miR-211 通过阻断卵巢癌细胞中的 DNA 损伤反应(DDR)促进铂类化疗敏感性。

miR-211 facilitates platinum chemosensitivity by blocking the DNA damage response (DDR) in ovarian cancer.

机构信息

Department of Pathology, Harbin Medical University, Harbin, 150081, China.

Faculty of Health Sciences, University of Macau, Macau, China.

出版信息

Cell Death Dis. 2019 Jun 24;10(7):495. doi: 10.1038/s41419-019-1715-x.

Abstract

The DNA damage response (DDR) is one of the most important mechanisms of platinum resistance in ovarian cancer. Some miRNAs have been identified to be involved in the regulatory network of DDR, thus the abnormal expression of miRNAs might affect platinum chemosensitivity in ovarian cancer. In this study, by assessing miRNAs simultaneously targeting a set of DDR genes that exhibited response to platinum, we found that miR-211 inhibited most of those genes, and proposed that miR-211 might affect the sensitivity of ovarian cancer cells to platinum by targeting multiple DDR genes and thereby determine the prognosis of ovarian cancer. To verify the hypothesis, we analyzed the association between miR-211 level and clinical prognosis, assessed the effect of miR-211 on DDR and platinum chemosensitivity, and explored the possible molecular mechanism. We revealed that miR-211 enhanced platinum chemosensitivity and was positively correlated with favorable outcomes in ovarian cancer patients. Many DDR genes including TDP1 were identified as targets of miR-211. In contrast, TDP1 suppressed DNA damage and platinum chemosensitivity. Moreover, the miR-211 level in tissues was shown to be associated with the good outcome of neoadjuvant chemotherapy and negatively correlated with the expression of TDP1. Conclusively, we demonstrated that miR-211 improves the prognosis of ovarian cancer patients by enhancing the chemosensitivity of cancer cells to platinum via inhibiting DDR gene expression, which provides an essential basis to identify novel treatment targets to block DDR effectively and improve chemosensitivity in ovarian cancer.

摘要

DNA 损伤反应(DDR)是卵巢癌铂类耐药的最重要机制之一。已经发现一些 miRNA 参与 DDR 的调控网络,因此 miRNA 的异常表达可能会影响卵巢癌对铂类药物的化疗敏感性。在这项研究中,通过评估同时靶向一组对铂类药物有反应的 DDR 基因的 miRNA,我们发现 miR-211 抑制了其中的大多数基因,并提出 miR-211 可能通过靶向多个 DDR 基因影响卵巢癌细胞对铂类药物的敏感性,从而决定卵巢癌的预后。为了验证这一假设,我们分析了 miR-211 水平与临床预后之间的关系,评估了 miR-211 对 DDR 和铂类化疗敏感性的影响,并探讨了可能的分子机制。我们发现 miR-211 增强了铂类化疗敏感性,并与卵巢癌患者的良好预后呈正相关。许多 DDR 基因,包括 TDP1,被鉴定为 miR-211 的靶基因。相反,TDP1 抑制了 DNA 损伤和铂类化疗敏感性。此外,组织中的 miR-211 水平与新辅助化疗的良好结局相关,与 TDP1 的表达呈负相关。总之,我们通过抑制 DDR 基因表达来增强癌细胞对铂类药物的化疗敏感性,证明了 miR-211 改善了卵巢癌患者的预后,为有效阻断 DDR 并提高卵巢癌化疗敏感性提供了重要的基础,从而确定新的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a633/6591289/e5a22930ab87/41419_2019_1715_Fig1_HTML.jpg

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