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长链非编码 RNA GATA3-AS1 通过稳定 PD-L1 并破坏 GATA3 促进三阴性乳腺癌的肿瘤进展和免疫逃逸。

LncRNA GATA3-AS1 facilitates tumour progression and immune escape in triple-negative breast cancer through destabilization of GATA3 but stabilization of PD-L1.

机构信息

Department of Breast Surgery, Harbin Medical University Cancer Hospital, Harbin, China.

Department of Internal Neurology, The First Hospital of Suihua City, Suihua, China.

出版信息

Cell Prolif. 2020 Sep;53(9):e12855. doi: 10.1111/cpr.12855. Epub 2020 Jul 20.

DOI:10.1111/cpr.12855
PMID:32687248
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7507373/
Abstract

OBJECTIVES

Long non-coding RNAs (lncRNAs) have been demonstrated as crucial regulators in cancer, but whether they are involved in the immune response of cancer cells remains largely undiscovered. GATA3-AS1 is a novel lncRNA that was upregulated in breast cancer (BC) according to online databases. However, its role in triple-negative breast cancer (TNBC) was elusive.

METHODS

GATA3-AS1 expression in BC tissues and adjacent normal tissues was obtained from online databases. Loss-of-function assays were designed and conducted to verify the functional role of GATA3-AS1 in TNBC cells. Bioinformatic analysis and mechanism experiments were applied to explore the downstream molecular mechanism of GATA3-AS1. Similarly, the upstream mechanism which led to the upregulation of GATA3-AS1 in TNBC cells was also investigated.

RESULTS

GATA3-AS1 was markedly overexpressed in TNBC tissues and cells. Knockdown of GATA3-AS1 suppressed TNBC cell growth and enhanced the resistance of TNBC cells to immune response. GATA3-AS1 induced the deubiquitination of PD-L1 through miR-676-3p/COPS5 axis. GATA3-AS1 destabilized GATA3 protein by promoting GATA3 ubiquitination.

CONCLUSION

GATA3-AS1 contributed to TNBC progression and immune evasion through stabilizing PD-L1 protein and degrading GATA3 protein, offering a new target for the treatment of TNBC.

摘要

目的

长链非编码 RNA（lncRNA）已被证明是癌症中的重要调控因子，但它们是否参与癌细胞的免疫反应在很大程度上尚未被发现。GATA3-AS1 是一种新型 lncRNA，根据在线数据库，其在乳腺癌（BC）中上调。然而，其在三阴性乳腺癌（TNBC）中的作用尚不清楚。

方法

从在线数据库中获取 BC 组织和相邻正常组织中的 GATA3-AS1 表达。设计并进行了功能丧失实验，以验证 GATA3-AS1 在 TNBC 细胞中的功能作用。应用生物信息学分析和机制实验来探索 GATA3-AS1 的下游分子机制。同样，也研究了导致 TNBC 细胞中 GATA3-AS1 上调的上游机制。

结果

GATA3-AS1 在 TNBC 组织和细胞中明显过表达。敲低 GATA3-AS1 抑制了 TNBC 细胞的生长，并增强了 TNBC 细胞对免疫反应的抵抗力。GATA3-AS1 通过 miR-676-3p/COPS5 轴诱导 PD-L1 的去泛素化。GATA3-AS1 通过促进 GATA3 泛素化来稳定 GATA3 蛋白。

结论

GATA3-AS1 通过稳定 PD-L1 蛋白和降解 GATA3 蛋白促进 TNBC 的进展和免疫逃逸，为 TNBC 的治疗提供了新的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/44b9ebdc2fd6/CPR-53-e12855-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/82d6f71bfdba/CPR-53-e12855-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/044e82c42b9d/CPR-53-e12855-g002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/73d883ba4def/CPR-53-e12855-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/54495abd5f10/CPR-53-e12855-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/9886973da911/CPR-53-e12855-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/1be4994c9fee/CPR-53-e12855-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/44b9ebdc2fd6/CPR-53-e12855-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/82d6f71bfdba/CPR-53-e12855-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/044e82c42b9d/CPR-53-e12855-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/1605a3ee5992/CPR-53-e12855-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/73d883ba4def/CPR-53-e12855-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/54495abd5f10/CPR-53-e12855-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/9886973da911/CPR-53-e12855-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/1be4994c9fee/CPR-53-e12855-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b5f4/7507373/44b9ebdc2fd6/CPR-53-e12855-g008.jpg

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