title: Elevation of β-galactoside α2,6-sialyltransferase 1 in a fructoseresponsive manner promotes pancreatic cancer metastasis.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of pancreatic cancer with clinical characteristics of local invasion and early metastasis. Recent cohort studies indicate high fructose intake is associated with an increase in pancreatic cancer risk. However, the mechanisms by which fructose promotes pancreatic tumorigenesis remain unclear. Herein, Kras+/LSLG12D mice were crossed with Elas-CreER transgenic mice to determine whether fructose intake directly contributes to tumor formation. Orthotopic tumor-xenograft experiments were performed to determine whether fructose substitution enhances the metastatic potential of PDAC cells. The mechanisms underlying the effects of fructose were explored by RNAseq analysis in combination with high-performance anion exchange chromatography. Dietary fructose was initially found to promote the development of aggressive pancreatic cancer in mice conditionally expressing KrasG12D in the adult pancreas. We further revealed that fructose substitution enhanced the metastatic potential of human PDAC cell via selective outgrowth of aggressive ABCG2-positive subpopulations and elevating N-acetylmannosamine levels that upregulated β-galactoside α2,6-sialyltransferase 1 (ST6Gal1), thereby promoting distant metastasis. Finally, we observed that PDAC patients expressing higher levels of ST6Gal1 and GLUT5 presented poorer prognosis compared to other groups. In conclusion, our findings have elucidated a crucial role of ST6Gal1 in regulating the invasiveness of PDACs in a fructose-responsive manner.
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taiwan.|Genomics Research Center and Academia Sinica, Taipei, Taiwan.
authors.forename: Chi-Che
authors.initials: CC
authors.lastname: Hsieh
authors.affiliation: Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Shyr
authors.affiliation: Genomics Research Center and Academia Sinica, Taipei, Taiwan.
authors.forename: Wen-Ying
authors.initials: WY
authors.lastname: Liao
authors.affiliation: Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.|Institute of Anatomy and Cell Biology and National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tien-Hua
authors.initials: TH
authors.lastname: Chen
authors.affiliation: Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.|Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shin-E
authors.initials: SE
authors.lastname: Wang
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Peir-Chuen
authors.initials: PC
authors.lastname: Lu
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Pei-Yu
authors.initials: PY
authors.lastname: Lin
authors.affiliation: Genomics Research Center and Academia Sinica, Taipei, Taiwan.
authors.forename: Yan-Bo
authors.initials: YB
authors.lastname: Chen
authors.affiliation: Genomics Research Center and Academia Sinica, Taipei, Taiwan.
authors.forename: Wan-Yu
authors.initials: WY
authors.lastname: Mao
authors.affiliation: Genomics Research Center and Academia Sinica, Taipei, Taiwan.
authors.forename: Hsin-Ying
authors.initials: HY
authors.lastname: Han
authors.affiliation: Genomics Research Center and Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: Genomics Research Center and Academia Sinica, Taipei, Taiwan.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Yang
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
authors.forename: Wen-Shan
authors.initials: WS
authors.lastname: Li
authors.affiliation: The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taiwan.|Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
authors.forename: Yuh-Pyng
authors.initials: YP
authors.lastname: Sher
authors.affiliation: Genomics Research Center and Academia Sinica, Taipei, Taiwan.|Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.|Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chia-Ning
authors.initials: CN
authors.lastname: Shen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism; D000368:Aged; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D000073417:Dietary Sugars / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005632:Fructose / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D011905:Genes, ras; D051296:Glucose Transporter Type 5 / Q000378:metabolism; D006595:Hexosamines / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D034622:RNA Interference; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D015703:Antigens, CD; D000970:Antineoplastic Agents; D000073417:Dietary Sugars; D005632:Fructose; D051296:Glucose Transporter Type 5; D006595:Hexosamines; D009363:Neoplasm Proteins; D012799:Sialyltransferases; C116614:ABCG2 protein, human; C495726:SLC2A5 protein, human; C093493:ST6GAL1 protein, human; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase; C002022:N-acetylmannosamine
keywords: 6-sialyltransferase 1; fructose; metastasis; pancreatic ductal adenocarcinoma; β-galactoside α2