Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory for Cellular Physiology of Ministry of Education, Shanxi Medical University, Taiyuan 030001, China.
Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan 030032, China.
Acta Biochim Biophys Sin (Shanghai). 2024 May 25;56(5):740-752. doi: 10.3724/abbs.2024009.
Dysregulation of microRNA (miRNA) expression in cancer is a significant factor contributing to the progression of chemoresistance. The objective of this study is to explore the underlying mechanisms by which miR-34b-3p regulates chemoresistance in cervical cancer (CC). Previous findings have demonstrated low expression levels of miR-34b-3p in both CC chemoresistant cells and tissues. In this study, we initially characterize the behavior of SiHa/DDP cells which are CC cells resistant to the chemotherapeutic drug cisplatin (DDP). Subsequently, miR-34b-3p mimics are transfected into SiHa/DDP cells. It is observed that overexpression of miR-34b-3p substantially inhibits the proliferation, migration, and invasion abilities of SiHa/DDP cells and also enhances their sensitivity to DDP-induced cell death. Quantitative RT-PCR and western blot analysis further reveal elevated expression levels of STC2 and FN1 in SiHa/DDP cells, contrary to the expression pattern of miR-34b-3p. Moreover, STC2 and FN1 contribute to DDP resistance, proliferation, migration, invasion, and decreased apoptosis in CC cells. Through dual-luciferase assay analysis, we confirm that STC2 and FN1 are direct targets of miR-34b-3p in CC. Finally, rescue experiments demonstrate that overexpression of either STC2 or FN1 can partially reverse the inhibitory effects of miR-34b-3p overexpression on chemoresistance, proliferation, migration and invasion in CC cells. In conclusion, our findings support the role of miR-34b-3p as a tumor suppressor in CC. This study indicates that targeting the miR-34b-3p/STC2 or FN1 axis has potential therapeutic implications for overcoming chemoresistance in CC patients.
miRNA（miRNA）表达失调是导致化疗耐药性进展的重要因素。本研究旨在探讨 miR-34b-3p 调节宫颈癌（CC）化疗耐药性的潜在机制。先前的研究结果表明，miR-34b-3p 在 CC 耐药细胞和组织中的表达水平较低。在本研究中，我们首先对顺铂（DDP）耐药的 CC 细胞 SiHa/DDP 的行为进行了特征描述。随后，将 miR-34b-3p 模拟物转染到 SiHa/DDP 细胞中。结果表明，miR-34b-3p 的过表达可显著抑制 SiHa/DDP 细胞的增殖、迁移和侵袭能力，并增强其对 DDP 诱导的细胞死亡的敏感性。定量 RT-PCR 和 Western blot 分析进一步显示，SiHa/DDP 细胞中 STC2 和 FN1 的表达水平升高，与 miR-34b-3p 的表达模式相反。此外，STC2 和 FN1 有助于 CC 细胞的 DDP 耐药性、增殖、迁移、侵袭和凋亡减少。通过双荧光素酶报告基因分析，我们证实 STC2 和 FN1 是 CC 中 miR-34b-3p 的直接靶标。最后，挽救实验表明，过表达 STC2 或 FN1 中的任何一种都可以部分逆转 miR-34b-3p 过表达对 CC 细胞化疗耐药性、增殖、迁移和侵袭的抑制作用。总之，我们的研究结果支持 miR-34b-3p 在 CC 中作为肿瘤抑制因子的作用。本研究表明，靶向 miR-34b-3p/STC2 或 FN1 轴可能为克服 CC 患者的化疗耐药性提供潜在的治疗意义。
