Hsieh Chi-Che, Shyr Yi-Ming, Liao Wen-Ying, Chen Tien-Hua, Wang Shin-E, Lu Peir-Chuen, Lin Pei-Yu, Chen Yan-Bo, Mao Wan-Yu, Han Hsin-Ying, Hsiao Michael, Yang Wen-Bin, Li Wen-Shan, Sher Yuh-Pyng, Shen Chia-Ning
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.
Oncotarget. 2017 Jan 31;8(5):7691-7709. doi: 10.18632/oncotarget.13845.
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.
胰腺导管腺癌（PDAC）是一种侵袭性胰腺癌，具有局部侵袭和早期转移的临床特征。最近的队列研究表明，高果糖摄入与胰腺癌风险增加有关。然而，果糖促进胰腺肿瘤发生的机制仍不清楚。在此，将Kras+/LSLG12D小鼠与Elas-CreER转基因小鼠杂交，以确定果糖摄入是否直接促进肿瘤形成。进行原位肿瘤异种移植实验，以确定果糖替代是否增强PDAC细胞的转移潜能。通过RNAseq分析结合高效阴离子交换色谱法探索果糖作用的潜在机制。最初发现，饮食中的果糖可促进成年胰腺中条件性表达KrasG12D的小鼠发生侵袭性胰腺癌。我们进一步发现，果糖替代通过侵袭性ABCG2阳性亚群的选择性生长和提高N-乙酰甘露糖胺水平来增强人PDAC细胞的转移潜能，N-乙酰甘露糖胺水平上调β-半乳糖苷α2,6-唾液酸转移酶1（ST6Gal1），从而促进远处转移。最后，我们观察到，与其他组相比，ST6Gal1和GLUT5表达水平较高的PDAC患者预后较差。总之，我们的研究结果阐明了ST6Gal1在以果糖反应性方式调节PDAC侵袭性方面的关键作用。
