肝癌為全球最常見的惡性腫瘤之一，其癌症相關致死率則排名全球第三，目前治療肝癌的方式侷限於肝臟切除與手術移植。肝癌的特性為具高度的血管分佈，能夠幫助腫瘤細胞生長。在肝癌細胞中細胞激素IL-6能夠活化STAT3蛋白。另外，中心體蛋白CPAP除了在中心體扮演重要角色外，亦為NF-B與STAT5的轉錄輔助活化因子 (transcriptional co-activator)。實驗室先前的研究發現，CPAP在B型肝炎病毒感染所致的肝癌病人中有過量表現的情形。本論文主要探討在肝癌中CPAP參與在IL-6/STAT3訊息傳遞途徑中的功能性角色。我們的研究發現，在IL-6刺激下，過量表現GFP-CPAP可增加STAT3轉錄活性及其下游標的基因的表現。在免疫共沉澱 (co- immunoprecipitation)的實驗中也觀察到CPAP可以和STAT3形成複合體。此外，我們也發現，在肝癌檢體中CPAP和p-STAT3的表現呈正相關，此外，根據研究報導指出IL-8會藉由增加血管內皮細胞存活、增生、基質金屬蛋白酶的分泌調控細胞內血管新生。有趣的是，在IL-6刺激下，過量表現GFP-CPAP可增加IL-8的啟動子活性，且在酵素免疫分析法 (ELISA)實驗中也發現，GFP-CPAP能增加IL-8與VEGF的蛋白分泌。利用原位異種移植與脾臟注射動物模式，我們發現CPAP會促進肝癌細胞之生長和轉移。此外，由肝癌檢體也發現CPAP與病人血清中IL-8蛋白的表現呈正相關。這些結果顯示，CPAP可能透過IL-6/STAT3途徑促進IL-8與VEGF的表現而導致肝癌的惡化。

Overexpression of GFP-CPAP significantly enhanced STAT3-driven transcriptional activation in response to IL-6 treatment. Overexpressed GFP-CPAP transcriptionally increased the targeted gene expression of STAT3 upon IL-6 stimulation. Co-immunoprecipitation showed that CPAP can form a complex with STAT3 in response to IL-6 treatment. Immunoblot analysis further indicates that overexpression of CPAP is positively correlated with activated STAT3 (p-STAT3) in HCC tissues. On the other hand, it was reported that interleukin-8 (IL-8) can regulate angiogenesis by enhancing endothelial cell survival, proliferation and matrix metalloproteinases production. Interestingly, overexpression of GFP-CPAP enhances the promoter activity of IL-8 under IL-6 treatment. The enhanced expression of IL-8 and VEGF by overexpressed GFP-CPAP were further confirmed by ELISA. By orthotopic and splenic mouse model, it showed that overexpressed CPAP can promote tumor growth and metastasis. Moreover, the expression of CPAP is positively correlated with plasma IL-8 in HCC patients. Taken together, our results suggest that CPAP may contribute to HCC malignancy through the IL-6/STAT3 pathway-mediated IL-8 and VEGF expressions.

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