Nakano Seiji, Murakami Kazuhiro, Meguro Makiko, Soejima Hidenobu, Higashimoto Ken, Urano Takeshi, Kugoh Hiroyuki, Mukai Tsunehiro, Ikeguchi Masahide, Oshimura Mitsuo
Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, 86 Nishimachi, Yonago, Tottori 683-8503, Japan.
Cancer Sci. 2006 Nov;97(11):1147-54. doi: 10.1111/j.1349-7006.2006.00305.x. Epub 2006 Sep 5.
The human chromosome region 11p15.5 contains a number of maternally and paternally imprinted genes, and the LIT1/KCNQ1OT1 locus acts as an imprinting center in the proximal domain of 11p15.5. Loss of imprinting (LOI) of LIT1 and its correlation with methylation status at a differentially methylated region, the KvDMR1, were investigated in 69 colorectal cancer tissue specimens. LIT1 expression profiles were also examined by RNA-fluorescence in situ hybridization in 13 colorectal cancer cell lines. In 69 colorectal cancer tissue specimens, LOI of LIT1 was observed in nine of the 17 (53%) informative cases. Moreover, LOI of LIT1 was only observed in tumor samples. In the cell lines, methylation status at the KvDMR1 correlated well with LIT1 expression profiles. Loss of expression of LIT1 also correlated with enrichment of H3 lysine 9 (H3-K9) dimethylation and reduction of H3 lysine 4 (H3-K4) dimethylation. Thus, LIT1 expression appears to be controlled by epigenetic modifications at the KvDMR1, although CDKN1C expression, which is considered to be controlled by LIT1, was not associated with epigenetic status at the KvDMR1 in some colorectal cancer cell lines. Therefore, these findings suggest that LOI of LIT1 via epigenetic disruption plays an important role in colorectal carcinogenesis, but it is not necessarily associated with CDKN1C expression.
人类染色体区域11p15.5包含许多母系和父系印记基因，LIT1/KCNQ1OT1基因座在11p15.5的近端区域充当印记中心。在69份结直肠癌组织标本中，研究了LIT1的印记丢失（LOI）及其与差异甲基化区域KvDMR1甲基化状态的相关性。还通过RNA荧光原位杂交检测了13种结直肠癌细胞系中的LIT1表达谱。在69份结直肠癌组织标本中，17例信息充分的病例中有9例（53%）观察到LIT1的LOI。此外，仅在肿瘤样本中观察到LIT1的LOI。在细胞系中，KvDMR1的甲基化状态与LIT1表达谱密切相关。LIT1表达缺失还与H3赖氨酸9（H3-K9）二甲基化富集和H3赖氨酸4（H3-K4）二甲基化减少相关。因此，尽管在一些结直肠癌细胞系中，被认为受LIT1调控的CDKN1C表达与KvDMR1的表观遗传状态无关，但LITI表达似乎受KvDMR1处的表观遗传修饰控制。因此，这些发现表明，通过表观遗传破坏导致的LIT1的LOI在结直肠癌发生中起重要作用，但不一定与CDKN1C表达相关。
