Enhancement of O-linked N-acetylglucosamine modification promotes metastasis in patients with colorectal cancer and concurrent type 2 diabetes mellitus
Enhancement of O-linked N-acetylglucosamine modification promotes metastasis in patients with colorectal cancer and concurrent type 2 diabetes mellitus
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DOI：
10.3892/ol.2020.11665
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发表时间：
2020-05
期刊：
影响因子：
2.9
通讯作者：
Yutaka Naka;T. Okada;T. Nakagawa;Eiko Kobayashi;Y. Kawasaki;Yasuyoshi Tanaka;Hideki Tawa;Yuki Hirata;K. Kawakami;K. Kakimoto;Takuya Inoue;T. Takeuchi;S. Fukunishi;Y. Hirose;K. Uchiyama;M. Asahi;K. Higuchi
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作者：
Yutaka Naka;T. Okada;T. Nakagawa;Eiko Kobayashi;Y. Kawasaki;Yasuyoshi Tanaka;Hideki Tawa;Yuki Hirata;K. Kawakami;K. Kakimoto;Takuya Inoue;T. Takeuchi;S. Fukunishi;Y. Hirose;K. Uchiyama;M. Asahi;K. Higuchi
O-连接的N-乙酰葡糖胺（O-GlcNAc）对丝氨酸和苏氨酸残基的可逆翻译后修饰（称为O-GlcNAc化）已被表明调节许多不同蛋白质的活性。增强的O-GlcNAc酰化有助于2型糖尿病（T2 DM）和癌症的病因学。此外，糖尿病会增加结直肠癌的风险。然而，O-GlcNAc化在结直肠癌合并T2 DM患者中的作用尚未阐明。本研究评价了伴或不伴T2 DM的结直肠癌患者的O-GlcNAc化水平。值得注意的是，与非T2 DM患者的组织相比，T2 DM患者的组织中的O-GlcNAc化水平显著更高，并且与相应的邻近组织相比，癌组织中的O-GlcNAc化水平更高。与非T2 DM患者相比，T2 DM患者的癌组织中O-GlcNAc化与癌症分期的相关性更强。此外，远处转移与T2 DM患者癌组织中的O-GlcNAc化显著相关。结直肠癌组织中的β-连环蛋白水平在晚期癌症和并发T2 DM的患者中最高。在SW 480人结肠癌细胞中，thiamet G（TMG）处理和OGA沉默（其增加O-GlcNAc化）在高葡萄糖下显著增加β-连环蛋白和SNAIL，但在正常葡萄糖条件下不显著增加。这些数据表明，O-GlcNAc化与远处转移密切相关，最有可能通过上调T2 DM结直肠癌患者中的β-连环蛋白/SNAIL信号通路。
Reversible post-translational modification of serine and threonine residues by O-linked N-acetylglucosamine (O-GlcNAc), termed O-GlcNAcylation has been indicated to regulate the activities of a number of different proteins. Augmented O-GlcNAcylation contributes to the etiologies of type 2 diabetes mellitus (T2DM) and cancer. Moreover, diabetic conditions increase the risk of colorectal cancer. However, the effect of O-GlcNAcylation in patients with colorectal cancer and concurrent T2DM has not been elucidated. The current study evaluated the level of O-GlcNAcylation in patients with colorectal cancer with or without T2DM. Notably, O-GlcNAcylation levels were significantly higher in tissues from patients with T2DM compared with those in patients without T2DM, and higher in cancer tissues compared with corresponding adjacent tissues. O-GlcNAcylation and cancer stage were more strongly correlated in cancer tissues from patients with T2DM compared with those from patients without T2DM. Additionally, distant metastasis was significantly correlated with O-GlcNAcylation in cancer tissues from patients with T2DM. β-catenin levels in colorectal cancer tissues were the highest in patients with advanced-stage cancer and concurrent T2DM. In SW480 human colon cancer cells, thiamet G (TMG) treatment and OGA silencing, which increased O-GlcNAcylation, significantly increased β-catenin and SNAIL in high-glucose, but not during normal-glucose conditions. These data suggest that O-GlcNAcylation is closely associated with distant metastasis, most likely through upregulation of the β-catenin/SNAIL signaling pathway in colorectal cancer patients with T2DM.