Core 3 mucin-type O-glycan restoration in colorectal cancer cells promotes MUC1/p53/miR-200c-dependent epithelial identity
Core 3 mucin-type O-glycan restoration in colorectal cancer cells promotes MUC1/p53/miR-200c-dependent epithelial identity
复制标题
结直肠癌细胞中核心 3 粘蛋白型 O-聚糖恢复促进 MUC1/p53/miR-200c 依赖性上皮身份
作者：
叶钧
由丝氨酸或苏氨酸（o -聚糖）介导的细胞表面碳水化合物与蛋白质的附着参与肿瘤转移；o -聚糖的作用取决于它们的结构，但o -聚糖触发信号控制肿瘤转移的详细机制在很大程度上是未知的。在本研究中，我们发现core 3合成酶的表达降低与结直肠癌（CRC）患者的淋巴结和远端器官转移相关，导致结直肠癌患者预后不良。机械地，我们发现黏液型核心3 o -聚糖是在结肠癌细胞中由于核心3合成酶的表达而在MUC1 N端膜系链上合成的。这进一步抑制了MUC1-C向细胞核的易位，启动了依赖于MUC1-C核易位抑制的p53基因转录，激活了p53介导的miR-200c表达，并导致间充质-上皮转化（MET）。在重表达的核心3合成酶结肠癌细胞中，通过小干扰RNA （siRNA）抑制MUC1进一步抑制MUC1- c核易位，增加p53和miR-200c的表达，增强MET。然而，在重表达的核心3合成酶结肠癌细胞中，通过siRNA或miR-200c抑制剂抑制p53，以可逆的方式促进上皮-间质转化（EMT）。结肠癌样品中Core 3合成酶mRNA水平与p53 mRNA水平或miR-200c水平呈正相关。我们的研究结果提示了一种新的机制，通过MUC1/p53/ mir -200c依赖的信号级联，将黏液型核心3o -聚糖与CRC细胞的EMT-MET可塑性联系起来，并揭示了治疗这种恶性肿瘤的治疗策略。
The attachment of cell-surface carbohydrates to proteins mediated by the amino acids serine or threonine (O-glycan) is involved in tumor metastasis; the roles of O-glycans vary depending on their structure, but the detailed mechanisms by which O-glycans trigger signaling to control tumor metastasis are largely unknown. In this study, we found that the reduced expression of core 3 synthase correlated with metastasis to lymph nodes and distant organs, resulting in poor prognosis for colorectal cancer (CRC) patients. Mechanically, we revealed that mucin-type core 3 O-glycan was synthesized at the membrane-tethered MUC1 N terminus because of core 3 synthase expression in colon cancer cells. This further inhibited the translocation of MUC1-C to the nucleus, initiated p53 gene transcription that was dependent on the inhibition of MUC1-C nucleus translocation, activated p53-mediated miR-200c expression and resulted in mesenchymal–epithelial transition (MET). Inhibition of MUC1 via small interfering RNA (siRNA) in re-expressed core 3 synthase colon cancer cells further inhibited MUC1-C nucleus translocation, increased p53 and miR-200c expression, and enhanced MET. However, inhibition of p53 via siRNA or miR-200c via miR-200c inhibitor in re-expressed core 3 synthase colon cancer cells promoted the epithelial–mesenchymal transition (EMT) in a reversible manner. Core 3 synthase mRNA levels and the p53 mRNA levels or miR-200c levels in the colon cancerous samples were positively correlated. Our findings suggest a novel mechanism linking mucin-type core 3 O-glycan to the EMT–MET plasticity of CRC cells via MUC1/p53/miR-200c-dependent signaling cascade and shed light on therapeutic strategies to treat this malignancy.
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影响因子：
24.5
作者：
Hur K;Toiyama Y;Takahashi M;Balaguer F;Nagasaka T;Koike J;Hemmi H;Koi M;Boland CR;Goel A
通讯作者：
Goel A
影响因子：
3.4
作者：
Gabriel, M;Zentner, A
通讯作者：
Zentner, A
影响因子：
29.4
作者：
Spaderna, Simone;Schmalhofer, Otto;Brabletz, Thomas
通讯作者：
Brabletz, Thomas
肠道O-聚糖的损失会促进自发性十二指肠肿瘤。
DOI：
10.1152/ajpgi.00060.2016
发表时间：
2016-07-01
影响因子：
4.5
作者：
Gao, Nan;Bergstrom, Kirk;Xia, Lijun
通讯作者：
Xia, Lijun
影响因子：
20.3
作者：
Ashujit Tagde;H. Rajabi;Audrey Bouillez;Maroof Alam;R. Gali;S. Bailey;Y. Tai;T. Hideshima;K. Anderson;D. Avigan;D. Kufe
通讯作者：
Ashujit Tagde;H. Rajabi;Audrey Bouillez;Maroof Alam;R. Gali;S. Bailey;Y. Tai;T. Hideshima;K. Anderson;D. Avigan;D. Kufe