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Elevation of ?-galactoside ?2,6-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 ?-galactoside ?2,6-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.

SUBMITTER: Hsieh CC 

PROVIDER: S-EPMC5352353 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Hsieh Chi-Che CC   Shyr Yi-Ming YM   Liao Wen-Ying WY   Chen Tien-Hua TH   Wang Shin-E SE   Lu Peir-Chuen PC   Lin Pei-Yu PY   Chen Yan-Bo YB   Mao Wan-Yu WY   Han Hsin-Ying HY   Hsiao Michael M   Yang Wen-Bin WB   Li Wen-Shan WS   Sher Yuh-Pyng YP   Shen Chia-Ning CN  

Oncotarget 20170101 5


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 format  ...[more]

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