Center for Genomics, Helmy Institute for Medical Sciences, Zewail City of Science and Technology, Giza, Egypt.
Bitechnology Program, Zoology Department, Faculty of Science, Port Said University, Port Said, Egypt.
Sci Rep. 2021 Jan 12;11(1):562. doi: 10.1038/s41598-020-78596-5.
Taxane is a family of front-line chemotherapeutic agents against ovarian cancer (OC). The therapeutic efficacy is frequently counteracted by the development of chemoresistance, leading to high rates of relapse in OC patients. The role(s) of microRNAs (miRNAs) in cancer chemoresistance had been supported by many evidences Epigenetic regulation by miRNAs has been reported to influence cancer development and response to therapeutics, however, their role in OC resistance to paclitaxel (PTX) is unclear. Here, we conducted miRNA profiling in the responsive and PTX-resistant OC cell lines before and after treatment with epigenetic modulators. We reveal 157 miRNAs to be downregulated in the PTX-resistant cells compared to parental controls. The expression of five miRNAs (miRNA-7-5p, -204-3p, -501-5p, -3652 and -4286) was restored after epigenetic modulation, which was further confirmed by qPCR. In silico analysis of the signaling pathways targeted by the selected miRNAs identified the PI3K-AKT pathway as the primary target. Subsequent cDNA array analysis confirmed multiple PI3K-AKT pathway members such as AKT2, PIK3R3, CDKN1A, CCND2 and FGF2 to be upregulated in PTX-resistant cells. STRING analysis showed the deregulated genes in PTX-resistant cells to be primarily involved in cell cycle progression and survival. Thus, high throughput miRNA and cDNA profiling coupled with pathway analysis and data mining provide evidence for epigenetically regulated miRNAs-induced modulation of signaling pathways in PTX resistant OC cells. It paves the way to more in-depth mechanistic studies and new therapeutic strategies to combat chemoresistance.
紫杉醇是一种用于治疗卵巢癌 (OC) 的一线化疗药物。但由于耐药性的产生，其治疗效果经常受到影响，导致 OC 患者的复发率很高。许多证据表明，miRNAs 在癌症耐药性中的作用，miRNAs 的表观遗传调控已被报道会影响癌症的发展和对治疗的反应，但它们在 OC 对紫杉醇 (PTX) 耐药性中的作用尚不清楚。在这里，我们在对顺铂敏感和耐药的 OC 细胞系中进行了 miRNA 谱分析，这些细胞系在经过表观遗传调节剂处理前后进行了分析。我们发现，与亲本对照相比，157 个 miRNA 在耐药细胞中下调。经过表观遗传修饰后，这五个 miRNA（miRNA-7-5p、-204-3p、-501-5p、-3652 和 -4286）的表达得到恢复，qPCR 进一步证实了这一点。对所选 miRNA 靶向的信号通路进行的计算机分析表明，PI3K-AKT 通路是主要靶点。随后的 cDNA 阵列分析证实，PTX 耐药细胞中多个 PI3K-AKT 通路成员如 AKT2、PIK3R3、CDKN1A、CCND2 和 FGF2 上调。STRING 分析表明，PTX 耐药细胞中失调的基因主要参与细胞周期进程和存活。因此，高通量 miRNA 和 cDNA 谱分析结合通路分析和数据挖掘为 PTX 耐药 OC 细胞中受表观遗传调控的 miRNA 诱导的信号通路调节提供了证据。它为深入的机制研究和新的治疗策略开辟了道路，以对抗耐药性。
