovarian cancer cells, while the final effects of PIK3R3 outweighed PTEN and APAF1 when miR-186 at high concentration so as to decrease the cisplatin sensitivity. We concluded the outcome of regulation of these opposite functional molecules contributed to the bidirectional regulatory effects of miR-186 in ovarian cancer cisplatin sensitivity. It deserves more attentions when developing therapeutic strategies based on the bidirectional functional miRNAs.