Long Non-coding RNA ITIH4-AS1 Accelerates the Proliferation and Metastasis of Colorectal Cancer by Activating JAK/STAT3 Signaling

Accumulating evidence has uncovered long non-coding RNAs (lncRNAs) as central regulators in the pathogenesis of diverse human cancers including colorectal cancer (CRC). The present study discovered that a novel lncRNA ITIH4 antisense RNA 1 (ITIH4-AS1) was frequently under-expressed in most normal hu...

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Published in:Molecular therapy. Nucleic acids 2019-12, Vol.18, p.183-193
Main Authors: Liang, Chaojie, Zhao, Tuanjie, Li, Haijun, He, Fucheng, Zhao, Xin, Zhang, Yuan, Chu, Xi, Hua, Chunlan, Qu, Yunhui, Duan, Yu, Ming, Liang, Guo, Jiansheng
Format: Article
Language:English
Subjects:
Antisense RNA
Antitumor activity
Apoptosis
Bioinformatics
Cell adhesion & migration
Cell growth
Colorectal cancer
Colorectal carcinoma
Experiments
FUS
Gene amplification
Gene silencing
ITIH4-AS1
Laboratory animals
Liver
Medical diagnosis
Metastases
Metastasis
Non-coding RNA
Nuclear transport
R&D
Research & development
REST
STAT3
Stat3 protein
Transcription factors
Tumorigenesis
Tumors
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Summary:Accumulating evidence has uncovered long non-coding RNAs (lncRNAs) as central regulators in the pathogenesis of diverse human cancers including colorectal cancer (CRC). The present study discovered that a novel lncRNA ITIH4 antisense RNA 1 (ITIH4-AS1) was frequently under-expressed in most normal human tissues, including colon tissues. Therefore, we aimed to investigate the role of ITIH4-AS1 in CRC. Interestingly, a significant overexpression of ITIH4-AS1 was observed in CRC cell lines relative to normal NCM460 cells. Also, we investigated the facilitating role of ITIH4-AS1 in CRC cell growth and metastasis both in vitro and in vivo. Additionally, we explained that ITIH4-AS1 upregulation in CRC was attributed to downregulation or even depletion of RE1 silencing transcription factor (REST), a presently identified transcriptional repressor for ITIH4-AS1. Meanwhile, the contribution of ITIH4-AS1 to CRC development was validated to rely on the activation of the JAK/STAT3 pathway. More importantly, we verified that FUS interacted with both ITIH4-AS1 and STAT3, and that ITIH4-AS1 evoked nuclear translocation of phosphorylated (p)-STAT3 in CRC through recruiting FUS. In summary, our findings unveiled for the first time that upregulation of ITIH4-AS1 induced by the downregulated REST exerts pro-tumor functions in CRC through FUS-dependent activation of the JAK/STAT3 pathway, implying that targeting ITIH4-AS1 may be a novel effective strategy for CRC therapy.
ISSN:2162-2531
2162-2531
DOI:10.1016/j.omtn.2019.08.009