Unique Methylation Pattern of Oncostatin M Receptor Gene in Cancers of Colorectum and Other Digestive Organs
Unique Methylation Pattern of Oncostatin M Receptor Gene in Cancers of Colorectum and Other Digestive Organs
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DOI：
10.1158/1078-0432.ccr-08-1778
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发表时间：
2009-03-01
影响因子：
11.5
通讯作者：
Kim, Young S.
中科院分区：
文献类型：
--
作者：
Deng, Guoren;Kakar, Sanjay;Kim, Young S.
目的：抑瘤素M（Oncostatin M，OSM）是白细胞介素-6（IL-6）家族的一员，在肿瘤中具有抑制细胞增殖、诱导细胞分化和凋亡的作用。在黑色素瘤细胞中，通过组蛋白去乙酰化作用使OSM受体（OSMR）的表观遗传沉默有助于逃避OSM对细胞生长的控制。实验设计：在原发性肿瘤和细胞系中通过测序或甲基化特异性PCR确定OSMR的甲基化状态。用DNA甲基转移酶抑制剂5-氮杂-2-脱氧胞苷或DNA甲基转移酶1小干扰RNA或组蛋白脱乙酰酶抑制剂阿司他汀A处理细胞系。逆转录-PCR法检测OSMR mRNA水平。结果：98例结直肠癌中88例（90%）、38例结直肠息肉中34例（89%）、31例结直肠癌旁正常黏膜中17例（55%）、40例胃癌中13例（33%）、10例胰腺癌中2例（20%）存在OSMR甲基化。OSMR甲基化在非癌症患者的正常结肠粘膜或非消化器官癌症（包括乳腺癌、肺癌、肝癌、前列腺癌、肾癌和黑素瘤）中不存在或很少检测到。我们在39个癌细胞系中观察到OSMR甲基化和mRNA表达缺失之间的显著相关性。用5-氮-2-脱氧胞苷、DNA甲基转移酶1小干扰RNA或抑制素A处理大肠癌细胞系后，OSMR mRNA的表达和组蛋白乙酰化水平的增加被观察到。结论：OSMR的表观遗传沉默和DNA甲基化在大肠癌中发生率较高，在非消化道肿瘤中较少。OSMR甲基化是结直肠癌发生的早期事件。
Purpose: Oncostatin M (OSM) is an interleukin-6 cytokine family member, which inhibits cell proliferation and induces cell differentiation and apoptosis in cancers. In melanoma cells, epigenetic silencing of OSM receptor (OSMR) by histone deacetylation contributes to escape of cell growth control by OSM. However, the silencing of OSMR by DNA methylation in any cancer has not been examined.Experimental Design: Methylation status of OSMR was determined by sequencing or methylation-specific PCR in primary tumors and cell lines. Cell lines were treated with DNA methyltransferase inhibitors 5-aza-2-deoxycytidine or DNA methyltransferase 1 small interfering RNA or a histone deacetylase inhibitor trichostatin A. OSMR mRNA level was determined by reverse transcription-PCR. The acetylation of histone H3 was analyzed by chromatin immunoprecipitation assay.Results: We observed methylation of OSMR in 88 of 98 (90%) colorectal cancers, 34 of 38 (89%) colorectal polyps, 17 of 31 (55%) normal-appearing mucosa adjacent to colorectal cancers, 13 of 40 (33%) gastric cancers, and 2 of 10 (20%) pancreatic cancers. OSMR methylation was absent or rarely detected in normal colonic mucosa from noncancer patients or in cancers of nondigestive organs, including breast, lung, liver, prostate, kidney, and melanoma. We observed a significant correlation between OSMR methylation and loss of mRNA expression in 39 cancer cell lines. Following the treatment of colorectal cancer cell lines with 5-aza-2deoxycytidine, DNA methyltransferase 1 small interfering RNA, or trichostatin A, the induction of OSMR mRNA and the enrichment in the level of histone acetylation were observed.Conclusions: The epigenetic silencing and DNA methylation of OSMR occur frequently in colorectal cancers and rarely in cancers of nondigestive organs. OSMR methylation is an early event in the colorectal carcinogenesis.