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RNA‐binding protein Trx regulates alternative splicing and promotes metastasis of HCC via interacting with LINC00152

RNA剪接 转移 基因敲除 癌症研究 选择性拼接 生物 转录组 下调和上调 长非编码RNA RNA结合蛋白 PI3K/AKT/mTOR通路 蛋白激酶B 核糖核酸 医学 细胞生物学 基因 信使核糖核酸 基因表达 信号转导 遗传学 癌症
作者
Xiangnan Teng,Jin Shang,Lingyao Du,Weiwei Huang,Yonghong Wang,Miao Liu,Yuanji Ma,Ming Wang,Hong Tang,Lang Bai
出处
期刊:Journal of Gastroenterology and Hepatology [Wiley]
标识
DOI:10.1111/jgh.16735
摘要

Abstract Background Epithelial‐mesenchymal transition (EMT) is central to HCC metastasis, in which RNA‐binding proteins (RBPs) play a key role. Methods To explore the role of RBPs in metastasis of hepatocellular carcinoma (HCC), whole transcriptome sequencing was conducted to identify differential RBPs between HCC with metastasis and HCC without metastasis. The influence of RBPs on metastasis of HCC was verified by in vitro and in vivo experiments. The interaction of RBPs with non‐coding RNAs was evaluated by RNA immunoprecipitation and pull‐down assays. RNA sequencing, whole‐genome sequencing, and alternative splicing analysis were further performed to clarify post‐transcriptional regulation mechanisms. Results Whole transcriptome sequencing results showed that expression of thioredoxin (Trx) was significantly upregulated in HCC patients with metastasis. Trx was also found to be associated with poor prognosis in HCC patients. Overexpression of Trx could promote migration and invasion of HCC cells in vitro and increase the rate of lung metastasis of HCC cells in vivo . Moreover, binding assays showed that Trx could bind to LINC00152. As a result, LINC00152 was verified to determine the pro‐metastasis function of Trx by knockdown assay. Furthermore, we revealed that Trx could regulate metastasis‐associated alternative splicing program. Specifically, angiopoietin 1 (ANGPT1) was the splicing target; the splicing isoform switching of ANGPT1 could activate the PI3K–Akt pathway, upregulate EMT‐associated proteins, and promote migration and invasion of HCC cells. Conclusions We found that Trx could interact with LINC00152 and promote HCC metastasis via regulating alternative splicing, indicating that Trx may serve as a novel therapeutic target for HCC treatment.
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