Elevation of β-galactoside α2,6-sialyltransferase 1 in a fructoseresponsive manner promotes pancreatic cancer metastasis.
Elevation of β-galactoside α2,6-sialyltransferase 1 in a fructoseresponsive manner promotes pancreatic cancer metastasis.
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DOI：
10.18632/oncotarget.13845
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发表时间：
2017-01-31
期刊：
影响因子：
--
通讯作者：
Shen CN
中科院分区：
文献类型：
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作者：
Hsieh CC;Shyr YM;Liao WY;Chen TH;Wang SE;Lu PC;Lin PY;Chen YB;Mao WY;Han HY;Hsiao M;Yang WB;Li WS;Sher YP;Shen CN
胰腺导管腺癌（PDAC）是一种以局部浸润和早期转移为特征的侵袭性胰腺癌。最近的队列研究表明，高果糖摄入量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。本文中，将Kras+/LSLG 12 D小鼠与Elas-CreER转基因小鼠杂交以确定果糖摄入是否直接有助于肿瘤形成。进行原位肿瘤异种移植实验以确定果糖取代是否增强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，在成年胰腺中条件性表达KrasG 12 D的小鼠中，膳食果糖可促进侵袭性胰腺癌的发展。我们进一步揭示了果糖替代通过选择性生长侵袭性ABCG 2阳性亚群和升高N-乙酰甘露糖胺水平来增强人PDAC细胞的转移潜力，所述N-乙酰甘露糖胺水平上调β-半乳糖苷α 2，6-唾液酸转移酶1（ST 6 Gal 1），从而促进远处转移。最后，我们观察到与其他组相比，表达较高水平的ST 6 Gal 1和GLUT 5的PDAC患者预后较差。总之，我们的研究结果阐明了ST 6 Gal 1在果糖应答方式调节PDAC侵袭性中的关键作用。
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.