β4 integrin/FAK複合體對癌進程之調控機制

Regulatory Mechanisms of β4 Integrin/FAK Complex in Cancer Progression

戴佑玲(Yu-Ling Tai)

指導教授 ： 沈湯龍

國立臺灣大學/生物資源暨農學院/植物病理與微生物學研究所/博士(2016年)

https://doi.org/10.6342/NTU201600626

摘要

β4 integrin和focal adhesion kinase (FAK)分別皆顯示與癌惡化有相關性，近期研究推測此二種蛋白質可共同調控癌惡化的訊息傳遞。在此，我們的研究首次發現，β4 integrin和FAK蛋白質的共同大量表現與具有三陰性型乳癌或晚期結腸癌的病人之間，呈現顯著的正相關性。此外，在in vivo和in vitro情況下，β4 integrin和FAK蛋白質之間，具有物理性和功能性的直接交互作用，進而參與調控三陰性型乳癌和晚期結腸癌的惡化。其中，FAK蛋白質的氨基端與激酶之間的連結片段和β4 integrin的cytodomain有直接交互作用。我們亦發現EGFR/Src的訊息傳遞或層黏蛋白質(laminin)的刺激會促進β4 integrin的酪胺酸之磷酸化，進一步吸引FAK與其結合，且促使FAK活化。再者，若阻斷β4 integrin/FAK複合體的形成或FAK的活性，會抑制致癌性與癌轉移。綜合言之，我們的研究發現EGFR/Src或層黏蛋白質調控β4 integrin/FAK複合體的形成會影響癌惡化，進而提供癌症治療的新策略。

關鍵字

β4 integrin ； FAK ； 三陰性型乳癌 ； 結腸癌 ； 致癌性 ； 癌轉移

並列摘要

Although β4 integrin and focal adhesion kinase (FAK) are associated with cancer malignancies, only recently has the signaling event of these two molecules been implicated in cancer malignancy. Here, we demonstrate, for the first time, that the concomitant overexpression of β4 integrin and FAK significantly correlates in patients with malignant triple-negative breast cancer or advanced stages of colon cancer. Consistently, in vitro and in vivo physical and functional interactions between β4 integrin and FAK regulate triple-negative breast cancer and colon cancer malignancy. An amino-terminal linker within FAK is essential for its binding to the cytodomain of β4 integrin. Moreover, the EGFR/Src-signaling or laminin triggers the tyrosine phosphorylation of β4 integrin, leading to recruitment of FAK to β4 integrin as well as FAK activation. Furthermore, disruption of the β4 integrin/FAK complex and/or FAK activation markedly reduces tumorigenicity and cancer metastasis. Our studies show an EGFR/Src and/or laminin-dependent β4 integrin/FAK complex that governs cancer malignancy and sheds a novel strategy for cancer therapies.

並列關鍵字

β4 integrin ； FAK ； triple-negative breast cancer ； colon cancer ； tumorigenicity ； cancer metastasis

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