2015-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/647497摘要：胰癌在美國癌症致死率排行中名列第四，在台灣則排行第九。即使目前在胰癌已有多科整合治療的進步，胰癌五年存活率依然只有百分之六。發展新一代的分子標記，可使具備分子標記的胰癌患者藉著標靶治療得到療效。丙酮酸激酶M2係一糖解酵素，負責將磷酸烯醇丙酮酸和ADP轉化為丙酮酸和ATP。丙酮酸激酶M2主要在胚胎組織以及腫瘤中表現。在腫瘤細胞中，丙酮酸激酶M2的存在形式，可以決定葡萄糖的代謝方式：高活性之四聚體形式，將致使分解成乳酸以產生能量(Warburg效應）；低活性之二聚體形式，將致使代謝成多種小單元用於細胞建構。近年來，關於丙酮酸激酶M2在非糖解作用的研究報告越來越多。缺氧誘導因子1(HIF-1)可啟動丙酮酸激酶M2基因的轉錄；反之，丙酮酸激酶M2也可以和缺氧誘導因子1a直接互動，促成缺氧誘導因子的標的基因活化。入核的丙酮酸激酶M2可以將stat3磷酸化，因而啟動癌症相關基因如MEK5的轉錄作用。入核的丙酮酸激酶M2可以促進P-catenin的活化，從而導致cyclin D1和c-Myc的表現增加。入核的丙酮酸激酶M2也可以將組蛋白H3磷酸化，接續著發生HDAC3脫離以及組蛋白H3乙醯化，造成cyclin D1和c-Myc的表現增加。丙酮酸激酶M2還能夠藉著參與共同活化轉錄因子Oct-4，來調節癌幹細胞。丙酮酸激酶M2經由組織標本的胜肽分析比較，在肺癌、肝癌、大腸癌、腎細胞癌、以及膀胱癌中，表現量均有增加。然而，丙酮酸激酶M2在胰癌的角色仍屬未定，而其表現型態的生物訊息傳遞也不清楚。我們初步的結果顯示，在胰臟腺癌檢體中，丙酮酸激酶M2的表現量確有增加；而對於丙酮酸激酶M2進行功能性抑制，可以降低胰癌細胞的移動能力。我們因此假設丙酮酸激酶M2在胰癌的侵襲及轉移性調節上，扮演一定的角色。在此研究中，我們將評估胰癌組織中丙酮酸激酶M2的表現量，藉著臨床資料的比對，來確定丙酮酸激酶M2對胰癌預後的影響。此外，我們也將釐清在胰癌的侵襲性表現中，丙酮酸激酶M2與其下游分子之間的互動關係。此研究將闡明丙酮酸激酶M2在胰癌的角色，而對人類胰癌提供可能的新一代標靶治療方式。<br> Abstract: Pancreatic cancer is the 4th leading cause of cancer-related death in the US, while it ranks the 9th in Taiwan. Despite the improvement of multidisciplinary therapies in pancreatic cancer, the five-year relative survival rate remains only 6%. Development of new molecular markers is necessary and may identify a subgroup of pancreatic cancer patients who shall benefit from further molecularly targeted therapies.Pyruvate kinase (PK) M2 is a glycolytic enzyme catalyzing the conversion of phosphoenolpyruvate and ADP to pyruvate and ATP. PKM2 is expressed predominantly in embryonic tissue and tumors. In tumor cells, PKM2 determines whether glucose is converted to lactate for regeneration of energy (high-activity tetrameric form, Warburg effect) or used for the synthesis of cell building blocks (low-activity dimeric form). In recent years, more and more reports document the nonglycolytic functions of PKM2. PKM2 gene transcription could be activated by hypoxia-inducible factor 1 (HIF-1). Besides, PKM2 could interact directly with the HIF-1a subunit and thereby promote transactivation of HIF-1 target genes. Nuclear PKM2 could phosphorylate stat3 and activate transcription of cancer-relevant genes such as MEK5. Nuclear PKM2 could promote P-catenin transactivation and lead to expression of cyclin D1 and c-Myc. Nuclear PKM2 also phosphorylates histone H3, which is required for the dissociation of HDAC3 and subsequent histone H3 acetylation with further expression of cyclin D1 and c-Myc. PKM2 may regulate cancer stem cells by coactivating the transcription factor Oct-4. PKM2 expression is increased among diverse human cancers including lung, liver, colon, kidney, and urinary bladder, compared to matched normal tissues by peptide analysis. However, the role of PKM2 in pancreatic cancer is still indeterminate, and the biological consequence of the expression patterns is unclear. Our preliminary data showed that PKM2 expression increased in pancreatic adenocarcinoma specimens, and functional inhibition of PKM2 would reduce migration ability of pancreatic cancer cells. We thus hypothesize that PKM2 may play important roles in invasion/metastasis of pancreatic cancer.In this study, we'll evaluate PKM2 expression in pancreatic cancer tissues and determine its prognostic significance by clinical correlation. Furthermore, we'll attempt to elucidate the mechanistic relationship of PKM2 and downstream molecules in terms of pancreatic cancer invasiveness. The current study may yield new insight into the roles of PKM2 in pancreatic cancer, and may provide the possibly novel therapeutic blocking agents with intervention of associated molecules in human pancreatic cancer.胰癌丙酮酸激酶M2非糖解作用侵襲性癌轉移pancreatic cancerpyruvate kinase M2nonglycolytic functioninvasivenessmetastasis