人類WWOX基因位在染色體上易斷裂 (fragile) 的位置上，可轉錄出含雙色胺酸功能區氧化還原酶 (WW domain-containing oxidoreductase，也稱作WWOX、FOR或WOX1)。在許多人類癌症組織中發現，WOX1蛋白質表現量有明顯下降的情形，顯示WOX1蛋白質表現量的下降與癌症發生有關。有趣的是，我們先前發現到當細胞中大量表現WOX1蛋白質時，可以調控和細胞存活有關的PI3K/AKT訊息傳遞路徑。我們最近的研究顯示，當SCC-15細胞大量表現WOX1時，可以調控參與細胞許多重要生理功能的ERK蛋白質磷酸化 (phosphorylation)。許多臨床研究也指出在癌症細胞中，ERK訊息傳遞途徑有異常活化的情形。因此，本研究想瞭解WOX1蛋白質調控ERK訊息傳遞的分子機制為何。在SCC-15細胞中，大量表現WOX1蛋白質也促進ERK上游分子MEK蛋白質磷酸化的情形。同樣地，利用HeLa Tet-on的系統，誘導出WOX1的表現後也可以增加MEK以及ERK蛋白質磷酸化的現象。MEK/ERK訊息傳遞途徑為mitogen-activating protein kinase (MAPK) 途徑的主要路徑之一，它負責調控細胞的增生、分化與存活。MEK抑制劑U0126可以明顯抑制WOX1提升ERK蛋白質磷酸化的情形。總結而言，WOX1蛋白質能活化MEK/ERK訊息傳遞。釐清WOX1蛋白質在MAPK訊息傳遞過程中所扮演的角色，將能提供一個全新的分子觀點來瞭解WOX1蛋白質在癌症進程中的影響。

WW domain-containing oxidoreductase (known as WWOX, FOR or WOX1) is encoded by a fragile gene WWOX. Loss of WOX1 protein expression has been shown in many human cancers. It has been suggested that downregulation of WOX1 protein expression is associated with tumorigenesis. Interestingly, we previously found that ectopic expression of WOX1 regulated the prosurvival PI3K/AKT signaling pathway. Our recent data showed that overexpression of WOX1 in SCC-15 cells regulated protein phosphorylation of ERK, a key kinase involved in many cellular functions. Substantial clinical evidences indicated that aberrant ERK signaling is frequently found in cancer cells. Thus, the aim of this study is to investigate the molecular mechanism by which WOX1 regulates ERK signaling pathway. In SCC-15 cells overexpressing WOX1, protein phosphorylation of ERK upstream kinase, MEK was also increased. Consistently, using HeLa tet-on system, our results demonstrated that inducible expression of WOX1 upregulated protein phosphorylation of MEK and ERK. MEK/ERK cascade is the main route of mitogen-activating protein kinase (MAPK) pathway that regulates cell proliferation, differentiation, and survival. MEK inhibitor U0126 significantly blocked WOX1-induced upregulation of ERK phosphorylation. In conclusion, our results suggest that WOX1 activates MEK/ERK pathway. Delineating the functional role of WOX1 in MAPK signaling pathway will provide a novel molecular insight into the influence of WOX1 on cancer progression.

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