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环状 RNA PVT1 通过靶向 ESR1 和 MAVS 促进 ER 阳性乳腺癌的发生和耐药性。

CircPVT1 promotes ER-positive breast tumorigenesis and drug resistance by targeting ESR1 and MAVS.

机构信息

Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation Research, The First Affiliated Hospital of Xiamen University, Xiamen, China.

State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China.

出版信息

EMBO J. 2023 May 15;42(10):e112408. doi: 10.15252/embj.2022112408. Epub 2023 Apr 3.

DOI:10.15252/embj.2022112408
PMID:37009655
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10183818/
Abstract

The molecular mechanisms underlying estrogen receptor (ER)-positive breast carcinogenesis and endocrine therapy resistance remain incompletely understood. Here, we report that circPVT1, a circular RNA generated from the lncRNA PVT1, is highly expressed in ERα-positive breast cancer cell lines and tumor samples and is functionally important in promoting ERα-positive breast tumorigenesis and endocrine therapy resistance. CircPVT1 acts as a competing endogenous RNA (ceRNA) to sponge miR-181a-2-3p, promoting the expression of ESR1 and downstream ERα-target genes and breast cancer cell growth. Furthermore, circPVT1 directly interacts with MAVS protein to disrupt the RIGI-MAVS complex formation, inhibiting type I interferon (IFN) signaling pathway and anti-tumor immunity. Anti-sense oligonucleotide (ASO)-targeting circPVT1 inhibits ERα-positive breast cancer cell and tumor growth, re-sensitizing tamoxifen-resistant ERα-positive breast cancer cells to tamoxifen treatment. Taken together, our data demonstrated that circPVT1 can work through both ceRNA and protein scaffolding mechanisms to promote cancer. Thus, circPVT1 may serve as a diagnostic biomarker and therapeutic target for ERα-positive breast cancer in the clinic.

摘要

雌激素受体（ER）阳性乳腺癌发生和内分泌治疗耐药的分子机制仍不完全清楚。在这里，我们报告 circPVT1，一种从长链非编码 RNA PVT1 产生的环状 RNA，在 ERα 阳性乳腺癌细胞系和肿瘤样本中高度表达，并且在促进 ERα 阳性乳腺癌发生和内分泌治疗耐药方面具有重要功能。circPVT1 作为竞争性内源性 RNA（ceRNA）可与 miR-181a-2-3p 结合，促进 ESR1 和下游 ERα 靶基因的表达和乳腺癌细胞的生长。此外，circPVT1 可直接与 MAVS 蛋白相互作用，破坏 RIGI-MAVS 复合物的形成，抑制 I 型干扰素（IFN）信号通路和抗肿瘤免疫。反义寡核苷酸（ASO）靶向 circPVT1 抑制 ERα 阳性乳腺癌细胞和肿瘤的生长，使他莫昔芬耐药的 ERα 阳性乳腺癌细胞对他莫昔芬重新敏感。总之，我们的数据表明，circPVT1 可以通过 ceRNA 和蛋白支架机制共同促进癌症的发生。因此，circPVT1 可能成为临床治疗 ERα 阳性乳腺癌的诊断标志物和治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9b6/10183818/8614081aba70/EMBJ-42-e112408-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9b6/10183818/8614081aba70/EMBJ-42-e112408-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9b6/10183818/b9c0ad26d618/EMBJ-42-e112408-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9b6/10183818/90b06abfc824/EMBJ-42-e112408-g014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9b6/10183818/a04e21609c56/EMBJ-42-e112408-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9b6/10183818/6b8b43bb5c51/EMBJ-42-e112408-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9b6/10183818/a5137aa3b622/EMBJ-42-e112408-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9b6/10183818/8385b9603c83/EMBJ-42-e112408-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9b6/10183818/e821fd22f2c0/EMBJ-42-e112408-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b9b6/10183818/8614081aba70/EMBJ-42-e112408-g007.jpg

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