CLC number:
On-line Access: 2023-01-10
Received: 2022-04-18
Revision Accepted: 2022-08-19
Crosschecked: 2023-01-16
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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,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2200224 @article{title="Targeting TRMT5 suppresses hepatocellular carcinoma progression via inhibiting the HIF-1α pathways", %0 Journal Article TY - JOUR
靶向TRMT5抑制HIF-1α信号通路调控肝癌进程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。 关键词组: Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article
Reference[1]AkulaSM, AbramsSL, SteelmanLS, et al., 2019. RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1 and TP53 pathways and regulatory miRs as therapeutic targets in hepatocellular carcinoma. Expert Opin Ther Targets, 23(11):915-929. [2]ArnasonT, HarknessT, 2015. Development, maintenance, and reversal of multiple drug resistance: at the crossroads of TFPI1, ABC transporters, and HIF1. Cancers (Basel), 7(4):2063-2082. [3]BarbieriI, KouzaridesT, 2020. Role of RNA modifications in cancer. Nat Rev Cancer, 20(6):303-322. [4]BergmanPJ, 2019. Cancer immunotherapies. Vet Clin North Am: Small Anim Pract, 49(5):881-902. [5]BlatchleyMR, HallF, WangSN, et al., 2019. Hypoxia and matrix viscoelasticity sequentially regulate endothelial progenitor cluster-based vasculogenesis. Sci Adv, 5(3):eaau7518. [6]BowyerC, LewisAL, LloydAW, et al., 2017. Hypoxia as a target for drug combination therapy of liver cancer. Anti-Cancer Drugs, 28(7):771-780. [7]ChristianT, GamperH, HouYM, 2013. Conservation of structure and mechanism by Trm5 enzymes. RNA, 19(9):1192-1199. [8]ChunYS, KimMS, ParkJW, 2002. Oxygen-dependent and -independent regulation of HIF-1alpha. J Korean Med Sci, 17(5):581-588. [9]DimriM, SatyanarayanaA, 2020. Molecular signaling pathways and therapeutic targets in hepatocellular carcinoma. Cancers (Basel), 12(2):491. [10]DoegeK, HeineS, JensenI, et al., 2005. Inhibition of mitochondrial respiration elevates oxygen concentration but leaves regulation of hypoxia-inducible factor (HIF) intact. Blood, 106(7):2311-2317. [11]EllinghausP, HeislerI, UnterschemmannK, et al., 2013. BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I. Cancer Med, 2(5):611-624. [12]EndresL, FasulloM, RoseR, 2019. tRNA modification and cancer: potential for therapeutic prevention and intervention. Future Med Chem, 11(8):885-900. [13]FornerA, LlovetJM, BruixJ, 2012. Hepatocellular carcinoma. Lancet, 379(9822):1245-1255. [14]GiraudJ, ChalopinD, BlancJF, et al., 2021. Hepatocellular carcinoma immune landscape and the potential of immunotherapies. Front Immunol, 12:655697. [15]HeQH, YangL, GaoKP, et al., 2020. FTSJ1 regulates tRNA 2'-O-methyladenosine modification and suppresses the malignancy of NSCLC via inhibiting DRAM1 expression. Cell Death Dis, 11(5):348. [16]JiJF, WangXW, 2012. Clinical implications of cancer stem cell biology in hepatocellular carcinoma. Semin Oncol, 39(4):461-472. [17]KeQD, CostaM, 2006. Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol, 70(5):1469-1480. [18]KingGT, SharmaP, DaviesSL, et al., 2018. Immune and autoimmune-related adverse events associated with immune checkpoint inhibitors in cancer therapy. Drugs Today (Barc), 54(2):103-122. [19]KirchnerS, IgnatovaZ, 2015. Emerging roles of tRNA in adaptive translation, signalling dynamics and disease. Nat Rev Genet, 16(2):98-112. [20]LiM, SuYD, GaoXY, et al., 2022. Transition of autophagy and apoptosis in fibroblasts depends on dominant expression of HIF-1α or p53. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 23(3):204-217. [21]LiuXF, QinSK, 2019. Immune checkpoint inhibitors in hepatocellular carcinoma: opportunities and challenges. Oncologist, 24(S1):S3-S10. [22]LuoDJ, WangZX, WuJY, et al., 2014. The role of hypoxia inducible factor-1 in hepatocellular carcinoma. Biomed Res Int, 2014:409272. [23]MaJ, HanH, HuangY, et al., 2021. METTL1/WDR4-mediated m7G tRNA modifications and m7G codon usage promote mRNA translation and lung cancer progression. Mol Ther, 29(12):3422-3435. [24]MasoudGN, LiW, 2015. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B, 5(5):378-389. [25]McCubreyJA, RakusD, GizakA, et al., 2016. Effects of mutations in Wnt/β-catenin, hedgehog, notch and PI3K pathways on GSK-3 activity-diverse effects on cell growth, metabolism and cancer. Biochim Biophys Acta (BBA)-Mol Cell Res, 1863(12):2942-2976. [26]Méndez-BlancoC, FondevilaF, Fernández-PalancaP, et al., 2019. Stabilization of hypoxia-inducible factors and BNIP3 promoter methylation contribute to acquired sorafenib resistance in human hepatocarcinoma cells. Cancers (Basel), 11(12):1984. [27]PowellCA, KopajtichR, D'SouzaAR, et al., 2015. TRMT5 mutations cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am J Hum Genet, 97(2):319-328. [28]Prieto-DomínguezN, Méndez-BlancoC, Carbajo-PescadorS, et al., 2017. Melatonin enhances sorafenib actions in human hepatocarcinoma cells by inhibiting mTORC1/p70S6K/HIF-1α and hypoxia-mediated mitophagy. Oncotarget, 8(53):91402-91414. [29]Rosselló-TortellaM, Llinàs-AriasP, SakaguchiY, et al., 2020. Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer. Proc Natl Acad Sci USA, 117(34):20785-20793. [30]SuzukiT, 2021. The expanding world of tRNA modifications and their disease relevance. Nat Rev Mol Cell Biol, 22(6):375-392. [31]SuzukiT, NagaoA, SuzukiT, 2011. Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases. Annu Rev Genet, 45:299-329. [32]UrtasunRC, KochCJ, FrankoAJ, et al., 1986. A novel technique for measuring human tissue pO2 at the cellular level. Br J Cancer, 54(3):453-457. [33]VadlapatlaRK, VadlapudiAD, MitraAK, 2013. Hypoxia-inducible factor-1 (HIF-1): a potential target for intervention in ocular neovascular diseases. Curr Drug Targets, 14(8):919-935. [34]WardC, LangdonSP, MullenP, et al., 2013. New strategies for targeting the hypoxic tumour microenvironment in breast cancer. Cancer Treat Rev, 39(2):171-179. [35]WheatonWW, WeinbergSE, HamanakaRB, et al., 2014. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife, 3:e02242. [36]WingD, 2020. Characterisation of RNA Modifications in Human Cancer Cells. PhD Dissemination, University of Cambridge, Cambridge, UK. [37]WuQ, YangZP, NieYZ, et al., 2014. Multi-drug resistance in cancer chemotherapeutics: mechanisms and lab approaches. Cancer Lett, 347(2):159-166. [38]YamamotoT, FujimuraA, WeiFY, et al., 2019. 2-Methylthio conversion of N6-isopentenyladenosine in mitochondrial trnas by CDK5RAP1 promotes the maintenance of glioma-initiating cells. iScience, 21:42-56. [39]YanX, QuX, LiuB, et al., 2021. Autophagy-induced HDAC6 activity during hypoxia regulates mitochondrial energy metabolism through the β-catenin/COUP-TFII axis in hepatocellular carcinoma cells. Front Oncol, 11:742460. [40]YangY, ZhangGM, GuoFZ, et al., 2020. Mitochondrial UQCC3 modulates hypoxia adaptation by orchestrating OXPHOS and glycolysis in hepatocellular carcinoma. Cell Rep, 33(5):108340. [41]YoestJM, 2017. Clinical features, predictive correlates, and pathophysiology of immune-related adverse events in immune checkpoint inhibitor treatments in cancer: a short review. Immunotargets Ther, 6:73-82. [42]ZhongC, LiYR, YangJ, et al., 2021. Immunotherapy for hepatocellular carcinoma: current limits and prospects. Front Oncol, 11:589680. [43]ZuoQZ, HeJ, ZhangS, et al., 2021. PPARγ coactivator-1α suppresses metastasis of hepatocellular carcinoma by inhibiting warburg effect by PPARγ-dependent WNT/β-catenin/pyruvate dehydrogenase kinase isozyme 1 axis. Hepatology, 73(2):644-660. Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou
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