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N6-甲基腺苷在肝细胞癌发生发展中的作用

马可 赵礼金

引用本文:
Citation:

N6-甲基腺苷在肝细胞癌发生发展中的作用

DOI: 10.3969/j.issn.1001-5256.2021.09.042
基金项目: 

国家自然科学基金 (81960125)

贵州省教育厅创新群体重大研究项目 (Qian Jiao He KY Zi〔2016〕039)

利益冲突声明:所有作者均声明不存在利益冲突。
作者贡献声明:马可负责课题设计,资料分析,撰写论文;赵礼金负责拟定写作思路,指导文章的撰写并最后定稿。
详细信息
    通信作者:

    赵礼金,zhaolijin66@sina.com

  • 中图分类号: R735.7

Role of N6-methyladenosine in the development and progression of hepatocellular carcinoma

Research funding: 

National Natural Science Foundation of China (81960125);

Major Research Projects of Innovative Groups of Guizhou Provincial Department of Education (Qian Jiao He KY Zi〔2016〕039)

  • 摘要: 肝细胞癌是原发性肝癌中最为常见的一种类型,具有较高的发病率和死亡率。N6-甲基腺苷(m6A)的异常修饰将会促进肝细胞癌的发生与发展。叙述了m6A的结构与功能并总结了决定m6A功能的甲基化酶复合物,包括甲基转移酶(编辑器)、去甲基酶(消码器)和m6A结合蛋白(读码器)在肝细胞癌中的作用机制。认为需要更深入的研究阐明甲基化酶复合物在肝细胞癌中作用的多样性和特异性,以期使之成为预防和治疗肝细胞癌的新靶点。

     

  • 表  1  m6A调节因子在HCC中的作用及机制

    调节因子 作用 机制 参考文献
    METTL3 促进HCC发生与发展 抑制SOCS2的表达促进HCC细胞的增殖和迁移 [21]
    增加LINC00958的表达抑制miR-3619-5p,导致HDGF表达上调,促进HCC中的脂肪形成 [23]
    与DGCR8结合,通过上调miR-873-5p抑制SMG1的表达 [24]
    抑制HCC发展和转移 UBC9诱导METTL3泛素化使其活性降低,导致snail mRNA的稳定性增加 [22]
    增加HCC对索拉非尼的敏感性 上调FOXO3抑制自噬的发生 [25]
    WTAP 促进HCC发展 抑制ETS1与HUR结合导致ETS1降解,促进HCC细胞增殖 [27]
    KIAA1429 促进HCC发展 抑制GATA3的表达促进HCC的增殖和转移 [28]
    抑制ID2的表达促进HCC的迁移和侵袭 [29]
    METTL14 抑制HCC发展 通过DGCR8促进pri-miRNA-126成熟,抑制HCC的转移 [30]
    ALKBH5 抑制HCC发生与发展 下调LYPD1的表达抑制HCC细胞的增殖和侵袭 [37]
    FTO 促进HCC发展 通过增加PKM2的表达促进HCC细胞增殖 [35]
    抑制HCC发展 下调CUL4A的表达抑制HCC的细胞增殖 [38]
    FTO降低导致GNAO1表达下降 [39]
    YTHDF1 促进HCC发展 激活FZD5/WNT/β-catenin信号通路促进HCC细胞的增殖、迁移和侵袭 [19]
    促进snail的表达,诱导上皮-间充质转化的发生 [41]
    YTHDF2 促进HCC肺转移 促进OCT4的表达,进而增加HCC干细胞表型,促进HCC肺转移 [42]
    抑制HCC发展 抑制HCC的炎症、血管重建和转移 [44]
    下调EGFR的表达抑制HCC细胞的增殖 [45]
    下载: 导出CSV
  • [1] BRAY F, FERLAY J, SOERJOMATARAM I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2018, 68(6): 394-424. DOI: 10.3322/caac.21492.
    [2] HUANG H, WENG H, CHEN J. m(6)A modification in coding and non-coding RNAs: Roles and therapeutic implications in cancer[J]. Cancer Cell, 2020, 37(3): 270-288. DOI: 10.1016/j.ccell.2020.02.004.
    [3] DOMINISSINI D, MOSHITCH-MOSHKOVITZ S, SCHWARTZ S, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq[J]. Nature, 2012, 485(7397): 201-206. DOI: 10.1038/nature11112.
    [4] LIU N, DAI Q, ZHENG G, et al. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions[J]. Nature, 2015, 518(7540): 560-564. DOI: 10.1038/nature14234.
    [5] MEYER KD, JAFFREY SR. Rethinking m6A readers, writers, and erasers[J]. Annu Rev Cell Dev Biol, 2017, 33: 319-342. DOI: 10.1146/annurev-cellbio-100616-060758.
    [6] PATIL DP, CHEN CK, PICKERING BF, et al. m(6)A RNA methylation promotes XIST-mediated transcriptional repression[J]. Nature, 2016, 537(7620): 369-373. DOI: 10.1038/nature19342.
    [7] WANG X, LU Z, GOMEZ A, et al. N6-methyladenosine-dependent regulation of messenger RNA stability[J]. Nature, 2014, 505(7481): 117-120. DOI: 10.1038/nature12730.
    [8] MOLINIE B, WANG J, LIM KS, et al. m(6)A-LAIC-seq reveals the census and complexity of the m(6)A epitranscriptome[J]. Nat Methods, 2016, 13(8): 692-698. DOI: 10.1038/nmeth.3898.
    [9] ALARCÓN CR, LEE H, GOODARZI H, et al. N6-methyladenosine marks primary microRNAs for processing[J]. Nature, 2015, 519(7544): 482-485. DOI: 10.1038/nature14281.
    [10] WANG X, ZHAO BS, ROUNDTREE IA, et al. N(6)-methyladenosine modulates messenger RNA translation efficiency[J]. Cell, 2015, 161(6): 1388-1399. DOI: 10.1016/j.cell.2015.05.014.
    [11] WANG X, LU Z, GOMEZ A, et al. N6-methyladenosine-dependent regulation of messenger RNA stability[J]. Nature, 2014, 505(7481): 117-120. DOI: 10.1038/nature12730.
    [12] KASOWITZ SD, MA J, ANDERSON SJ, et al. Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development[J]. PLoS Genet, 2018, 14(5): e1007412. DOI: 10.1371/journal.pgen.1007412.
    [13] ALARCóN CR, GOODARZI H, LEE H, et al. HNRNPA2B1 is a mediator of m(6)A-dependent nuclear RNA processing events[J]. Cell, 2015, 162(6): 1299-1308. DOI: 10.1016/j.cell.2015.08.011.
    [14] LIN S, GREGORY RI. Methyltransferases modulate RNA stability in embryonic stem cells[J]. Nat Cell Biol, 2014, 16(2): 129-131. DOI: 10.1038/ncb2914.
    [15] KARIKÓ K, BUCKSTEIN M, NI H, et al. Suppression of RNA recognition by Toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA[J]. Immunity, 2005, 23(2): 165-175. DOI: 10.1016/j.immuni.2005.06.008.
    [16] DURBIN AF, WANG C, MARCOTRIGIANO J, et al. RNAs containing modified nucleotides fail to trigger RIG-I conformational changes for innate immune signaling[J]. mBio, 2016, 7(5). DOI: 10.1128/mBio.00833-16.
    [17] ZHAO X, YANG Y, SUN BF, et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis[J]. Cell Res, 2014, 24(12): 1403-1419. DOI: 10.1038/cr.2014.151.
    [18] HUA W, ZHAO Y, JIN X, et al. METTL3 promotes ovarian carcinoma growth and invasion through the regulation of AXL translation and epithelial to mesenchymal transition[J]. Gynecol Oncol, 2018, 151(2): 356-365. DOI: 10.1016/j.ygyno.2018.09.015.
    [19] LIU X, QIN J, GAO T, et al. YTHDF1 Facilitates the progression of hepatocellular carcinoma by promoting FZD5 mRNA translation in an m6A-dependent manner[J]. Mol Ther Nucleic Acids, 2020, 22: 750-765. DOI: 10.1016/j.omtn.2020.09.036.
    [20] LIU GM, ZENG HD, ZHANG CY, et al. Identification of METTL3 as an adverse prognostic biomarker in hepatocellular carcinoma[J]. Dig Dis Sci, 2021, 66(4): 1110-1126. DOI: 10.1007/s10620-020-06260-z.
    [21] CHEN M, WEI L, LAW CT, et al. RNA N6-methyladenosine methyltransferase-like 3 promotes liver cancer progression through YTHDF2-dependent posttranscriptional silencing of SOCS2[J]. Hepatology, 2018, 67(6): 2254-2270. DOI: 10.1002/hep.29683.
    [22] XU H, WANG H, ZHAO W, et al. SUMO1 modification of methyltransferase-like 3 promotes tumor progression via regulating Snail mRNA homeostasis in hepatocellular carcinoma[J]. Theranostics, 2020, 10(13): 5671-5686. DOI: 10.7150/thno.42539.
    [23] ZUO X, CHEN Z, GAO W, et al. M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma[J]. J Hematol Oncol, 2020, 13(1): 5. DOI: 10.1186/s13045-019-0839-x.
    [24] ZHAO M, JIA M, XIANG Y, et al. METTL3 promotes the progression of hepatocellular carcinoma through m 6 A-mediated up-regulation of microRNA-873-5p[J]. Am J Physiol Gastrointest Liver Physiol, 2020, 319(5): g636. DOI: 10.1152/ajpgi.00161.2020.
    [25] LIN Z, NIU Y, WAN A, et al. RNA m6 A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy[J]. EMBO J, 2020, 39(12): e103181. DOI: 10.15252/embj.2019103181.
    [26] DOHERTY J, BAEHRECKE EH. Life, death and autophagy[J]. Nat Cell Biol, 2018, 20(10): 1110-1117. DOI: 10.1038/s41556-018-0201-5.
    [27] CHEN Y, PENG C, CHEN J, et al. WTAP facilitates progression of hepatocellular carcinoma via m6A-HuR-dependent epigenetic silencing of ETS1[J]. Mol Cancer, 2019, 18(1): 127. DOI: 10.1186/s12943-019-1053-8.
    [28] LAN T, LI H, ZHANG D, et al. KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3[J]. Mol Cancer, 2019, 18(1): 186. DOI: 10.1186/s12943-019-1106-z.
    [29] CHENG X, LI M, RAO X, et al. KIAA1429 regulates the migration and invasion of hepatocellular carcinoma by altering m6A modification of ID2 mRNA[J]. Onco Targets Ther, 2019, 12: 3421-3428. DOI: 10.2147/OTT.S180954.
    [30] MA JZ, YANG F, ZHOU CC, et al. METTL14 suppresses the metastatic potential of hepatocellular carcinoma by modulating N6-methyladenosine-dependent primary MicroRNA processing[J]. Hepatology, 2017, 65(2): 529-543. DOI: 10.1002/hep.28885.
    [31] LI Z, LI F, PENG Y, et al. Identification of three m6A-related mRNAs signature and risk score for the prognostication of hepatocellular carcinoma[J]. Cancer Med, 2020, 9(5): 1877-1889. DOI: 10.1002/cam4.2833.
    [32] KISHIMOTO T, KOKURA K, NAKADAI T, et al. Overexpression of cysteine sulfinic acid decarboxylase stimulated by hepatocarcinogenesis results in autoantibody production in rats[J]. Cancer Res, 1996, 56(22): 5230-5237. http://hwmaint.cancerres.aacrjournals.org/cgi/reprint/56/22/5230.pdf
    [33] JIANG H, ZHANG X, SHEN J, et al. Association between CYP2E1 and GOT2 gene polymorphisms and susceptibility and low-dose N, N-dimethylformamide occupational exposure-induced liver injury[J]. Int Arch Occup Environ Health, 2019, 92(7): 967-975. DOI: 10.1007/s00420-019-01436-1.
    [34] YANG H, ZHOU L, SHI Q, et al. SIRT3-dependent GOT2 acetylation status affects the malate-aspartate NADH shuttle activity and pancreatic tumor growth[J]. EMBO J, 2015, 34(8): 1110-1125. DOI: 10.15252/embj.201591041.
    [35] LI J, ZHU L, ZHI Y, et al. m6A demethylase FTO promotes hepatocellular carcinoma tumorigenesis via mediating PKM2 demethylation[J]. Am J Transl Res, 2019, 11(9): 6084-6092. http://www.ncbi.nlm.nih.gov/pubmed/31632576
    [36] WANG P, WANG X, ZHENG L, et al. Gene signatures and prognostic values of m6A regulators in hepatocellular carcinoma[J]. Front Genet, 2020, 11: 540186. DOI: 10.3389/fgene.2020.540186.
    [37] CHEN Y, ZHAO Y, CHEN J, et al. ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1[J]. Mol Cancer, 2020, 19(1): 123. DOI: 10.1186/s12943-020-01239-w.
    [38] MITTENBVHLER MJ, SAEDLER K, NOLTE H, et al. Hepatic FTO is dispensable for the regulation of metabolism but counteracts HCC development in vivo[J]. Mol Metab, 2020, 42: 101085. DOI: 10.1016/j.molmet.2020.101085.
    [39] LIU X, LIU J, XIAO W, et al. SIRT1 Regulates N6 -Methyladenosine RNA modification in hepatocarcinogenesis by inducing RANBP2-dependent FTO SUMOylation[J]. Hepatology, 2020, 72(6): 2029-2050. DOI: 10.1002/hep.31222.
    [40] KONG W, LI X, XU H, et al. Development and validation of a m6A-related gene signature for predicting the prognosis of hepatocellular carcinoma[J]. Biomark Med, 2020, 14(13): 1217-1228. DOI: 10.2217/bmm-2020-0178.
    [41] LIN X, CHAI G, WU Y, et al. RNA m6A methylation regulates the epithelial mesenchymal transition of cancer cells and translation of Snail[J]. Nat Commun, 2019, 10(1): 2065. DOI: 10.1038/s41467-019-09865-9.
    [42] ZHANG C, HUANG S, ZHUANG H, et al. YTHDF2 promotes the liver cancer stem cell phenotype and cancer metastasis by regulating OCT4 expression via m6A RNA methylation[J]. Oncogene, 2020, 39(23): 4507-4518. DOI: 10.1038/s41388-020-1303-7.
    [43] YANG Z, LI J, FENG G, et al. MicroRNA-145 modulates N6-methyladenosine levels by targeting the 3'-untranslated mrna region of the N6-methyladenosine binding YTH domain family 2 protein[J]. J Biol Chem, 2017, 292(9): 3614-3623. DOI: 10.1074/jbc.M116.749689.
    [44] HOU J, ZHANG H, LIU J, et al. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma[J]. Mol Cancer, 2019, 18(1): 163. DOI: 10.1186/s12943-019-1082-3.
    [45] ZHONG L, LIAO D, ZHANG M, et al. YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma[J]. Cancer Lett, 2019, 442: 252-261. DOI: 10.1016/j.canlet.2018.11.006.
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  • 收稿日期:  2021-02-01
  • 录用日期:  2021-03-18
  • 出版日期:  2021-09-20
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