Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
J Cell Mol Med. 2019 Oct;23(10):6885-6896. doi: 10.1111/jcmm.14572. Epub 2019 Aug 7.
Aberrant expression of Sialyl-Tn (STn) antigen correlates with poor prognosis and reduced patient survival. We demonstrated that expression of Tn and STn in pancreatic ductal adenocarcinoma (PDAC) is due to hypermethylation of Core 1 synthase specific molecular chaperone (COSMC) and enhanced the malignant properties of PDAC cells with an unknown mechanism. To explore the mechanism, we have genetically deleted COSMC in PDAC cells to express truncated O-glycans (SimpleCells, SC) which enhanced cell migration and invasion. Since epithelial-to-mesenchymal transition (EMT) play a vital role in metastasis, we have analysed the induction of EMT in SC cells. Expressions of the mesenchymal markers were significantly high in SC cells as compared to WT cells. Equally, we found reduced expressions of the epithelial markers in SC cells. Re-expression of COSMC in SC cells reversed the induction of EMT. In addition to this, we also observed an increased cancer stem cell population in SC cells. Furthermore, orthotopic implantation of T3M4 SC cells into athymic nude mice resulted in significantly larger tumours and reduced animal survival. Altogether, these results suggest that aberrant expression of truncated O-glycans in PDAC cells enhances the tumour aggressiveness through the induction of EMT and stemness properties.
唾液酸化-Tn（STn）抗原的异常表达与不良预后和患者生存率降低相关。我们证明，胰腺导管腺癌（PDAC）中 Tn 和 STn 的表达是由于核心 1 合酶特异性分子伴侣（COSMC）的 hypermethylation 所致，并通过未知机制增强了 PDAC 细胞的恶性特性。为了探索这种机制，我们在 PDAC 细胞中基因敲除了 COSMC，以表达截断的 O-聚糖（SimpleCells，SC），这增强了细胞迁移和侵袭。由于上皮-间充质转化（EMT）在转移中起着至关重要的作用，我们分析了 SC 细胞中 EMT 的诱导。与 WT 细胞相比，SC 细胞中间充质标志物的表达明显升高。同样，我们发现 SC 细胞中上皮标志物的表达减少。在 SC 细胞中重新表达 COSMC 逆转了 EMT 的诱导。除此之外，我们还观察到 SC 细胞中癌症干细胞群体增加。此外，将 T3M4 SC 细胞原位植入无胸腺裸鼠中导致肿瘤明显增大和动物存活率降低。总之，这些结果表明，PDAC 细胞中截断的 O-聚糖的异常表达通过诱导 EMT 和干性特性增强了肿瘤的侵袭性。
