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长链非编码RNA USP2-AS1通过在缺氧条件下增强YBX1介导的HIF1α蛋白翻译促进肝细胞癌生长。

LncRNA USP2-AS1 Promotes Hepatocellular Carcinoma Growth by Enhancing YBX1-Mediated HIF1α Protein Translation Under Hypoxia.

作者信息

Chen Shi-Ping, Zhu Gui-Qi, Xing Xiao-Xia, Wan Jing-Lei, Cai Jia-Liang, Du Jun-Xian, Song Li-Na, Dai Zhi, Zhou Jian

机构信息

Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Shanghai, China.

Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China.

出版信息

Front Oncol. 2022 May 25;12:882372. doi: 10.3389/fonc.2022.882372. eCollection 2022.

DOI:10.3389/fonc.2022.882372
PMID:35692750
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9174509/
Abstract

Recently, the role of lncRNAs in tumorigenesis and development has received increasing attention, but the mechanism underlying lncRNAs-mediated tumor growth in the hypoxic microenvironment of solid tumors remains obscure. Using RNA sequencing, 25 hypoxia-related lncRNAs were found to be upregulated in HCC, of which lncRNA USP2-AS1 were significantly increased under hypoxia. We further confirmed that USP2-AS1 was significantly upregulated in liver cancer using FISH assay and that USP2-AS1 was associated with advanced liver cancer and increased tumor size. Furthermore, overexpression of USP2-AS1 under hypoxia dramatically increased HCC proliferation and clone formation, whereas the opposite results were observed after USP2-AS1 knockdown. We also found that overexpression of USP2-AS1 increased migration and invasion of HCC cells, while USP2-AS1 knockdown led to the opposite effect. In addition, USP2-AS1 knockdown can increase the efficacy of lenvatinib in our mice tumor xenograft model. Our findings also suggest that USP2-AS1 could increase the protein level of HIF1α by enhancing YBX1 protein binding to HIF1α mRNA under hypoxia and the therapeutic effect of lenvatinib can be enhanced by combination with HIF1α inhibitors in liver cancer.

摘要

最近，长链非编码RNA（lncRNAs）在肿瘤发生和发展中的作用受到越来越多的关注，但lncRNAs在实体瘤缺氧微环境中介导肿瘤生长的机制仍不清楚。通过RNA测序，发现25种缺氧相关lncRNAs在肝癌中上调，其中lncRNA USP2-AS1在缺氧条件下显著增加。我们进一步使用荧光原位杂交（FISH）检测证实USP2-AS1在肝癌中显著上调，且USP2-AS1与晚期肝癌及肿瘤大小增加有关。此外，缺氧条件下USP2-AS1的过表达显著增加肝癌细胞的增殖和克隆形成，而USP2-AS1敲低后则观察到相反的结果。我们还发现USP2-AS1的过表达增加肝癌细胞的迁移和侵袭，而USP2-AS1敲低则产生相反的效果。此外，在我们的小鼠肿瘤异种移植模型中，USP2-AS1敲低可提高乐伐替尼的疗效。我们的研究结果还表明，USP2-AS1在缺氧条件下可通过增强YBX1蛋白与HIF1α mRNA的结合来增加HIF1α的蛋白水平，并且在肝癌中联合使用HIF1α抑制剂可增强乐伐替尼的治疗效果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ef/9174509/20cb59430be4/fonc-12-882372-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ef/9174509/085fa6727ca0/fonc-12-882372-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ef/9174509/27fed24ce7b2/fonc-12-882372-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ef/9174509/773401f15a22/fonc-12-882372-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ef/9174509/ee303ad4b437/fonc-12-882372-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ef/9174509/4923a6738e68/fonc-12-882372-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ef/9174509/20cb59430be4/fonc-12-882372-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ef/9174509/085fa6727ca0/fonc-12-882372-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ef/9174509/27fed24ce7b2/fonc-12-882372-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ef/9174509/773401f15a22/fonc-12-882372-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/21ef/9174509/20cb59430be4/fonc-12-882372-g006.jpg

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