ST3Gal1对血管生成素的唾液酸化促进TGF-β1介导的肿瘤血管生成和进展,International Journal of Cancer

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ST3Gal1对血管生成素的唾液酸化促进TGF-β1介导的肿瘤血管生成和进展
International Journal of Cancer ( IF 5.7 ) Pub Date : 2019-01-03 , DOI: 10.1002/ijc.31891
Hui Ling Yeo, Tan‐Chi Fan, Ruey‐Jen Lin, Jyh‐Cherng Yu, Guo‐Shiou Liao, Eric Sheng‐Wen Chen, Ming‐Yi Ho, Wen‐Der Lin, Kowa Chen, Chein‐Hung Chen, Jung‐Tung Hung, Jen‐Chine Wu, Nai‐Chuan Chang, Margaret Dah‐Tsyr Chang, John Yu, Alice Lin‐Tsing Yu

ST3Gal1是关键的唾液酸转移酶，可将α2,3连接的唾液酸添加至底物并生成核心1 O聚糖结构。ST3Gal1的上调与乳腺癌患者的预后较差有关。但是，与肿瘤进展有关的ST3Gal1的蛋白质底物仍然难以捉摸。在我们的研究中，我们证明了ST3GAL1沉默显着降低了肿瘤的生长，同时MCF7异种移植肿瘤的血管明显减少。我们鉴定出可与TGF-β1结合的血管收缩素（VASN）是将ST3Gal1与血管生成联系起来的潜在候选物。对MCF7分泌的VASN的LC-MS / MS分析表明，其O-聚糖中80％以上是唾液酸3T和二唾液酸T。ST3GAL1神经氨酸酶对VASN的沉默或去唾液酸化作用使其与TGF-β1的结合增加了2到3倍，从而抑制了TGF-β1的信号传导和血管生成，如HUVEC的管形成受损，抑制了血管生成的基因表达并降低了Smad2的激活所表明的那样和Smad3在HUVEC细胞中。对114例新鲜原发性乳腺癌及其附近正常组织进行检查，发现ST3Gal1和TGFB1在肿瘤部位高表达，且两个基因的表达呈正相关。Kaplan Meier生存分析显示，对于那些VASN表达较低的患者，无复发生存期明显缩短，尤其是低VASN与高ST3GAL1的组合产生更高的复发风险（p = 0.025，HR = 2.967，95％CI = 1.14–7.67）。由于已知TGF-β1可以转录激活ST3Gal1，因此我们的发现说明了一个反馈调节环，其中TGF - β1上调ST3Gal1以规避VASN的负面影响。

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Sialylation of vasorin by ST3Gal1 facilitates TGF‐β1‐mediated tumor angiogenesis and progression

ST3Gal1 is a key sialyltransferase which adds α2,3‐linked sialic acid to substrates and generates core 1 O‐glycan structure. Upregulation of ST3Gal1 has been associated with worse prognosis of breast cancer patients. However, the protein substrates of ST3Gal1 implicated in tumor progression remain elusive. In our study, we demonstrated that ST3GAL1‐silencing significantly reduced tumor growth along with a notable decrease in vascularity of MCF7 xenograft tumors. We identified vasorin (VASN) which was shown to bind TGF‐β1, as a potential candidate that links ST3Gal1 to angiogenesis. LC‐MS/MS analysis of VASN secreted from MCF7, revealed that more than 80% of its O‐glycans are sialyl‐3T and disialyl‐T. ST3GAL1‐silencing or desialylation of VASN by neuraminidase enhanced its binding to TGF‐β1 by 2‐ to 3‐fold and thereby dampening TGF‐β1 signaling and angiogenesis, as indicated by impaired tube formation of HUVECs, suppressed angiogenesis gene expression and reduced activation of Smad2 and Smad3 in HUVEC cells. Examination of 114 fresh primary breast cancer and their adjacent normal tissues showed that the expression levels of ST3Gal1 and TGFB1 were high in tumor part and the expression of two genes was positively correlated. Kaplan Meier survival analysis showed a significantly shorter relapse‐free survival for those with lower expression VASN, notably, the combination of low VASN with high ST3GAL1 yielded even higher risk of recurrence (p = 0.025, HR = 2.967, 95% CI = 1.14–7.67). Since TGF‐β1 is known to transcriptionally activate ST3Gal1, our findings illustrated a feedback regulatory loop in which TGF‐β1 upregulates ST3Gal1 to circumvent the negative impact of VASN.

更新日期：2019-01-03

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