肺癌是世界上造成癌症死亡最重要的原因，大約有百分之十五的肺癌病人於初期診斷時已有惡性肋膜積水產生，且惡性肋膜積水會發生於一半以上的肺癌末期病人。已知一些致癌基因對於肺癌發生扮演重要角色，包括Ras與Stat3。在臨床檢體的分析發現伴隨惡性肋膜積水的肺腺癌病人其腫瘤組織有Stat3持續活化的現象，其肋膜積水中也有IL-6與VEGF的過度表達。在PC14PE6/AS2人類肺腺癌細胞株中，我們發現Stat3持續活化的原因是透由細胞自我分泌IL-6進而促使JAK活化Stat3。在小鼠動物模式中發現過度表達顯性抑制型的Stat3可以降低VEGF的表現、腫瘤血管新生、腫瘤血管通透性、肺部轉移、惡性腹腔積水與惡性肋膜積水。
Ras致癌基因是MAPK訊息傳遞路徑中的重要調節蛋白質，受到Ras致癌基因轉型的細胞會引起形態上的改變。而Stat3致癌基因可以被細胞激素刺激所活化。本研究中發現在NIH3T3小鼠纖維母細胞中，Ras致癌基因過度表達會透過MEK/ERK訊息傳遞路徑抑制Stat3蛋白質的表現，而Ras致癌基因過度表達所引起的細胞形態改變可以被MEK/ERK抑制劑PD98059與U0126所抑制。進一步以蛋白質降解抑制劑的結果顯示蛋白質降解機制參與在Stat3蛋白質表現的調控。此外過度表達Stat3可以抑制由Ras所引起的細胞形態改變。綜上所述，我們的研究結果顯示IL-6/Stat3的訊息傳遞路徑在合併惡性肋膜積水的肺腺癌發生過程中扮演重要的角色，進一步也對於合併惡性肋膜積水的肺腺癌提供了治療的新方向。進ㄧ步研究證實，Stat3的蛋白質表現在Ras引起的細胞形態改變過程中扮演重要的角色。

Lung cancer is the leading cause of cancer death in the world. Approximately 15% of lung cancer patients have the pleural effusion at the time of initial diagnosis, and 50% develop the pleural effusion later in their courses. Several oncogenes play important roles in human lung cancer, including Ras and Stat3 (Signal Transducer and Activator of Transcription 3). Analysis of clinical specimen, we demonstrate constitutively activated Stat3 in several human lung cancer cell lines and in tumor cells infiltrated in the pleurae of patients with adenocarcinoma cell lung cancers (ADCLC) and malignant pleural effusion (MPE). Higher levels of IL-6 and VEGF were also found in the pleural fluids of patients with ADCLC than in patients with congestive heart failure. In PC14PE6/AS2 human adenocarcinoma cells, autocrine IL-6 activated Stat3 via JAKs, not via Src kinase. In an animal model, we found that overexpression of dominant-negative Stat3 in PC14PE6/AS2 reduced VEGF expression, induction of microvessel density and vascular permeability, ability for lung metastasis, and formation of malignant ascites and pleural effusion.
Ras is a key regulator of the MAP kinase-signaling cascade and may cause morphological changes of Ras transformed cells. Stat3 can be activated by cytokine stimulation. We found that Ha-rasV12 overexpression could down-regulate the expression level of Stat3 protein in NIH3T3 cells through MEK/ERK pathway. The morphological changes induced by Ha-rasV12 overexpression was blocked by treating the cells with MEK/ERK pathway inhibitors, PD98059 and U0126. Our data also indicates proteosome degradation is participated in the Ha-rasV12 overexpression down-regulated Stat3. Moreover, Ha-rasV12 overexpression induced morphological changes was reversed by restoration of Stat3 expression. Taken together, these findings suggest an important role for the IL-6/Stat3 pathway in the pathogenesis of ADCLC and MPE and provide novel targets for the management of MPE. Moreover, the expression of Stat3 protein plays the critical role in Ha-rasV12 overexpression induced morphological changes of NIH3T3 cells.

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