IL-6在胃癌形成過程中調控人類甲基化酵素(DNMT1)及基因甲基化所扮演之角色

The role of IL-6 in regulation of human DNMT1 gene and methylation in gastric carcinogenesis

羅雅婷(Ya-Ting Lo)

指導教授 ： 張玲麗

高雄醫學大學/醫學院/醫學研究所/碩士(2007年)

摘要

經由研究指出慢性發炎與癌症的發生有很密切之相關性，其中與慢性發炎相關的發炎激素IL-6具有多種的生理功能，且被發現與胃癌的病程以及預後有關。不過，目前IL-6在胃癌中如何促進癌症發生的機制仍不清楚。哺乳類動物基因核甘酸CpG位置會經由甲基化酵素DNMT1的作用變成甲基化狀態，此CpG上的甲基化對於一些細胞內基因的epigenetic調控扮演著很重要的角色。然而，根據先前的研究，IL-6能夠調控DNMT1的表現及其promoter區域的活性。因此，本研究欲利用胃癌細胞株AGS及MKN45研究IL-6對於調控甲基化酵素DNMT1所扮演的角色以及使用甲基化特異性、反轉錄聚合酶連鎖反應觀察在此兩株細胞株中SOCS-1基因的表現情形。結果顯示，在AGS及MKN45這兩株細胞株中，甲基化酵素DNMT1的表現量與IL-6並無顯著的相關，此外，細胞內SOCS-1基因並無甲基化，且其mRNA也可以正常表現。由次證實，在胃癌的致癌過程中，IL-6似乎不會透過調控甲基化酵素表現而促成基因靜默導致癌化。

關鍵字

胃癌 ； 基因甲基化 ； 甲基化酵素

並列摘要

A strong association exists between chronic inflammation and cancer. Interleukin-6(IL-6) is a multifunctional cytokine that is association with the disease status and outcomes of gastric cancer. Nonetheless, the underlying mechanism of how IL-6 promoters the carcinogenesis of gastric cancer is still unclear. Methylation of mammalian DNA by the DNA methyltransferase (DNMT1) at CpG dinucleotide sequences has been recognized as an important epigenetic control mechanism in regulating the expression of cellular genes. Previous report showed that IL-6 regulate the DNMT1 promoter and resulting enzyme activity. In this study, in order to investigate the role of IL-6 in regulating the expression of DNMT1 in gastric cancer cell lines AGS and MKN45, and expression level of SOCS-1 in AGS and MKN45 cell lines using methylation specific polymerase chain reaction and RT-PCR. In our results, expression level of DNMT1 did not correlate with IL-6 treatment in both of the cell lines. Moreover, unmethylation of SOCS-1 was detected and correlated with its mRNA expression in AGS and MKN45 gastric cancer cell lines. In conclusion, it seems IL-6 is incapable in regulating DNMT1 activity in gastric carcinogenesis.

並列關鍵字

gastric cancer ； DNA methylation ； DNA methyltransferase-1(DNMT1) ； IL-6 ； SOCS-1

參考文獻

Akira, S., T. Taga, et al. (1993). "Interleukin-6 in biology and medicine." Adv Immunol 54: 1-78.

Ashizawa, T., R. Okada, et al. (2005). "Clinical significance of interleukin-6 (IL-6) in the spread of gastric cancer: role of IL-6 as a prognostic factor." Gastric Cancer 8: 124-31.

Bartsch, R., S. Woehrer, et al. (2006). "Serum interleukin-6 levels in patients with gastric MALT lymphoma compared to gastric and pancreatic cancer." Anticancer Res 26: 3187-90.

Borsellino, N., A. Belldegrun, et al. (1995). "Endogenous interleukin 6 is a resistance factor for cis-diamminedichloroplatinum and etoposide-mediated cytotoxicity of human prostate carcinoma cell lines." Cancer Res 55: 4633-9.

Brysha, M., J. G. Zhang, et al. (2001). "Suppressor of cytokine signaling-1 attenuates the duration of interferon gamma signal transduction in vitro and in vivo." J Biol Chem 276: 22086-9.