Department of Laboratory Medicine, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China.
Department of Information Technology, First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi 341000, P.R. China.
Mol Med Rep. 2021 May;23(5). doi: 10.3892/mmr.2021.11992. Epub 2021 Mar 24.
Cisplatin (DDP)‑based chemotherapy is a standard treatment for cervical cancer, although chemotherapy resistance remains a major concern. Hypoxia‑inducible factor‑2 α (HIF‑2α) plays an important role in chemotherapy resistance. MicroRNAs (miRs) can inhibit gene expression by binding to the 3'‑untranslated region of the target gene. The authors' previous study showed that miR‑519d‑3p plays an important role in the regulation of HIF‑2α expression under hypoxic conditions in cervical cancer. However, the function and regulatory mechanisms of the miR‑519d‑3p/HIF‑2α axis in DDP‑resistance in cervical cancer are not fully understood. Therefore, the aim of the present study was to investigate whether the miR‑519d‑3p/HIF‑2α axis increased DDP resistance by regulating the PI3K/AKT signaling pathway. It was found that the expression of miR‑519d‑3p was lower in DDP‑resistant cervical cancer cells (CaSki/DDP and HeLa/DDP) compared with CaSki and HeLa cells under hypoxic conditions. Additionally, miR‑519d‑3p overexpression decreased the IC50 value in CaSki/DDP and HeLa/DDP cells, and inhibited HIF‑2α protein expression and the PI3K/AKT signaling pathway under hypoxic conditions. Furthermore, it was demonstrated that HIF‑2α overexpression reduced the effect of miR‑519d‑3p overexpression on HeLa/DDP and CaSki/DDP cells. Moreover, the present results suggested that HIF‑2α overexpression increased the IC50 value in CaSki/DDP and HeLa/DDP cells. It was also found that HIF‑2α overexpression reduced the effect of miR‑519d‑3p overexpression on the PI3K/AKT signaling pathway. Therefore, the present results indicated that the miR‑519d‑3p/HIF‑2α axis increased DDP resistance of cervical cancer cells by suppressing the PI3K/AKT signaling pathway under hypoxic conditions.
顺铂（DDP）为基础的化疗是宫颈癌的标准治疗方法，尽管化疗耐药仍然是一个主要关注点。缺氧诱导因子-2α（HIF-2α）在化疗耐药中起重要作用。microRNAs（miRs）可以通过与靶基因的 3'非翻译区结合来抑制基因表达。作者之前的研究表明，miR-519d-3p 在宫颈癌缺氧条件下对 HIF-2α表达的调节中起重要作用。然而，miR-519d-3p/HIF-2α 轴在宫颈癌 DDP 耐药中的功能和调节机制尚不完全清楚。因此，本研究旨在探讨 miR-519d-3p/HIF-2α 轴是否通过调节 PI3K/AKT 信号通路增加 DDP 耐药性。研究发现，与低氧条件下的 CaSki 和 HeLa 细胞相比，DDP 耐药性宫颈癌细胞（CaSki/DDP 和 HeLa/DDP）中 miR-519d-3p 的表达水平较低。此外，miR-519d-3p 过表达降低了低氧条件下 CaSki/DDP 和 HeLa/DDP 细胞的 IC50 值，并抑制了 HIF-2α 蛋白表达和 PI3K/AKT 信号通路。进一步证实，HIF-2α 过表达降低了 miR-519d-3p 过表达对 HeLa/DDP 和 CaSki/DDP 细胞的影响。此外，本研究结果表明，HIF-2α 过表达增加了 CaSki/DDP 和 HeLa/DDP 细胞的 IC50 值。还发现，HIF-2α 过表达降低了 miR-519d-3p 过表达对 PI3K/AKT 信号通路的影响。因此，本研究结果表明，miR-519d-3p/HIF-2α 轴通过抑制低氧条件下的 PI3K/AKT 信号通路增加宫颈癌细胞的 DDP 耐药性。
