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.
['Yeo|Hui Ling|HL|', 'Fan|Tan-Chi|TC|', 'Lin|Ruey-Jen|RJ|', 'Yu|Jyh-Cherng|JC|', 'Liao|Guo-Shiou|GS|', 'Chen|Eric Sheng-Wen|ES|', 'Ho|Ming-Yi|MY|', 'Lin|Wen-Der|WD|', 'Chen|Kowa|K|', 'Chen|Chein-Hung|CH|', 'Hung|Jung-Tung|JT|', 'Wu|Jen-Chine|JC|', 'Chang|Nai-Chuan|NC|', 'Chang|Margaret Dah-Tsyr|MD|', 'Yu|John|J|0000-0002-3237-4272', 'Yu|Alice Lin-Tsing|AL|0000-0003-2444-0505']
D000818:Animals D001940:Breast D001943:Breast Neoplasms D002352:Carrier Proteins D018450:Disease Progression D005260:Female D061307:Human Umbilical Vein Endothelial Cells D006801:Humans D061986:MCF-7 Cells D008565:Membrane Proteins D051379:Mice D009364:Neoplasm Recurrence, Local D009389:Neovascularization, Pathologic D034741:RNA, Small Interfering D012794:Sialic Acids D012799:Sialyltransferases D015398:Signal Transduction D016019:Survival Analysis D053773:Transforming Growth Factor beta1 D015854:Up-Regulation D023041:Xenograft Model Antitumor Assays
sialylation vasorin ST3Gal1 angiogenesis breast cancer TGF-β1