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长链非编码 RNA 'UCA1' 通过直接结合 miR-27a-5p 并控制 UBE2N 水平来调节卵巢癌对化疗的反应。

The lncRNA 'UCA1' modulates the response to chemotherapy of ovarian cancer through direct binding to miR-27a-5p and control of UBE2N levels.

机构信息

UNICAEN, Inserm U1086 ANTICIPE (Interdisciplinary Research Unit for Cancer Prevention and Treatment), Normandie Univ, Caen, France.

Cancer Centre François Baclesse, UNICANCER, Caen, France.

出版信息

Mol Oncol. 2021 Dec;15(12):3659-3678. doi: 10.1002/1878-0261.13045. Epub 2021 Jul 13.

DOI:10.1002/1878-0261.13045
PMID:34160887
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8637575/
Abstract

Ovarian cancer (OC) is the leading cause of death in patients with gynecologic cancers. Due to late diagnosis and resistance to chemotherapy, the 5-year survival rate in patients with OC is below 40%. We observed that UCA1, a lncRNA previously reported to play an oncogenic role in several malignancies, is overexpressed in the chemoresistant OC cell line OAW42-R compared to their chemotherapy-sensitive counterpart OAW42. Additionally, UCA1 overexpression was related to poor prognosis in two independent patient cohorts. Currently, the molecular mechanisms through which UCA1 acts in OC are poorly understood. We demonstrated that downregulation of the short isoform of UCA1 sensitized OC cells to cisplatin and that UCA1 acted as competing endogenous RNA to miR-27a-5p. Upon UCA1 downregulation, miR-27a-5p downregulated its direct target UBE2N leading to the upregulation of BIM, a proapoptotic protein of the Bcl2 family. The upregulation of BIM is the event responsible for the sensitization of OC cells to cisplatin. In order to model response to therapy in patients with OC, we used several patient-derived organoid cultures, a model faithfully mimicking patient's response to therapy. Inhibition of UBE2N sensitized patient-derived organoids to platinum salts. In conclusion, response to treatment in patients with OC is regulated by the UCA1/miR-27a-5p/UBE2N axis, where UBE2N inhibition could potentially represent a novel therapeutic strategy to counter chemoresistance in OC.

摘要

卵巢癌 (OC) 是妇科癌症患者死亡的主要原因。由于诊断较晚和对化疗的耐药性，OC 患者的 5 年生存率低于 40%。我们观察到，先前报道在几种恶性肿瘤中发挥致癌作用的 lncRNA UCA1 在耐药 OC 细胞系 OAW42-R 中的表达高于其化疗敏感的对照 OAW42。此外，UCA1 的过表达与两个独立患者队列的不良预后相关。目前，UCA1 在 OC 中发挥作用的分子机制尚不清楚。我们证明下调 UCA1 的短异构体使 OC 细胞对顺铂敏感，并且 UCA1 作为竞争性内源性 RNA 与 miR-27a-5p 相互作用。下调 UCA1 后，miR-27a-5p 下调其直接靶标 UBE2N，导致 Bcl2 家族促凋亡蛋白 BIM 的上调。BIM 的上调是 OC 细胞对顺铂敏感的原因。为了模拟 OC 患者对治疗的反应，我们使用了几种患者来源的类器官培养物，这是一种忠实地模拟患者对治疗反应的模型。UBE2N 的抑制使患者来源的类器官对铂盐敏感。总之，OC 患者对治疗的反应受 UCA1/miR-27a-5p/UBE2N 轴的调节，抑制 UBE2N 可能代表 OC 中对抗化疗耐药性的一种新的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8cdc/8637575/6cb7acacf9bb/MOL2-15-3659-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8cdc/8637575/4dcd11d42b09/MOL2-15-3659-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8cdc/8637575/212a54aeb8fa/MOL2-15-3659-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8cdc/8637575/f594c027c003/MOL2-15-3659-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8cdc/8637575/b2cc321fb65a/MOL2-15-3659-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8cdc/8637575/6cb7acacf9bb/MOL2-15-3659-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8cdc/8637575/4dcd11d42b09/MOL2-15-3659-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8cdc/8637575/e1da48e58c6a/MOL2-15-3659-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8cdc/8637575/212a54aeb8fa/MOL2-15-3659-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8cdc/8637575/8597d2faefbb/MOL2-15-3659-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8cdc/8637575/f594c027c003/MOL2-15-3659-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8cdc/8637575/b2cc321fb65a/MOL2-15-3659-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8cdc/8637575/6cb7acacf9bb/MOL2-15-3659-g005.jpg

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