Elevation of β-galactoside α2,6-sialyltransferase 1 in a fructose-responsive manner promotes pancreatic cancer metastasis

// Chi-Che Hsieh 1, 2 , Yi-Ming Shyr 4, 10 , Wen-Ying Liao 2 , Tien-Hua Chen 4, 5 , Shin-E Wang 4, 10 , Peir-Chuen Lu 6 , Pei-Yu Lin 7 , Yan-Bo Chen 2 , Wan-Yu Mao 2 , Hsin-Ying Han 2 , Michael Hsiao 2 , Wen-Bin Yang 2 , Wen-Shan Li 3 , Yuh-Pyng Sher 1, 8 , Chia-Ning Shen 2, 6, 9 1 The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taiwan 2 Genomics Research Center and Academia Sinica, Taipei, Taiwan 3 Institute of Chemistry, Academia Sinica, Taipei, Taiwan 4 Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan 5 Institute of Anatomy and Cell Biology and National Yang-Ming University, Taipei, Taiwan 6 Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan 7 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 8 Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan 9 Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan 10 Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan Correspondence to: Chia-Ning Shen, email: cnshen@gate.sinica.edu.tw Keywords: fructose, pancreatic ductal adenocarcinoma, metastasis, β-galactoside α2, 6-sialyltransferase 1 Received: May 24, 2016 Accepted: November 30, 2016 Published: December 09, 2016 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 Kras G12D 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.