表皮生長因子(EGFR)在大腸直腸癌的發展之中扮演很重要的角色。作為EGFR的下游受體，Eps8在許多種癌症都有過度表達的現象，其中也包含大腸直腸癌。Eps8蛋白質包含了proline-rich序列，有助於和Src的SH3 domain進行交互作用，並加以活化下游的FAK，導致細胞遷移及增生能力的上升。在我們實驗室之前的研究中發現，IRSp53也會和Eps8參與在v-Src調控的癌變當中。已知IRSp53會和Eps8進行交互作用，Cdc42也可以和IRSp53的CRIB domain進行交互作用。這些蛋白質聚合體會活化IRSp53，進而使其移動到細胞膜上而促使絲狀偽足(filopodia)的形成。Eps8和IRSp53的交互作用也被證實能夠藉由誘導Rac的活性來促進human fibrosarcoma cell的移動性及侵略性。在本篇研究之中，我們確認了在實驗室之前所看到IRSp53S在大腸癌細胞中扮演著負調控生長的角色。除此之外，同時表達Eps8及IRSp53S在SW480細胞中會促進細胞凋亡的發生，藉此指出IRSp53S抑制腫瘤的角色。不像IRSp53S，IRSp58M在細胞培養及Soft agar中都看到會促進大腸直腸癌細胞的生長。除此之外，藉由TCGA database我們也發現IRSp58M和大腸直腸癌患者的無病死亡率有著負相關，指出IRSp58M在大腸直腸癌扮演著促進的角色。

Epidermal growth factor receptor (EGFR) plays an important role in the progression of colorectal cancer (CRC). As a downstream substrate of EGFR, epidermal growth factor pathway substrate number 8 (Eps8) is highly overexpressed in several human cancers, including CRC. Eps8 protein contains proline-rich regions to interact with the SH3 domain of Src, leading to the activation of focal adhesion kinase (FAK) and increased cell migration and cell proliferation in CRC cells. Previous studies in our lab have shown that insulin receptor tyrosine kinase substrate protein of 53 kDa (IRSp53) may also interact with Eps8 participating in v-Src-mediated transformation. It is known that when IRSp53 interacts with Eps8, Cdc42 will also interact with the CRIB domain of IRSp53. This protein complex will translocate to cell membrane to promote the formation of filopodia. The interaction of Eps8-IRSp53 has also been proved to promote migration and invasion in human fibrosarcoma cell by inducing Rac activity. In this study, we confirmed our previous findings that IRSp53S might play a negative role in promoting cell proliferation in CRC. Furthermore, double co-overexpressing IRSp53S and Eps8 promotes apoptosis in SW480 cells, indicating tumor suppressor role of IRSp53S. Unlike IRSp53S decreased colony formation in SW480 cells, overexpression of IRSp58M promoted the growth of CRC cells in both culture dish and soft agar. Furthermore, the expression of IRSp58M is negatively correlated with the disease free survival in CRC in TCGA database, suggesting IRSp58M has an oncogenic role in CRC.

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