近年來，非小細胞肺癌的發生率正快速地增加中。由於非小細胞肺癌的預後非常差，因此藉由了解肺癌進展的分子機制，進而制定出有效的治療方法是當務之急。在腫瘤的進展過程中，惡性轉型的腫瘤細胞破壞組織內的恆定性，並發展出對抗細胞凋亡（apoptosis）的機制而不斷增生。此外，透過抗凋亡逃避細胞死亡的方式也造成治療效果降低與較差的預後結果，因此需要深入探討腫瘤細胞的抗凋亡機制，並從中找到新穎治療標的。根據過去的研究指出，Oct4與Stat1蛋白均在非小細胞肺癌中有過量表現的情形，並參與在細胞抗凋亡的機制中。本研究目的為探討Oct4在非小細胞肺癌中，是否透過促進Stat1的表現進而抑制細胞凋亡的進行。我們利用54個臨床非小細胞肺癌檢體分析Oct4與Stat1的表現量，結果顯示Oct4與Stat1表現量呈現正相關，而且高度表達的Oct4與Stat1更與病人較差的預後有關聯性。接著，經由啟動子活性分析與染色質免疫沉澱證明，Oct4透過直接結合至Stat1啟動子來增加Stat1的表現量。另一方面，Stat1的下游基因Mcl-1也可受到Oct4的調控而增加表現量。除此之外，若在Oct4過量表現的細胞中抑制Stat1的表現，可以有效增加細胞對於化療藥物cisplatin的敏感性。另外在動物實驗中也發現過量表現Oct4會增加Stat1的表現量並促進腫瘤細胞的生長，而在抑制Stat1的表現後則會減緩Oct4所誘導的腫瘤生長。綜合以上的實驗結果說明Oct4經由調控Stat1的表現而參與在抗細胞凋亡的機制中，並進一步影響非小細胞肺癌病患的預後。

In recent years, the incidence of non-small-cell lung cancer (NSCLC) has increased rapidly. Because the prognosis of NSCLC is poor, there is an urgent need to understand the molecular mechanisms of NSCLC and thereby develop effective treatment. During tumor progression, cells with malignantly transformed phenotypes disrupt tissue homeostasis. Tumor cells usually proliferate indefinitely through their anti-apoptotic properties. Furthermore, evasion of cell death also leads to ineffective therapy and poor prognosis in cancer patients. Therefore, elucidating the anti-apoptotic mechanism of tumors and identifying novel therapeutic targets are urgently needed. Previous studies have revealed that both Oct4 and Stat1 are overexpressed in NSCLC and play roles in the anti-apoptotic mechanism. In this study, we investigated whether expression of Oct4 in NSCLC cells induces Stat1 gene expression and ultimately results in anti-apoptosis phenotypes. A total of 54 human NSCLC specimens were used to analyze the expression of Oct4 and Stat1. There was a positive correlation between the expression levels of Oct4 and those of Stat1. Furthermore, there expression was positively correlated with poor prognosis of the patients. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays reveal that Oct4 directly bound to the Stat1 promoter to induce Stat1 expression. Expression of the Stat1 downstream anti-apoptotic gene Mcl-1 was increased in Oct4-overexpressing cancer cells. Knockdown of Stat1 in Oct4-overexpressing cells sensitized them to cisplatin-induced apoptosis. Furthermore, in vivo studies indicate that Oct4 promoted Stat1 expression and tumor growth, whereas silencing of Stat1 ameliorated Oct4-induced tumor growth. Collectively, these results suggest the anti-apoptotic role of Oct4 is through upregulating Stat1 expression and may contribute to the poor prognosis in patients with NSCLC.

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