Tn抗原通过H-Ras介导的上皮-间质转化激活促进人类结直肠癌转移

2019年11月，首都医科大学附属北京朝阳医院肿瘤科；首都医科大学附属北京朝阳医院医学研究中心(Department of Oncology, Beijing Chao Yang Hospital, Capital Medical University,Beijing, China；Medical Research Center, Beijing Chao Yang Hospital, Capital Medical University,Beijing, China) Tao Wen老师研究团队在《JOURNAL OF CELLULAR AND MOLECULAR MEDICINE》上发表论文：

“Tn antigen promotes human colorectal cancer metastasis via H-Ras mediated epithelial-mesenchymal transition activation”

“Tn抗原通过H-Ras介导的上皮-间质转化激活促进人类结直肠癌转移”

Abstract：

Tn antigen is a truncated O-glycan, frequently detected in colorectal cancer (CRC), but its precise role in CRC metastasis is not well addressed. Here we investigated the effects of Core 1 β3Gal-T specific molecular chaperone (Cosmc) deletion-mediated Tn antigen exposure on CRC metastasis and its underlying mechanism. We first used CRISPR/Cas9 technology to knockout Cosmc, which is required for normal O-glycosylation, and thereby obtained Tn-positive CRC cells. We then investigated the biological consequences of Tn antigen expression in CRC. The results showed that Tn-positive cells exhibited an enhanced metastatic capability both in vitro and in vivo. A further analysis indicated that Tn antigen expression induced typical activation of epithelial-mesenchymal transition (EMT). Mechanistically, we found that H-Ras, which is known to drive EMT, was markedly up-regulated in Tn-positive cells, whereas knockdown of H-Ras suppressed Tn antigen induced activation of EMT. Furthermore, we confirmed that LS174T cells (Tn-positive) transfected with wild-type Cosmc, thus expressing no Tn antigen, had down-regulation of H-Ras expression and subsequent inhibition of EMT process. In addition, analysis of 438 samples in TCGA cohort demonstrated that Cosmc expression was reversely correlated with H-Ras, underscoring the significance of Tn antigen-H-Ras signalling in CRC patients. These data demonstrated that Cosmc deletion-mediated Tn antigen exposure promotes CRC metastasis, which is possibly mediated by H-Ras-induced EMT activation.

摘要：

Tn抗原是一种截断的o聚糖，在结直肠癌(CRC)中经常检测到，但其在结直肠癌转移中的确切作用尚未得到很好的解决。本研究探讨了core1 β3Gal-T特异性分子伴侣(Cosmc)缺失介导的Tn抗原暴露对结直肠癌转移的影响及其潜在机制。我们首先利用CRISPR/Cas9技术敲除正常o糖基化所需的Cosmc，从而获得tn阳性的CRC细胞。然后我们研究了Tn抗原在结直肠癌中表达的生物学后果。结果表明，n-阳性细胞在体外和体内均表现出增强的转移能力。进一步分析表明，Tn抗原表达诱导典型的上皮-间质转化(EMT)激活。在机制上，我们发现已知驱动EMT的H-Ras在Tn阳性细胞中显着上调，而敲低H-Ras则抑制Tn抗原诱导的EMT激活。此外，我们证实转染野生型Cosmc的LS174T细胞(Tn阳性)不表达Tn抗原，从而下调H-Ras的表达，从而抑制EMT过程。此外，TCGA队列中438个样本的分析表明，Cosmc表达与H-Ras呈负相关，强调了Tn抗原H-Ras信号传导在CRC患者中的重要性。这些数据表明，Cosmc缺失介导的Tn抗原暴露促进结直肠癌转移，这可能是由h - ras诱导的EMT激活介导的。

该论文中，人结直肠癌细胞系HCT116和SW480以及人胚胎肾细胞HEK293T的体外培养是使用Ausbian特级胎牛血清完成的。欲了解或购买Ausbian特级胎牛血清可以联系北京缔一生物400-166-8600.