RNAi and Functional Genomics Lab, Department of Life Science, National Institute of Technology Rourkela, Rourkela, 769008, Odisha, India.
Commun Biol. 2021 Nov 19;4(1):1312. doi: 10.1038/s42003-021-02844-1.
Resistance to doxorubicin (DOX) is an obstacle to successful sarcoma treatment and a cause of tumor relapse, with the underlying molecular mechanism still unknown. PIWI-interacting RNAs (piRNAs) have been shown to enhance patient outcomes in cancers. However, there are few or no reports on piRNAs affecting chemotherapy in cancers, including fibrosarcoma. The current study aims to investigate the relationship between piR-39980 and DOX resistance and the underlying mechanisms. We reveal that piR-39980 is less expressed in DOX-resistant HT1080 (HT1080/DOX) fibrosarcoma cells. Our results show that inhibition of piR-39980 in parental HT1080 cells induces DOX resistance by attenuating intracellular DOX accumulation, DOX-induced apoptosis, and anti-proliferative effects. Its overexpression in HT1080/DOX cells, on the other hand, increases DOX sensitivity by promoting intracellular DOX accumulation, DNA damage, and apoptosis. The dual-luciferase reporter assay indicates that piR-39980 negatively regulates RRM2 and CYP1A2 via direct binding to their 3'UTRs. Furthermore, overexpressing RRM2 induces DOX resistance of HT1080 cells by rescuing DOX-induced DNA damage by promoting DNA repair, whereas CYP1A2 confers resistance by decreasing intracellular DOX accumulation, which piR-39980 restores. This study reveals that piR-39980 could reduce fibrosarcoma resistance to DOX by modulating RRM2 and CYP1A2, implying that piRNA can be used in combination with DOX.
多柔比星（DOX）耐药性是肉瘤治疗成功的障碍，也是肿瘤复发的原因，但其潜在的分子机制尚不清楚。PIWI 相互作用 RNA（piRNAs）已被证明能提高癌症患者的预后。然而，关于 piRNAs 影响癌症（包括纤维肉瘤）化疗的报道很少或没有。本研究旨在探讨 piR-39980 与 DOX 耐药性的关系及其潜在机制。我们揭示 piR-39980 在 DOX 耐药的 HT1080（HT1080/DOX）纤维肉瘤细胞中表达水平降低。我们的结果表明，抑制亲本 HT1080 细胞中的 piR-39980 会通过减弱细胞内 DOX 积累、DOX 诱导的细胞凋亡和抗增殖作用来诱导 DOX 耐药性。另一方面，在 HT1080/DOX 细胞中过表达 piR-39980 会通过促进细胞内 DOX 积累、DNA 损伤和细胞凋亡来增加 DOX 敏感性。双荧光素酶报告基因检测表明，piR-39980 通过直接结合其 3'UTR 负调控 RRM2 和 CYP1A2。此外，过表达 RRM2 通过促进 DNA 修复来挽救 DOX 诱导的 DNA 损伤，从而诱导 HT1080 细胞对 DOX 的耐药性，而 CYP1A2 通过减少细胞内 DOX 积累来赋予耐药性，piR-39980 可以恢复这种耐药性。本研究揭示 piR-39980 可以通过调节 RRM2 和 CYP1A2 降低纤维肉瘤对 DOX 的耐药性，这意味着 piRNA 可与 DOX 联合使用。
