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Tn抗原通過H-Ras介導的上皮-間質轉化激活促進人類結直腸癌轉移

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發表時間：2024-09-03 14:29

2019年11月，首都醫科大學附屬北京朝陽醫院腫瘤科；首都醫科大學附屬北京朝陽醫院醫學研究中心(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老師研究團隊在《JOURNAL OF CELLULAR AND MOLECULAR MEDICINE》上發表論文：

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

“Tn抗原通過H-Ras介導的上皮-間質轉化激活促進人類結直腸癌轉移”

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抗原是一種截斷的o聚糖，在結直腸癌(CRC)中經常檢測到，但其在結直腸癌轉移中的確切作用尚未得到很好的解決。本研究探討了core1 β3Gal-T特異性分子伴侶(Cosmc)缺失介導的Tn抗原暴露對結直腸癌轉移的影響及其潛在機制。我們首先利用CRISPR/Cas9技術敲除正常o糖基化所需的Cosmc，從而獲得tn陽性的CRC細胞。然后我們研究了Tn抗原在結直腸癌中表達的生物學后果。結果表明，n-陽性細胞在體外和體內均表現出增強的轉移能力。進一步分析表明，Tn抗原表達誘導典型的上皮-間質轉化(EMT)激活。在機制上，我們發現已知驅動EMT的H-Ras在Tn陽性細胞中顯著上調，而敲低H-Ras則抑制Tn抗原誘導的EMT激活。此外，我們證實轉染野生型Cosmc的LS174T細胞(Tn陽性)不表達Tn抗原，從而下調H-Ras的表達，從而抑制EMT過程。此外，TCGA隊列中438個樣本的分析表明，Cosmc表達與H-Ras呈負相關，強調了Tn抗原H-Ras信號傳導在CRC患者中的重要性。這些數據表明，Cosmc缺失介導的Tn抗原暴露促進結直腸癌轉移，這可能是由h - ras誘導的EMT激活介導的。