A Specific TRNA Half, 5'tiRNA-His-GTG, Responds to Hypoxia Via the HIF1α/ANG Axis and Promotes Colorectal Cancer Progression by Regulating LATS2

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2021 Feb 16

PMID 33588913

Citations 63

Authors

En-Wei Tao

Hao-Lian Wang

Wing Yin Cheng

Qian-Qian Liu

Ying-Xuan Chen

Qin-Yan Gao

Affiliations

Soon will be listed here.

Abstract

Background: Currently, tRNA-derived small RNAs (tsRNAs) are recognized as a novel and potential type of non-coding RNAs (ncRNAs), which participate in various cellular processes and play an essential role in cancer progression. However, tsRNAs involvement in colorectal cancer (CRC) progression remains unclear.

Methods: Sequencing analyses were performed to explore the tsRNAs with differential expression in CRC. Gain- and loss-of functions of 5'tiRNA-His-GTG were performed in CRC cells and xenograft tumor to discover its role in the progression of CRC. Hypoxia culture and hypoxia inducible factor 1 subunit alpha (HIF1α) inhibitors were performed to uncover the biogenesis of 5'tiRNA-His-GTG. The regulation of 5'tiRNA-His-GTG for large tumor suppressor kinase 2 (LATS2) were identified by luciferase reporter assay, western blot, and rescue experiments.

Results: Here, our study uncovered the profile of tsRNAs in human CRC tissues and confirmed a specific tRNA half, 5'tiRNA-His-GTG, is upregulated in CRC tissues. Then, in vitro and in vivo experiments revealed the oncogenic role of 5'tiRNA-His-GTG in CRC and found that targeting 5'tiRNA-His-GTG can induce cell apoptosis. Mechanistically, the generation of 5'tiRNA-His-GTG seems to be a responsive process of tumor hypoxic microenvironment, and it is regulated via the HIF1α/angiogenin (ANG) axis. Remarkably, LATS2 was found to be an important and major target of 5'tiRNA-His-GTG, which renders 5'tiRNA-His-GTG to "turn off" hippo signaling pathway and finally promotes the expression of pro-proliferation and anti-apoptosis related genes.

Conclusions: In summary, the findings revealed a specific 5'tiRNA-His-GTG-engaged pathway in CRC progression and provided clues to design a novel therapeutic target in CRC.

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