STK11/LKB1為serine/threonine 蛋白激酶，主要是腺嘌呤磷酸激酶活化蛋白激酶（AMPK）的上游活化激酶，對於細胞維持能量平衡的代謝反應是一個很重要的調控因子。由許多文獻指出LKB1基因發生突變會造成Peutz–Jeghers syndrome (PJS)以及一些癌症尤其在肺腺癌中，但LKB1如何影響肺癌發展的過程仍然了解甚少。因此，我們建立體外肺癌細胞模式來研究LKB1在人類肺腺癌中訊息傳遞所扮演的角色。結果發現當我們將LKB1回復在LKB1 缺失的肺癌細胞後，LKB1會抑制細胞的轉移與增生。此外，為了了解體內LKB1的抗癌機制，我們利用免疫沉澱與液相層析高解析度質譜儀分析 (IP-LC-MS) 確定與Lkb1有交互作用的新蛋白。利用IP-LC-MS結果發現Lkb1與Apc蛋白質間的相互作用。在正常細胞的條件下，藉由免疫沉澱檢測分析進一步證實Lkb1和Apc之間的相互作用。我們的研究結果指出，在肺癌細胞中Lkb1與Apc相互作用會抑制Wnt路徑的訊號傳遞，參與調節細胞增殖和遷移，LKB1調控Wnt下游基因分別為CD44、 COX-2和SURVIVIN。因此，我們的研究結果顯示，LKB1調控Wnt路徑的訊息傳遞可抑制人類肺癌細胞的致癌性及轉移能力。

STK11/LKB1, a serine/threonine protein kinase, is a key upstream kinase of adenine monophosphate-activated protein kinase (AMPK), a necessary kinase in the control of cell polarity and maintains cellular energy homeostasis. Although it has become clear that LKB1 is mutated in a significant number of Peutz–Jeghers syndrome (PJS) and sporadic cancers, most frequently in adenocarcinoma of the lung. Little is known about how the LKB1 involves in lung cancer progression process. Here, we employed Immunoprecipitation-HPLC-Mass Spectrometry (IP-LC-MS) to identify the novel proteins interacting with Lkb1 in lung cancer cells. We found that Lkb1 interacts with Apc, under normal cell conditions, and this physical interaction between Lkb1 and Apc was further confirmed by reverse-immunoprecipitation assays. Our findings here provide the first evidence that Lkb1 interacts with Apc to suppress WNT pathway, which involves in the regulation of cell proliferation and migration in lung cancer cells, and LKB1 downstream gene analyses lead to the identification of several Wnt regulated genes, CD44, COX-2 and SURVIVIN, whose expression levels are altered in vitro. Altogether, our results indicate that LKB1 regulates Wnt pathway to suppress tumorigenic/metastatic potential of human lung cancer cells.

Abstract in Chinese ------------------------------------------------- iii
Abstract in English -------------------------------------------------- iv
Abbreviations ---------------------------------------------------------- v
Introduction ------------------------------------------------------------ 1
Materials and Methods --------------------------------------------- 7
Results ---------------------------------------------------------------- 16
Discussion ------------------------------------------------------------ 25
Figures and Tables -------------------------------------------------- 34
References ------------------------------------------------------------ 59

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