Wnt/β-catenin傳遞路徑是肝癌(HCC)中經常失調的傳遞路徑，不僅參與調控胚胎的早期發育，也參與成年動物的正常生理調節以及癌症的發生在沒有Wnt蛋白刺激的情況下，細胞質中的多蛋白破壞複合物(multiprotein destruction complex)會促進β-catenin的磷酸化，進一步將β-catenin降解；當受到Wnt蛋白刺激時，破壞複合物會被吸附至細胞膜上，使β-catenin在細胞質中累積，最終進入細胞核，與LEF-1和TCF結合，活化Wnt標靶基因的表達。Wnt/β-catenin傳遞路徑的失調，以及Wnt/β-catenin標靶基因的異常活化，在各種人類癌症中非常常見，並且會促進癌症發展。因此，鑑定Wnt/β-catenin傳遞路徑的標靶基因是很重要的。在過去我們使用生物資訊學和實驗相結合的方法，找到三個新穎的Wnt/β-catenin標靶基因：POMGNT2 (C3orf39)、RMI2和ZNF496。而在本研究中還有四個潛在的基因待驗證，分別為CCDC77、ETV4、GPR107和METTL1。為了進一步確認這四個基因所預測的TCF結合位點，我們使用冷光素酶報告基因檢測(luciferase reporter assay)、截短實驗(truncation assay)和點突變實驗(point mutation assay)完成驗證。另外，確定基因在肝癌中的表達也是本研究的重點。由luciferase reporter assay發現CCDC77轉錄活性不受β-catenin的影響，但在一系列的truncation assay和point mutation assay中，顯示CCDC77的TBE2可能是弱的WRE。GPR107亦檢測到弱的啟動子(promoter)活性，且不受β-catenin調控，根據其啟動子轉錄活性檢測結果，推測內部具有不只一個的轉錄抑制位點。而ETV4和METL1的啟動子則具有高度轉錄活性，並且可以被β-catenin活化。通過連續啟動子truncation assay並以β-catenin活化，比較了不同大小片段的目標基因作用，顯示ETV4和METTL1的高轉錄活性並非源自生物資訊軟體所預測的TCF結合位點，並且ETV4的Wnt響應元件(Wnt responsive element, WRE)可能在-116 bp內，而METTL1則是在-295 bp至-148 bp之間。同時，根據TCGA數據庫的分析，顯示四個潛在基因與肝癌的存活率顯著相關。透過半定量RT-PCR，檢測了15例來自國立成功大學醫學院附設醫院肝癌患者的腫瘤組織和鄰近的非腫瘤組織的基因表達。結果發現基因在肝腫瘤組織中有很高的機率過表現，而這些與TCGA數據庫的分析結果一致。總結目前的研究成果，我們確認了ETV4和METTL1是Wnt/β-catenin傳遞路徑中的相關基因，並且很可能是該傳遞路徑的直接標靶基因。這兩個基因仍然需要以point mutation assay來驗證WRE的位置。對於CCDC77和GPR107，雖然皆檢測到低的轉錄活性，但目前的研究還不能認定此兩個基因非Wnt/β-catenin直接標靶基因。可能的TCF結合位點需要再往啟動子的上游尋找約3kb才能確定。另一方面，此四個基因都有在肝臟腫瘤中過表達的趨勢，並可能成為肝癌臨床治療的癌症標誌物。期望在這四個潛在基因中驗證出數個新穎的Wnt/β-catenin傳遞路徑標靶基因。

Previously, we used a combined bioinformatics and experimental approach to find three novel Wnt/β-catenin target genes. In this study, there are additional four potential genes remained to be verified: CCDC77, ETV4, GPR107 and METTL1. To further validate the putative TCF-binding element of four novel Wnt/β-catenin direct targets, we used the luciferase reporter assay, truncation assay and point mutation assay. The promoters of ETV4 and METTL1 showed high transcriptional activity and were regulated by β-catenin, but they did not derive from predicted typical TCF-binding elements. GPR107 didn’t detect a strong promoter activity and appeared to have transcriptional inhibition sites. CCDC77 didn’t show strong activity in its promoter, but TBE2 may be a weak Wnt responsive element (WRE). Moreover, four genes show significant correlation with the survival of HCC and were upregulated in HCC tumor tissues compared with their normal counterparts. Collectively, we confirmed that ETV4 and METTL1 were likely to be direct target genes in the Wnt/β-catenin signaling pathway. For CCDC77 and GPR107, although no strong transcriptional activity had been detected, the potential TCF binding element may be upstream of the promoter. Finally, we believe that these four genes still have research potential and may become cancer markers for clinical treatment of HCC.

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