Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Cell Mol Life Sci. 2023 Aug 17;80(9):256. doi: 10.1007/s00018-023-04906-5.
Increasing evidences has indicated that primary and acquired resistance of ovarian cancer (OC) to platinum is mediated by multiple molecular and cellular factors. Understanding these mechanisms could promote the therapeutic efficiency for patients with OC.
Here, we screened the expression pattern of circRNAs in samples derived from platinum-resistant and platinum-sensitive OC patients using RNA-sequencing (RNA-seq). The expression of hsa_circ_0010467 was validated by Sanger sequencing, RT-qPCR, and fluorescence in situ hybridization (FISH) assays. Overexpression and knockdown experiments were performed to explore the function of hsa_circ_0010467. The effects of hsa_circ_0010467 on enhancing platinum treatment were validated in OC cells, mouse model and patient-derived organoid (PDO). RNA pull-down, RNA immunoprecipitation (RIP), and dual-luciferase reporter assays were performed to investigate the interaction between hsa_circ_0010467 and proteins.
Increased expression of hsa_circ_0010467 is observed in platinum-resistant OC cells, tissues and serum exosomes, which is positively correlated with advanced tumor stage and poor prognosis of OC patients. Hsa_circ_0010467 is found to maintain the platinum resistance via inducing tumor cell stemness, and silencing hsa_circ_0010467 substantially increases the efficacy of platinum treatment on inhibiting OC cell proliferation. Further investigation reveals that hsa_circ_0010467 acts as a miR-637 sponge to mediate the repressive effect of miR-637 on leukemia inhibitory factor (LIF) and activates the LIF/STAT3 signaling pathway. We further discover that AUF1 could promote the biogenesis of hsa_circ_0010467 in OC.
Our study uncovers the mechanism that hsa_circ_0010467 mediates the platinum resistance of OC through AUF1/hsa_circ_0010467/miR-637/LIF/STAT3 axis, and provides potential targets for the treatment of platinum-resistant OC patients.
越来越多的证据表明，卵巢癌（OC）对铂类药物的原发和获得性耐药是由多种分子和细胞因素介导的。了解这些机制可以提高 OC 患者的治疗效果。
在这里，我们使用 RNA 测序（RNA-seq）筛选了来自铂耐药和铂敏感 OC 患者样本中 circRNAs 的表达模式。通过 Sanger 测序、RT-qPCR 和荧光原位杂交（FISH）实验验证了 hsa_circ_0010467 的表达。进行了过表达和敲低实验以探索 hsa_circ_0010467 的功能。在 OC 细胞、小鼠模型和患者来源的类器官（PDO）中验证了 hsa_circ_0010467 增强铂类药物治疗的效果。进行了 RNA 下拉、RNA 免疫沉淀（RIP）和双荧光素酶报告基因测定，以研究 hsa_circ_0010467 与蛋白质之间的相互作用。
在铂耐药 OC 细胞、组织和血清外泌体中观察到 hsa_circ_0010467 的表达增加，这与 OC 患者的晚期肿瘤分期和不良预后呈正相关。研究发现，hsa_circ_0010467 通过诱导肿瘤细胞干性来维持铂类耐药，沉默 hsa_circ_0010467 可显著提高铂类药物抑制 OC 细胞增殖的疗效。进一步研究表明，hsa_circ_0010467 作为 miR-637 的海绵体，介导 miR-637 对白血病抑制因子（LIF）的抑制作用，并激活 LIF/STAT3 信号通路。我们进一步发现，AUF1 可以促进 OC 中 hsa_circ_0010467 的生物发生。
我们的研究揭示了 hsa_circ_0010467 通过 AUF1/hsa_circ_0010467/miR-637/LIF/STAT3 轴介导 OC 的铂类耐药的机制，并为铂耐药 OC 患者的治疗提供了潜在靶点。
