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MNNG 처리에 의해 조절되는 암발생 유발 유전자의 조사

MNNG-Regulated Differentially Expressed Genes that Contribute to Cancer Development in Stomach Cells

  • 김태진 (호서대학교 임상병리학과) ;
  • 김명관 (호서대학교 임상병리학과) ;
  • 정동주 (호서대학교 임상병리학과)
  • Kim, Tae-Jin (Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University) ;
  • Kim, Myeong-Kwan (Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University) ;
  • Jung, Dongju (Department of Biomedical Laboratory Science, College of Life and Health Sciences, Hoseo University)
  • 투고 : 2021.10.22
  • 심사 : 2021.11.21
  • 발행 : 2021.12.31

초록

암은 전 세계적인 건강문제이다. 암의 종류는 다양하나 암의 발생과정에서의 유사성은 상당히 높다. 모든 암은 유전자의 발현 변화가 있다는 점에서 공통점을 갖는다. 암 발생과정에서 변화되는 유전자의 발현을 이해하는 것은 암치료제나 암백신 개발에 큰 도움을 줄 것이다. 이번 연구에서는 잘 알려진 암발생 물질인 MNNG를 이용하여 정상 위세포에서 암발생 시 변화되는 유전자 발현을 분석하였다. MNNG 처리에 의해 정상 세포와는 다르게 발현되는 유전자인 DEG들을 찾고 이들을 암세포에서 발현되는 DEG들과 비교하였다. 여기에 더해 DEG의 단백질 결과물들의 기능과 단백질들 간의 결합을 분석하여 단순히 유전자의 발현뿐만 아니라 이들 단백질의 신호전달 과정에서의 연관성도 함께 분석하였다. 이 결과 위암 발생과정에서 관여하는 유전자들과 이들 유전자의 단백질 결과물들의 상호 작용을 밝히게 되었다.

Cancer is a global health problem. There are diverse types of cancers, but there are several common pathways which lead to the development of cancer. Changes in gene expression might be the most common similarity found in almost all cancers. An understanding of the underlying changes in gene expression during cancer progression could lay a valuable foundation for the development of cancer therapeutics and even cancer vaccines. In this study, a well-known carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), was employed to induce changes in gene expression in normal stomach cells. MNNG is known to cause cancer by inducing damage to DNA in MNNG-treated mammalian cells and animals fed with this carcinogen. An analysis was performed by comparing the differentially expressed genes (DEGs) caused by MNNG treatment with DEGs in stomach cancer cell lines. To this end, methods of analysis for functional categorization and protein-protein interaction networks, such as gene ontology (GO), the database for annotation, visualization, and integrated discovery (DAVID), Kyoto encyclopedia of genes and genomics (KEGG) and search tool for the retrieval of interacting genes/proteins (STRING), were used. As a result of these analyses, MNNG-regulated specific genes and interaction networks of their protein products that contributed to stomach cancer were identified.

키워드

과제정보

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) grant (http://nrf.re.kr) to Dongju Jung (NRF-2019R1I1A3A01061981).

참고문헌

  1. Hong S, Won YJ, Lee JJ, Jung KW, Kong HJ, Im JS, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2018. Cancer Res Treat. 2021;53:301-315. https://doi.org/10.4143/crt.2021.291
  2. Sugimura T, Fujimura S, Tumour production in glandular stomach of rat by N-methyl-N'-nitro-N-nitrosoguanidine. Nature. 1967;216:943-944. https://doi.org/10.1038/216943a0
  3. Lin L, Wei H, Yi J, Xie B, Chen J, Zhou C, et al. Chronic CagA-positive Helicobacter pylori infection with MNNG stimulation synergistically induces mesenchymal and cancer stem cell-like properties in gastric mucosal epithelial cells. J Cell Biochem. 2019;120:17635-17649. https://doi.org/10.1002/jcb.29031
  4. Kobori O, Masako M, Morioka Y, Wiestler O, Kleihues P. Biochemical study of the position specificity of rat gastrointestinal cancer induced by MNNG. Nihon Shokakibyo Gakkai Zasshi. 1984;81:277.
  5. Miri H., Bathaie SZ, Mohagheghi MA, Mokhtari-Dizaji M, Ahahbazfar AA. A noninvasive method for early detection of MNNG-induced gastric cancer of male Wistar rat: ultrasonic study. Ultrasound Med Biol. 2011;37:780-787. https://doi.org/10.1016/j.ultrasmedbio.2010.11.015
  6. Deng X, Liang X, Zhou M, Jiang X, Zhao X, Fu L, et al. Protective effect and mechanisms of Weining granule on N-methyl-N'-nitro-N- nitrosoguanidine-induced gastric cancer in rats. J Tradit Chin Med. 2019;39:393-401.
  7. Zhang Y, Zheng E, Pan E, Zhao C, Zhang H, Liu R, et al. Synergism of HPV and MNNG repress miR-218 promoting Het-1A cell malignant transformation by targeting GAB2. Toxicology. 2021;447:152635. https://doi.org/10.1016/j.tox.2020.152635
  8. Szklarczyk D, Franceschini A, Wyder S, Forslund SK, Heller D, Huerta-Cepas J, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43:D447-452. https://doi.org/10.1093/nar/gku1003
  9. Sager R. Expression genetics in cancer: shifting the focus from DNA to RNA. Proc Natl Acad Sci USA. 1997;94:952-955. https://doi.org/10.1073/pnas.94.3.952
  10. Cai J, Wang M, Zhu M, Zhang Q, Zhang X, Yan Y, et al. N-methyl-N-nitro-N '-nitrosoguanidine induces the expression of CCR2 in human gastric epithelial cells promoting CCL2-mediated migration. Mol Med Rep. 2016;13:1083-1090. https://doi.org/10.3892/mmr.2015.4650
  11. Bralow SP, Gruenstein M, Meranze DR. Adenocarcinoma of glandular stomach and duodenum in Wistar rats ingesting N-methyl-N'-nitro-N-nitrosoguanidine, histopathology and associated secretory changes. Cancer Res. 1970;30:1215-1222.
  12. Abe M, Yamashita S, Kuramoto T, Hirayama Y, Tsukamoto T, Ohta T, et al. Global expression analysis of N-methyl-N'-nitro-N-nitrosoguanidine-induced rat stomach carcinomas using oligonucleotide microarrays. Carcinogenesis. 2003;24:861-867. https://doi.org/10.1093/carcin/bgg030
  13. Yuan F, Pan X, Chen L, Zhang YH, Huang T, Cai YD. Analysis of protein-protein functional associations by using gene ontology and KEGG pathway. Biomed Research International. 2019:4963289. https://doi.org/10.1155/2019/4963289
  14. Szklarczyk D, Gable AL, Lyon D, Jung A, Wyder S, Huerta-Cepas J, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607-D613. https://doi.org/10.1093/nar/gky1131
  15. Tarkkonen KM, Nilsson EM, Kahkonen TE, Dey JH, Heikkila JE, Tuomela JM, et al. Differential roles of fibroblast growth factor receptors (FGFR) 1, 2 and 3 in the regulation of S115 breast cancer cell growth. PLoS One. 2012;7:e49970. https://doi.org/10.1371/journal.pone.0049970
  16. Herbst RS. Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys. 2004;59:21-26. https://doi.org/10.1016/j.ijrobp.2003.11.041
  17. Milligan G, Kostenis E. Heterotrimeric G-proteins: a short history. Br J Pharmacol. 2006;147:S46-55. https://doi.org/10.1038/sj.bjp.0706405
  18. Goodfellow PJ, Nevanlinna HA, Gorman P, Sheer D, Lam G, Goodfellow PN. Assignment of the gene encoding the beta-subunit of the human fibronectin receptor (beta-FNR) to chromosome 10p11.2. Ann Hum Genet. 1989;53:15-22. https://doi.org/10.1111/j.1469-1809.1989.tb01118.x