Kamimae Seiko, Yamamoto Eiichiro, Kai Masahiro, Niinuma Takeshi, Yamano Hiro-o, Nojima Masanori, Yoshikawa Kennjiro, Kimura Tomoaki, Takagi Ryo, Harada Eiji, Harada Taku, Maruyama Reo, Sasaki Yasushi, Tokino Takashi, Shinomura Yasuhisa, Sugai Tamotsu, Imai Kohzoh, Suzuki Hiromu
Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Department of Gastroenterology, Rheumatology, Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Oncotarget. 2015 Oct 6;6(30):29975-90. doi: 10.18632/oncotarget.5034.
Our aim was to identify DNA methylation changes associated with the growth pattern and invasiveness of colorectal cancers (CRCs). Comparison of the methylation statuses of large (≥ 20 mm in diameter along the colonic surface) noninvasive tumors (NTs) and small (<20 mm in diameter along the colonic surface) invasive tumors (ITs) using CpG island microarray analysis showed neurotensin receptor 1 (NTSR1) to be hypermethylated in large NTs. Quantitative bisulfite pyrosequencing revealed that NTSR1 is frequently methylated in colorectal tumors, with large NTs exhibiting the highest methylation levels. The higher NTSR1 methylation levels were associated with better prognoses. By contrast, NTSR1 copy number gains were most frequent among small ITs. Methylation of NTSR1 was associated with the gene's silencing in CRC cell lines, whereas ectopic expression of NTSR1 promoted proliferation and invasion by CRC cells. Analysis of primary tumors composed of adenomatous and malignant portions revealed that NTSR1 is frequently methylated in the adenomatous portion, while methylation levels are generally lower in the cancerous portions. These results suggest that NTSR1 methylation is associated with lateral and noninvasive growth of colorectal tumors, while low levels of methylation may contribute to the malignant potential through activation of NTSR1. Our data also indicate that NTSR1 methylation may be a prognostic biomarker in CRC.
我们的目的是确定与结直肠癌（CRC）生长模式和侵袭性相关的DNA甲基化变化。使用CpG岛微阵列分析比较大的（沿结肠表面直径≥20mm）非侵袭性肿瘤（NTs）和小的（沿结肠表面直径<20mm）侵袭性肿瘤（ITs）的甲基化状态，结果显示神经降压素受体1（NTSR1）在大的NTs中呈高甲基化。亚硫酸氢盐焦磷酸测序定量分析表明，NTSR1在结直肠肿瘤中经常发生甲基化，大的NTs甲基化水平最高。较高的NTSR1甲基化水平与较好的预后相关。相比之下，NTSR1拷贝数增加在小的ITs中最为常见。NTSR1的甲基化与CRC细胞系中该基因的沉默相关，而NTSR1的异位表达促进CRC细胞的增殖和侵袭。对由腺瘤性和恶性部分组成的原发性肿瘤进行分析发现，NTSR1在腺瘤性部分经常发生甲基化，而在癌性部分甲基化水平通常较低。这些结果表明，NTSR1甲基化与结直肠肿瘤的侧向和非侵袭性生长相关，而低水平的甲基化可能通过激活NTSR1促进恶性潜能。我们的数据还表明，NTSR1甲基化可能是CRC的一种预后生物标志物。
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