山东大学学报 (医学版) ›› 2023, Vol. 61 ›› Issue (9): 10-18.doi: 10.6040/j.issn.1671-7554.0.2022.1289
孙菁果1,朱文帅1,鲁艺2,马晓丽1,郏雁飞1
SUN Jingguo1, ZHU Wenshuai1, LU Yi2, MA Xiaoli1, JIA Yanfei1
摘要: 目的 探讨幽门螺杆菌感染对胃癌中m6A水平的影响及机制。 方法 将胃癌细胞株MGC-803分别与幽门螺杆菌标准菌株NCTC 11637、NCTC 26695、PM SS1在MOI=100的条件下共培养8 h,用dot-blot和ELISA方法检测细胞总体m6A水平。用qRT-PCR 和Western blotting检测METTL3和METTL14的表达。下载GEO 数据库中的原始数据,分析m6A 甲基化转移酶与临床病理参数之间的关系。运用GEPIA分析TCGA和GTEx数据库中m6A甲基化转移酶METTL14在胃癌和正常组织中的表达差异。 结果 幽门螺杆菌可导致胃癌细胞m6A水平上调;幽门螺杆菌感染诱导了胃癌细胞中 METTL14 表达; METTL14表达与胃癌组织LAUREN分型相关,且在肠型胃癌组织中表达更高;胃癌组织中METTL14的表达高于癌旁正常组织。 结论 幽门螺杆菌感染诱导胃癌细胞总体m6A水平上调,其机制与m6A 甲基化转移酶METTL14表达上调有关。
中图分类号:
[1] Smyth E, Nilssin M, Grabsch H, et al. Gastric cancer [J]. Lancet(London, England), 2020, 396(10251): 635-648. [2] Wu Y, Li Y, Giovannucci E. Potential impact of time trend of lifestyle risk factors on burden of major gastrointestinal cancers in China [J]. Gastroenterology, 2021, 161(6): 1830-1841. [3] Li X, Sun Z, Peng G, et al. Single-cell RNA sequencing reveals a pro-invasive cancer-associated fibroblast subgroup associated with poor clinical outcomes in patients with gastric cancer [J]. Theranostics, 2022, 12(2): 620-638. [4] Stewart OA, Wu F, Chen Y. The role of gastric microbiota in gastric cancer [J]. Gut Microbes, 2020, 11(5): 1220-1230. [5] Sandasivam S, Decaprio J. The DREAM complex: master coordinator of cell cycle-dependent gene expression [J]. Nat Rev Cancer, 2013, 13(8): 585-595. [6] Muhammad J, Eladl M, Khoder G. Helicobacter pylori-induced DNA methylation as an epigenetic modulator of gastric cancer: recent outcomes and future direction [J]. Pathogens, 2019, 8(1):23. doi: 10.3390/pathogens8010023. [7] Vahidi S, Mirzajani E, Norollahi S, et al. Performance of DNA Methylation on the molecular pathogenesis of helicobacter pylori in gastric cancer; targeted therapy approach [J]. J Pharmacopuncture, 2022, 25(2): 88-100. [8] Ding S, Goldberg J, Hatakeyama M. Helicobacter pylori infection, oncogenic pathways and epigenetic mechanisms in gastric carcinogenesis [J]. Future Oncology(London, England), 2010, 6(5): 851-862. [9] Sun T, Wu R, Ming L. The role of m6A RNA methylation in cancer [J]. Biomed Pharmacother, 2019, 112: 108613. doi:10.1016/j.biopha.2019.108613. [10] Yang Y, Hsu P, Chen Y, et al. Dynamic transcriptomic m(6)A decoration: writers, erasers, readers and functions in RNA metabolism[J]. Cell Res, 2018, 28(6): 616-624. [11] An Y, Duan H. The role of m6A RNA methylation in cancer metabolism [J]. Mol Cancer, 2022, 21(1): 14. doi: 10.1186/s12943-022-01500-4. [12] He L, Li H, Wu A, et al. Functions of N6-methyladenosine and its role in cancer [J]. Mol Cancer, 2019, 18(1): 176. doi:10.1186/s12943-019-1109-9. [13] XU Y, Huang C. Progress and application of epitranscriptomic m(6)A modification in gastric cancer [J]. RNA Biology, 2022, 19(1): 885-896. [14] Yue B, Song C, Yang L, et al. METTL3-mediated N6-methyladenosine modification is critical for epithelial-mesenchymal transition and metastasis of gastric cancer [J]. Mol Cancer, 2019, 18(1): 142. [15] Chen D, Cheung H, Lau H, et al. N(6)-methyladenosine RNA-binding protein YTHDF1 in gastrointestinal cancers: function, molecular mechanism and clinical implication [J]. Cancers, 2022, 14(14):3489. doi: 10.3390/cancers14143489. [16] Fenolla F, Bouam A, Ballouchem M, et al. Evaluation of the panbio COVID-19 rapid antigen detection test device for the screening of patients with COVID-19 [J]. J Clin Microbiol, 2021, 59(2):3. doi: 10.1128/JCM.02589-20. [17] Yang X, Zhang S, He C, et al. METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST [J]. Mol Cancer, 2020, 19(1): 46. [18] Wang M, Liu J, Zhao Y, et al. Upregulation of METTL14 mediates the elevation of PERP mRNA N(6)adenosine methylation promoting the growth and metastasis of pancreatic cancer [J]. Mol Cancer, 2020, 19(1): 130. [19] Cullin N, Azevedo C, Straussman R, et al. Microbiome and cancer [J]. Cancer Cell, 2021, 39(10): 1317-1341. [20] Morgan R, Saleh S, Farrag H, et al. Bacterial cyclomodulins: types and roles in carcinogenesis [J]. Crit Rev Microbiol, 2022, 48(1): 42-66. [21] Kostyusheva A, Brezgin S, Glebe D, et al. Host-cell interactions in HBV infection and pathogenesis: the emerging role of m6A modification [J]. Emerg Microbes Infect, 2021, 10(1): 2264-2275. [22] Dang W, Xie Y, Cao P, et al. N(6)-methyladenosine and viral infection[J]. Front Microbiol, 2019, 10:417. doi:10.3389/fmicb.2019.00417. [23] Murata N, Hatakeyama M. Helicobacter pylori-induced DNA double-stranded break in the development of gastric cancer [J]. Cancer Sci, 2022, 113(6): 1909-1918. [24] Wu S, Li XF, Wu YY, et al. N6 -methyladenosine and rheumatoid arthritis: a comprehensive review [J]. Front Immunol, 2021, 12: 731842. doi: 10.3389/fimmu.2021.731842. [25] Zhou H, Yin K, Zhang Y, et al. The RNA m6A writer METTL14 in cancers: roles, structures, and applications [J]. Biochim Biophys Acta Rev Cancer, 2021, 1876(2): 188609. doi:10.1016/j.bbcan.2021.188609. [26] Deng LJ, Deng WQ, Fan SR, et al. m6A modification: recent advances, anticancer targeted drug discovery and beyond [J]. Mol Cancer, 2022, 21(1): 52. [27] Peng F, XU J, Cui B, et al. Oncogenic AURKA-enhanced N(6)-methyladenosine modification increases DROSHA mRNA stability to transactivate STC1 in breast cancer stem-like cells [J]. Cell Res, 2021, 31(3): 345-361. [28] Zhang C, OU S, Zhou Y, et al. m(6)A methyltransferase METTL14-mediated upregulation of cytidine deaminase promoting gemcitabine resistance in pancreatic cancer[J]. Front Oncol, 2021, 11: 696371. doi:10.3389/fonc.2021.696371. [29] Weng H, Huang H, WU H, et al. METTL14 inhibits hematopoietic stem/progenitor differentiation and promotes leukemogenesis via mRNA m(6)A modification [J]. Cell Stem Cell, 2018, 22(2): 191-205. [30] Yang Z, Yang S, Cui YH, et al. METTL14 facilitates global genome repair and suppresses skin tumorigenesis [J]. Proc National Acad Sci U S A, 2021, 118(35):e2025948118. doi:10.1073/pnas.2025948118. [31] Nagase L, Murata N, Hatakeyama M. Potentiation of helicobacter pylori CagA protein virulence through homodimerization [J]. J Biol Chem, 2011, 286(38): 33622-33631. [32] Müller A. Multistep activation of the helicobacter pylori effector CagA [J]. J Clin Invest, 2012, 122(4): 1192-1195. [33] Hatakeyama M. Oncogenic mechanisms of the Helicobacter pylori CagA protein [J]. Nat Rev Cancer, 2004, 4(9): 688-694. [34] Yao P, Kartsonaki C, Butt J, et al. Helicobacter pylori multiplex serology and risk of non-cardia and cardia gastric cancer: a case-cohort study and meta-analysis [J]. Int J Epidemiol, 2023. doi:10.1093/ije/dyad007. [35] Goldenring J. No H. pylori, no adenocarcinoma for patients with autoimmune gastritis [J]. Gut, 2023, 72(1): 1-2. [36] Holokai L, Chakrabarti J, Broda T, et al. Increased programmed death-ligand 1 is an early epithelial cell response to helicobacter pylori infection [J]. PLoS Pathog, 2019, 15(1): e1007468. doi: 10.1371/journal.ppat.1007468. [37] Wang Q, Guo F, Jin Y, et al. Applications of human organoids in the personalized treatment for digestive diseases [J]. Signal Transduct Target Ther, 2022, 7(1): 336. [38] LI K, Luo H, Huang L, et al. Microsatellite instability: a review of what the oncologist should know [J]. Cancer Cell Int, 2020, 20: 16. doi: 10.1186/s12935-019-1091-8. [39] Lower S, Mcgurk M,Clsrk A, et al. Satellite DNA evolution: old ideas, new approaches [J]. Curr Opin Genet Dev, 2018, 49: 70-78. doi: 10.1016/j.gde.2018.03.003. [40] Ye P, Shi Y, LI A. Association between hMLH1 promoter methylation and risk of gastric cancer: a meta-analysis [J]. Front Physiol, 2018, 9: 368. doi: 10.3389/fphys.2018.00368. [41] Hashimoto T, Kurokawa Y, Takahashi T, et al. Predictive value of MLH1 and PD-L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer [J]. Gastric Cancer, 2019, 22(4): 785-792. [42] 周高云, 林龙, 林进维, 等. MLH1表达对胃癌患者预后及术前新辅助化疗反应的预测价值[J]. 中国癌症防治杂志, 2022, 14(1): 65-69. ZHOU Gaoyun, LIN Long, LIN Jinwei, et al.Predictive value of MLH1 expression on prognosis and preoperative neoadjuvant chemotherapy response in patients with gastric cancer[J]. Chinese Journal of Oncology Prevention and Treatment, 2022, 14(1): 65-69. [43] Deng S, Zhang J, Su J, et al. RNA m(6)A regulates transcription via DNA demethylation and chromatin accessibility [J]. Nat Genet, 2022, 54(9): 1427-1437. [44] Chen X, Xu M, Xu X, et al. METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer [J]. Molecular Cancer, 2020, 19(1): 106. [45] Gong PJ, Shao YC, Yang Y, et al. Analysis of N6-methyladenosine methyltransferase reveals METTL14 and ZC3H13 as tumor suppressor genes in breast cancer [J]. Front Oncol, 2020,10:578963.doi:10.3389/fonc.2020.578963. [46] Zhang X, Li D, Jia C, et al. METTL14 promotes tumorigenesis by regulating lncRNA OIP5-AS1/miR-98/ADAMTS8 signaling in papillary thyroid cancer [J]. Cell Death Dis, 2021, 12(6): 617. [47] Fan HN, Chen ZY, Chen XY, et al. METTL14-mediated m(6)A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis [J]. Mol Cancer, 2022, 21(1): 51. [48] Liu X, Xiao M, Zhang L, et al. The m6A methyltransferase METTL14 inhibits the proliferation, migration, and invasion of gastric cancer by regulating the PI3K/AKT/mTOR signaling pathway [J]. J Clin Lab Anal, 2021, 35(3): e23655. doi: 10.1002/jcla.23655. |
[1] | 闫丛丛,陈辰,谢倩,王亚楠,张鑫璐,张迎春,武斌. 双酚A暴露对KGN细胞m6A修饰水平的影响[J]. 山东大学学报 (医学版), 2023, 61(8): 17-23. |
[2] | 樊荣,李彬彬,马晓丽,汪运山,郏雁飞. 胃癌中DEC2、HIF-2α的表达及临床意义[J]. 山东大学学报 (医学版), 2023, 61(7): 12-18. |
[3] | 郭崇勇,赵朋,刘海盟,王强, 贾宗师,张建. 胸前丘疹为首发表现的胃癌1例[J]. 山东大学学报 (医学版), 2023, 61(4): 119-120. |
[4] | 穆彦熹,李金洲,陈康,梁红英,姚亚龙,汪文杰,陈晓. 443例胃癌根治术后发生肺部并发症的危险因素[J]. 山东大学学报 (医学版), 2023, 61(4): 37-41. |
[5] | 王赞,徐晓涵,张瑜,曲业敏,王明义,陈艾. 幽门螺杆菌感染对胃癌细胞糖酵解的影响[J]. 山东大学学报 (医学版), 2023, 61(2): 16-24. |
[6] | 付佳,王路路,胡帅,陈哲平,刘东义,李青松,卢国栋,张贺,赵鑫,冯昌. 不同入路腰方肌阻滞对胃癌根治患者术后恢复的影响[J]. 山东大学学报 (医学版), 2022, 60(8): 50-57. |
[7] | 王景,谢艳,李培龙,杜鲁涛,王传新. GZMB基因cg16212145位点的异常甲基化芯片测定对胃癌早筛的价值[J]. 山东大学学报 (医学版), 2022, 60(6): 26-34. |
[8] | 包舒晴,杨明月,刘端瑞,汪运山,郏雁飞. NOX4在幽门螺旋杆菌诱导胃癌细胞ROS中的作用[J]. 山东大学学报 (医学版), 2022, 60(6): 19-25. |
[9] | 高惠茹,杜甜甜,王允山,杜鲁涛,王传新. 基于单细胞转录组测序数据分析胃癌调节性T细胞特征[J]. 山东大学学报 (医学版), 2022, 60(5): 43-49. |
[10] | 吕岩红,张志勉. 2 809名体检人群中高血压与幽门螺杆菌感染的关联性[J]. 山东大学学报 (医学版), 2022, 60(2): 43-47. |
[11] | 穆彦熹,汪文杰,陈康,姚亚龙,李金洲,魏浩旗,刘海鹏,黄泽平,陈晓. 探寻一家系短期3例胃癌的临床病理及其相关肿瘤特征[J]. 山东大学学报 (医学版), 2022, 60(11): 96-101. |
[12] | 褚晏,刘端瑞,朱文帅,樊荣,马晓丽,汪运山,郏雁飞. DNA甲基化转移酶在胃癌中的表达及其临床意义[J]. 山东大学学报 (医学版), 2021, 59(7): 1-9. |
[13] | 罗兵. EB病毒对胃癌表观遗传学的影响[J]. 山东大学学报 (医学版), 2021, 59(5): 30-39. |
[14] | 史爽,李娟,米琦,王允山,杜鲁涛,王传新. 胃癌miRNAs预后风险评分模型的构建与应用[J]. 山东大学学报 (医学版), 2020, 1(7): 47-52. |
[15] | 支梦伟,江志伟,戴新娟,王刚,程伟. 加速康复外科指导下胃癌患者围手术期心率变异度的临床观察[J]. 山东大学学报 (医学版), 2020, 58(11): 85-91. |
|