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揭示与奥拉帕利耐药和卵巢癌细胞 PEO1-OR 再敏化相关的 miRNA-mRNA 调控网络，该通路抑制剂为 ATR/CHK1 通路抑制剂。

Uncovering miRNA-mRNA Regulatory Networks Related to Olaparib Resistance and Resensitization of Ovarian Cancer PEO1-OR Cells with the ATR/CHK1 Pathway Inhibitors.

机构信息

Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland.

Doctoral School of Exact and Natural Sciences, University of Lodz, Jana Matejki 21/23, 90-237 Lodz, Poland.

出版信息

Cells. 2024 May 17;13(10):867. doi: 10.3390/cells13100867.

DOI:10.3390/cells13100867
PMID:38786089
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11119970/
Abstract

Resistance to olaparib is the major obstacle in targeted therapy for ovarian cancer (OC) with poly(ADP-ribose) polymerase inhibitors (PARPis), prompting studies on novel combination therapies to enhance olaparib efficacy. Despite identifying various mechanisms, understanding how OC cells acquire PARPi resistance remains incomplete. This study investigated microRNA (miRNA) expression in olaparib-sensitive (PEO1, PEO4) and previously established olaparib-resistant OC cell lines (PEO1-OR) using high-throughput RT-qPCR and bioinformatic analyses. The role of miRNAs was explored regarding acquired resistance and resensitization with the ATR/CHK1 pathway inhibitors. Differentially expressed miRNAs were used to construct miRNA-mRNA regulatory networks and perform functional enrichment analyses for target genes with miRNet 2.0. TCGA-OV dataset was analyzed to explore the prognostic value of selected miRNAs and target genes in clinical samples. We identified potential processes associated with olaparib resistance, including cell proliferation, migration, cell cycle, and growth factor signaling. Resensitized PEO1-OR cells were enriched in growth factor signaling via PDGF, EGFR, FGFR1, VEGFR2, and TGFβR, regulation of the cell cycle via the G2/M checkpoint, and caspase-mediated apoptosis. Antibody microarray analysis confirmed dysregulated growth factor expression. The addition of the ATR/CHK1 pathway inhibitors to olaparib downregulated FGF4, FGF6, NT-4, PLGF, and TGFβ1 exclusively in PEO1-OR cells. Survival and differential expression analyses for serous OC patients revealed prognostic miRNAs likely associated with olaparib resistance (miR-99b-5p, miR-424-3p, and miR-505-5p) and resensitization to olaparib (miR-324-5p and miR-424-3p). Essential miRNA-mRNA interactions were reconstructed based on prognostic miRNAs and target genes. In conclusion, our data highlight distinct miRNA profiles in olaparib-sensitive and olaparib-resistant cells, offering molecular insights into overcoming resistance with the ATR/CHK1 inhibitors in OC. Moreover, some miRNAs might serve as potential predictive signature molecules of resistance and therapeutic response.

摘要

对聚（ADP-核糖）聚合酶抑制剂（PARPi）的卵巢癌（OC）的靶向治疗的主要障碍是耐药性，这促使人们研究新的联合治疗方法以增强奥拉帕利的疗效。尽管已经确定了各种机制，但对于 OC 细胞如何获得 PARPi 耐药性仍不完全了解。本研究使用高通量 RT-qPCR 和生物信息学分析，研究了奥拉帕利敏感（PEO1、PEO4）和先前建立的奥拉帕利耐药 OC 细胞系（PEO1-OR）中的 microRNA（miRNA）表达。使用 ATR/CHK1 通路抑制剂探索了 miRNA 在获得性耐药和再敏化中的作用。差异表达的 miRNA 用于构建 miRNA-mRNA 调控网络，并使用 miRNet 2.0 对靶基因进行功能富集分析。分析 TCGA-OV 数据集以探索选定 miRNA 和靶基因在临床样本中的预后价值。我们确定了与奥拉帕利耐药相关的潜在过程，包括细胞增殖、迁移、细胞周期和生长因子信号转导。再敏化的 PEO1-OR 细胞通过 PDGF、EGFR、FGFR1、VEGFR2 和 TGFβR 富集于生长因子信号转导，通过 G2/M 检查点调节细胞周期，通过 Caspase 介导的细胞凋亡。抗体微阵列分析证实了生长因子表达失调。ATR/CHK1 通路抑制剂与奥拉帕利联合使用可特异性地下调 PEO1-OR 细胞中的 FGF4、FGF6、NT-4、PLGF 和 TGFβ1。对浆液性 OC 患者的生存和差异表达分析显示，预后 miRNA 可能与奥拉帕利耐药（miR-99b-5p、miR-424-3p 和 miR-505-5p）和对奥拉帕利的再敏化（miR-324-5p 和 miR-424-3p）相关。基于预后 miRNA 和靶基因重建了关键的 miRNA-mRNA 相互作用。总之，我们的数据突出了奥拉帕利敏感和耐药细胞中独特的 miRNA 谱，为克服 OC 中 ATR/CHK1 抑制剂的耐药性提供了分子见解。此外，一些 miRNA 可能作为耐药性和治疗反应的潜在预测特征分子。

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