期刊首页 优先出版 当期阅读 过刊浏览 作者中心 关于期刊 English

《工程(英文)》 >> 2022年 第16卷 第9期 doi: 10.1016/j.eng.2021.07.020

促进肝癌致癌活性和细胞代谢的新型介质——miR-516a-3p

a Department of Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
b Department of Surgery, Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
c Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China

收稿日期: 2020-08-13 修回日期: 2021-06-11 录用日期: 2021-07-26 发布日期: 2021-10-19

下一篇 上一篇

摘要

肝细胞肝癌(HCC)是目前最致命的恶性肿瘤之一。根据先前的研究,19 号染色体miRNA簇(C19MC)与肝癌患者的肿瘤高负荷和不良预后相关。目前的研究旨在探讨miR-516a-3p 在HCC 中的作用。miR-516a-3p 是一种由C19MC 4 个致癌前体miRNA(即mir-516a-1、mir-516a-2、mir-516b-1 和mir-516b-2)所共同剪接而成的相同的成熟体miRNA。在肝癌队列中,与瘤旁组织相比,miR-516a-3p 在肝癌组织中显著高表达。肿瘤miR-516a-3p 的高表达与肝癌高肿瘤负荷相关,可以区分高HCC复发率和死亡率,并独立预测肝癌的不良预后。进一步通过体外实验发现miR-516a-3p 增强了肝癌细胞的增殖、迁移和侵袭性,并通过体内实验验证miR-516a-3p 促进了肿瘤的增殖和远处转移能力。在肝癌细胞中,miR-516a-3p 可以通过外泌体进行递送,并增加受体肝癌细胞的致癌活性。此外,为探索miR-516a-3p 致癌的潜在机制,本研究进行了全面的转录组学、蛋白质组学和代谢组学分析。多组学DIABLO分析显示,蛋白质组学和代谢组学数据之间具有密切的相关性和较强的聚类一致性。进一步证实了6 种基因的mRNA(即LMBR1、CHST9、RBM3、SLC7A6、PTGFRN和NOL12)是miR-516a-3p 的直接靶点,并在miR-516a-3p 介导的代谢调节中发挥核心作用。综合多组学和共富集途径分析表明,miR-516a-3p 可以调节肝癌细胞的代谢途径,特别是嘌呤代谢和嘧啶代谢。总之,本研究发现,miR-516a-3p 可以通过调节细胞代谢和外泌体递送系统
影响相邻细胞,促进肝癌细胞的肿瘤恶性进展。因此,miR-516a-3p可作为肝癌治疗的新分子靶点。

 

图片

图1

图2

图3

图4

图5

图6

参考文献

[ 1 ] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018; 68(1):7‒30. 链接1

[ 2 ] Cronin KA, Lake AJ, Scott S, Sherman RL, Noone AM, Howlader N, et al. Annual report to the nation on the status of cancer, part I: national cancer statistics. Cancer 2018;124(13):2785‒800. 链接1

[ 3 ] Ryder SD. Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults. Gut 2003;52:iii1‒8. 链接1

[ 4 ] Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;389(10064):56‒66. 链接1

[ 5 ] Livraghi T, Meloni F, Di Stasi M, Rolle E, Solbiati L, Tinelli C, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: is resection still the treatment of choice? Hepatology 2008;47(1):82‒9. 链接1

[ 6 ] Bruix J, Sala M, Llovet JM. Chemoembolization for hepatocellular carcinoma. Gastroenterology 2004;127(5 Suppl 1):S179‒88. 链接1

[ 7 ] Sapisochin G, Bruix J. Liver transplantation for hepatocellular carcinoma: outcomes and novel surgical approaches. Nat Rev Gastroenterol Hepatol 2017;14(4):203‒17. 链接1

[ 8 ] Berindan-Neagoe I, Monroig PDC, Pasculli B, Calin GA. MicroRNAome genome: a treasure for cancer diagnosis and therapy. CA Cancer J Clin 2014;64(5): 311‒36. 链接1

[ 9 ] Wang Y, Luo J, Zhang H, Lu J. microRNAs in the same clusters evolve to coordinately regulate functionally related genes. Mol Biol Evol 2016;33(9):2232‒47. 链接1

[10] Kabekkodu SP, Shukla V, Varghese VK, D´Souza J, Chakrabarty S, Satyamoorthy K. Clustered miRNAs and their role in biological functions and diseases. Biol Rev 2018;93(4):1955‒86. 链接1

[11] Gennarino VA, D’Angelo G, Dharmalingam G, Fernandez S, Russolillo G, Sanges R, et al. Identification of microRNA-regulated gene networks by expression analysis of target genes. Genome Res 2012;22(6):1163‒72. 链接1

[12] Pagliuca A, Valvo C, Fabrizi E, di Martino S, Biffoni M, Runci D, et al. Analysis of the combined action of miR-143 and miR-145 on oncogenic pathways in colorectal cancer cells reveals a coordinate program of gene repression. Oncogene 2013;32(40):4806‒13. 链接1

[13] Noguer-Dance M, Abu-Amero S, Al-Khtib M, Lefevre A, Coullin P, Moore GE, et al. The primate-specific microRNA gene cluster (C19MC) is imprinted in the placenta. Hum Mol Genet 2010;19(18):3566‒82. 链接1

[14] Rui T, Xu S, Zhang X, Huang H, Feng S, Zhan S, et al. The chromosome 19 microRNA cluster, regulated by promoter hypomethylation, is associated with tumour burden and poor prognosis in patients with hepatocellular carcinoma. J Cell Physiol 2020;235(9):6103‒12. 链接1

[15] Augello C, Vaira V, Caruso L, Destro A, Maggioni M, Park YN, et al. MicroRNA profiling of hepatocarcinogenesis identifies C19MC cluster as a novel prognostic biomarker in hepatocellular carcinoma. Liver Int 2012;32(5):772‒82. 链接1

[16] Fornari F, Milazzo M, Chieco P, Negrini M, Marasco E, Capranico G, et al. In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2. J Pathol 2012;227(3):275‒85. 链接1

[17] Toffanin S, Hoshida Y, Lachenmayer A, Villanueva A, Cabellos L, Minguez B, et al. MicroRNA-based classification of hepatocellular carcinoma and oncogenic role of miR-517a. Gastroenterology 2011;140(5):1618‒28.e16. 链接1

[18] Mills J, Capece M, Cocucci E, Tessari A, Palmieri D. Cancer-derived extracellular vesicle-associated microRNAs in intercellular communication: one cell’s trash is another cell’s treasure. Int J Mol Sci 2019;20(24):6109. 链接1

[19] Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol 2014;30(1):255‒89. 链接1

[20] Delorme-Axford E, Bayer A, Sadovsky Y, Coyne CB. Autophagy as a mechanism of antiviral defense at the maternal-fetal interface. Autophagy 2013;9(12):2173‒4. 链接1

[21] Delorme-Axford E, Donker RB, Mouillet JF, Chu T, Bayer A, Ouyang Y, et al. Human placental trophoblasts confer viral resistance to recipient cells. Proc Natl Acad Sci USA 2013;110(29):12048‒53. 链接1

[22] Bullerdiek J, Flor I. Exosome-delivered microRNAs of “chromosome 19 microRNA cluster” as immunomodulators in pregnancy and tumorigenesis. Mol Cytogenet 2012;5(1):27. 链接1

[23] Zhang X, Ye P, Huang H, Wang B, Dong F, Ling Q. TCF7L2 rs290487 C allele aberrantly enhances hepatic gluconeogenesis through allele-specific changes in transcription and chromatin binding. Aging 2020;12(13):13365‒87. 链接1

[24] Chong J, Soufan O, Li C, Caraus I, Li S, Bourque G, et al. MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res 2018;46(W1):W486‒94. 链接1

[25] Singh A, Shannon CP, Gautier B, Rohart F, Vacher M, Tebbutt SJ, et al. DIABLO: an integrative approach for identifying key molecular drivers from multi-omics assays. Bioinformatics 2019;35(17):3055‒62. 链接1

[26] Karnovsky A, Weymouth T, Hull T, Tarcea VG, Scardoni G, Laudanna C, et al. Metscape 2 bioinformatics tool for the analysis and visualization of metabolomics and gene expression data. Bioinformatics 2012;28(3):373‒80. 链接1

[27] Rui T, Zhang X, Feng S, Huang H, Zhan S, Xie H, et al. The similar effects of miR-512-3p and miR-519a-2-5p on the promotion of hepatocellular carcinoma: different tunes sung with equal skill. Front Oncol 2020;10:1244. 链接1

[28] Meunier J, Lemoine F, Soumillon M, Liechti A, Weier M, Guschanski K, et al. Birth and expression evolution of mammalian microRNA genes. Genome Res 2013;23(1):34‒45. 链接1

[29] Heusermann W, Hean J, Trojer D, Steib E, von Bueren S, Graff-Meyer A, et al. Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER. J Cell Biol 2016;213(2):173‒84. 链接1

[30] Tian T, Wang Y, Wang H, Zhu Z, Xiao Z. Visualizing of the cellular uptake and intracellular trafficking of exosomes by live-cell microscopy. J Cell Biochem 2010;111(2):488‒96. 链接1

[31] Tseng LL, Lin CL, Tzen KY, Chang SC, Chang MF. LMBD1 protein serves as a specific adaptor for insulin receptor internalization. J Biol Chem 2013;288(45):32424‒32. 链接1

[32] Shi H, Yao R, Lian S, Liu P, Liu Y, Yang YY, et al. Regulating glycolysis, the TLR4 signal pathway and expression of RBM3 in mouse liver in response to acute cold exposure. Stress 2019;22(3):366‒76. 链接1

[33] Orlicky DJ, Lieber JG, Morin CL, Evans RM. Synthesis and accumulation of a receptor regulatory protein associated with lipid droplet accumulation in 3T3-L1 cells. J Lipid Res 1998;39(6):1152‒61. 链接1

[34] Scott DD, Trahan C, Zindy PJ, Aguilar LC, Delubac MY, Van Nostrand EL, et al. Nol12 is a multifunctional RNA binding protein at the nexus of RNA and DNA metabolism. Nucleic Acids Res 2017;45(21):12509‒28. 链接1

[35] Liu P, Ge M, Hu J, Li X, Che L, Sun K, et al. A functional mammalian target of rapamycin complex 1 signaling is indispensable for c-Myc-driven hepatocarcinogenesis. Hepatology 2017;66(1):167‒81. 链接1

[36] Vander Heiden MG, DeBerardinis RJ. Understanding the intersections between metabolism and cancer biology. Cell 2017;168(4):657‒69. 链接1

[37] Villa E, Ali ES, Sahu U, Ben-Sahra I. Cancer cells tune the signaling pathways to empower de novo synthesis of nucleotides. Cancers 2019;11(5):688. 链接1

[38] Yin J, Ren W, Huang X, Deng J, Li T, Yin Y. Potential mechanisms connecting purine metabolism and cancer therapy. Front Immunol 2018;9:1697. 链接1

[39] Ma F, Zhu Y, Liu X, Zhou Q, Hong X, Qu C, et al. Dual-specificity tyrosine phosphorylation-regulated kinase 3 loss activates purine metabolism and promotes hepatocellular carcinoma progression. Hepatology 2019;‍70(5):1785‒803. 链接1

[40] Santana-Codina N, Roeth AA, Zhang Yi, Yang A, Mashadova O, Asara JM, et al. Oncogenic KRAS supports pancreatic cancer through regulation of nucleotidesynthesis. Nat Commun 2018;9(1):4945. 链接1

[41] Feng X, Ma D, Zhao J, Song Y, Zhu Y, Zhou Q, et al. UHMK1 promotes gastric cancer progression through reprogramming nucleotide metabolism. Embo J 2020;39(5):e102541. 链接1

[42] Newman AC, Maddocks ODK. One-carbon metabolism in cancer. Br J Cancer 2017;116(12):1499‒504. 链接1

[43] Ribbenstedt A, Ziarrusta H, Benskin JP, Schopfer FJ. Development, characterization and comparisons of targeted and non-targeted metabolomics methods. PLoS ONE 2018;13(11):e0207082. 链接1

[44] Piazza I, Kochanowski K, Cappelletti V, Fuhrer T, Noor E, Sauer U, et al. A map of protein-metabolite interactions reveals principles of chemical communication. Cell 2018;172(1‒2):358‒72.e23.

相关研究