高果糖飲食加劇胰腺導管腺癌的發展

Abstract

胰臟癌作為一高度侵襲性癌症具有高發病率和高死亡率，在台灣癌症十大死因中排名第八。胰臟癌因具有高度轉移性且早期發現不易，導致病患手術無效、預後不佳或是易復發的情形，使其五年內存活率低於百分之五。先前研究證實，將近百分之九十以上的胰臟癌都因為KRAS基因點突變所誘發，導致胰臟出現胰腺上皮內瘤病變，從而發展為胰腺導管腺癌。近幾年來已有若干研究證明果糖的攝取與罹患胰臟癌有相關性，儘管發現果糖代謝與葡萄糖代謝相異，以此增加胰臟癌細胞的增殖能力，但是果糖飲食如何加劇胰臟癌的機制目前尚未清楚。 本研究之目標將試圖釐清果糖飲食於胰臟癌中之分子機制。我們藉由基因工程小鼠Pdx1-Cre;KrasG12D小鼠建立胰腺上皮內瘤病變模型，並持續餵食高果糖飼料16周以作觀察。我們發現餵食高果糖的Pdx1-Cre ;KrasG12D小鼠平均壽命較短，觀察胰臟切片也證實其胰腺上皮內瘤病變程度較為嚴重。利用血中胰澱粉酶值、胰解脂酶值、血糖值和胰島素值比較也發現餵食高果糖之Pdx1-Cre;KrasG12D小鼠胰臟一直處於高度發炎和功能衰竭的狀態。最後，利用PI3K/AKT-MEK/ERK、NF-κB、發炎因子、上皮間質轉化和癌症幹細胞信號途徑證實高果糖會促進癌細胞增殖、分化，並抑制凋亡，並增加癌細胞轉移能力以加速胰臟癌發展。

The Pancreatic cancer is a highly invasion carcinoma with high morbidity and mortality. It is the tenth most common cause of cancer deaths in Taiwan and little known about in its treatment over the past years. About 90% of pancreatic cancer is caused by Kras mutation and leads to precursor lesions which are known as Pancreatic Intraepithelial Neoplasia (PanIN) to progress to 100% in advanced Pancreatic ductal adenocarcinoma (PDAC). The fructose diet has been widely used in modern Western society. Several reports have been demonstrated that fructose intake is associated with increased pancreatic cancer development. Although fructose metabolism is different from glucose metabolism, and provides a substrate to induce pancreatic cancer cell proliferation and metastasis, the mechanisms of the fructose diet how to exacerbate pancreatic cancer is still unclear. In the present study, we aim to identify the mechanisms of the fructose diet in pancreatic cancer using genetically engineered pancreatic cancer mouse model, Pdx1-Cre;KrasG12D mice for this study. The Pdx1-Cre;KrasG12D mice kept on a high fructose diet for 4 months, and found the survival rate of Pdx1-Cre;KrasG12D mice with high fructose diet was shorter than Pdx1-Cre;KrasG12D mice with normal chow. Moreover, we also observed that Pdx1-Cre;KrasG12D mice with high fructose diet were significantly increased PanIN lesions, particularly in PanIN 3. The plasma levels of amylase, lipase, glucose and insulin were increased in Pdx1-Cre;KrasG12D mice with high fructose diet. The PI3K/AKT-MEK/ERK, NF-κB, Inflammation, EMT and CSCs signaling pathways were also enhanced in Pdx1-Cre;KrasG12D mice with high fructose diet as compared to Pdx1-Cre;KrasG12D mice with normal chow. Overall, Pdx1-Cre;KrasG12D mice with high fructose diet exacerbate pancreatic cancer development may through several signaling pathways, especially EMT and CSCs signaling pathway.