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On-line Access: 2023-01-10

Received: 2022-04-18

Revision Accepted: 2022-08-19

Crosschecked: 2023-01-16

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 ORCID:

Ye Chen

https://orcid.org/0000-0003-3671-2504

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Journal of Zhejiang University SCIENCE B 2023 Vol.24 No.1 P.50-63

http://doi.org/10.1631/jzus.B2200224


Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways


Author(s):  Qiong ZHAO, Luwen ZHANG, Qiufen HE, Hui CHANG, Zhiqiang WANG, Hongcui CAO, Ying ZHOU, Ruolang PAN, Ye CHEN

Affiliation(s):  Department of Genetics, and Department of Genetic and Metabolic Disease, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; more

Corresponding email(s):   yechency@zju.edu.cn, panrl@zju.edu.cn

Key Words:  Transfer RNA (tRNA), tRNA methyltransferase 5 (TRMT5), Hepatocellular carcinoma (HCC), Hypoxia-inducible factor-1α, (HIF-1α, )


Qiong ZHAO, Luwen ZHANG, Qiufen HE, Hui CHANG, Zhiqiang WANG, Hongcui CAO, Ying ZHOU, Ruolang PAN, Ye CHEN. Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways[J]. Journal of Zhejiang University Science B, 2023, 24(1): 50-63.

@article{title="Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways",
author="Qiong ZHAO, Luwen ZHANG, Qiufen HE, Hui CHANG, Zhiqiang WANG, Hongcui CAO, Ying ZHOU, Ruolang PAN, Ye CHEN",
journal="Journal of Zhejiang University Science B",
volume="24",
number="1",
pages="50-63",
year="2023",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2200224"
}

%0 Journal Article
%T Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways
%A Qiong ZHAO
%A Luwen ZHANG
%A Qiufen HE
%A Hui CHANG
%A Zhiqiang WANG
%A Hongcui CAO
%A Ying ZHOU
%A Ruolang PAN
%A Ye CHEN
%J Journal of Zhejiang University SCIENCE B
%V 24
%N 1
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%@ 1673-1581
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%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2200224

TY - JOUR
T1 - Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways
A1 - Qiong ZHAO
A1 - Luwen ZHANG
A1 - Qiufen HE
A1 - Hui CHANG
A1 - Zhiqiang WANG
A1 - Hongcui CAO
A1 - Ying ZHOU
A1 - Ruolang PAN
A1 - Ye CHEN
J0 - Journal of Zhejiang University Science B
VL - 24
IS - 1
SP - 50
EP - 63
%@ 1673-1581
Y1 - 2023
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2200224


Abstract: 
Accumulating evidence has confirmed the links between )%29&ck%5B%5D=abstract&ck%5B%5D=keyword'>transfer RNA (tRNA) modifications and tumor progression. The present study is the first to explore the role of )%29&ck%5B%5D=abstract&ck%5B%5D=keyword'>tRNA methyltransferase 5 (TRMT5), which catalyzes the m1G37 modification of mitochondrial tRNAs in )%29&ck%5B%5D=abstract&ck%5B%5D=keyword'>hepatocellular carcinoma (HCC) progression. Here, based on bioinformatics and clinical analyses, we identified that TRMT5 expression was upregulated in HCC, which correlated with poor prognosis. Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro, which may be partially explained by declined extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Mechanistically, we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1 (HIF-1) signaling pathway by preventing HIF-1α stability through the enhancement of cellular oxygen content. Moreover, our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-‍1α. In conclusion, our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs. Thus, TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.

靶向TRMT5抑制HIF-1α信号通路调控肝癌进程

赵琼1,2,张璐雯1,2,何秋芬1,2,常慧1,2,王志强1,2,曹红翠3,周颖4,潘若浪5,陈烨1,2
1浙江大学医学院附属儿童医院遗传代谢科,国家儿童健康临床医学研究中心,中国杭州市,310052
2浙江省遗传缺陷与发育障碍研究重点实验室,浙江大学遗传研究所,中国杭州市,310058
3传染病诊治国家重点实验室,国家感染性疾病临床医学研究中心,浙江大学医学院附属第一医院,中国杭州市,310003
4象山县中医医院医疗健康集团,中国宁波市,315700
5浙江省细胞药物与应用技术研究重点实验室,中国杭州市,311121
概要:越来越多研究表明转运RNA(tRNA)修饰与肿瘤进程有关。本研究首次探索了线粒体tRNA G37位甲基化修饰酶TRMT5(tRNA甲基转移酶5)在肝细胞癌发生发展中的作用。生物信息学和临床分析发现TRMT5在肝癌组织中高表达且与预后不良相关。体内外实验表明TRMT5敲低可诱导肝癌细胞代谢重编程,减弱肝癌细胞的增殖和转移能力。进一步研究发现TRMT5敲低降低了肝癌细胞内缺氧诱导因子1α(HIF-1α)的稳定性,进而抑制肝癌细胞生长与转移。此外,TRMT5敲低还导致肝癌细胞对阿霉素的敏感性增加。综上所述,本研究表明靶向TRMT5可以抑制肝癌进程并提升肝癌细胞对化疗药物的敏感性。因此,TRMT5是一个新的致癌候选基因,可以作为肝癌治疗的潜在靶点。

关键词:转运RNA(tRNA);tRNA甲基转移酶5(TRMT5);肝细胞癌;缺氧诱导因子1α(HIF-1α)

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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