食道鱗狀細胞癌為具高度轉移風險與高致死率的癌症之一，目前對於其轉移的機制仍不完全清楚。先前的研究中發現大量的纖連蛋白(fibronectin)聚集在食道癌CE81T細胞表面會促進該細胞癌轉移，並且與微小核糖核酸miR-146a的表現呈顯著之負相關，更證實miR-146a專一性地降解其標靶基因-纖維蛋白(vimentin)進而抑制食道鱗狀細胞癌爬行能力。然而CE81FN+食道鱗狀細胞在腫瘤生成與轉移的試驗中生長過於緩慢，需四個月。為了縮短該細胞於動物試驗中腫瘤生成的能力以利於轉移機制的研究，本研究目標透過植入致癌性基因以增強CE81FN+細胞的致癌性並縮短其腫瘤生成所需的時間，以了解miR-146a及纖維蛋白如何影響腫瘤轉移。因此我們建立以誘導方式表現致癌性K-Ras基因，同時帶有冷光報導基因的細胞株(CE81FN+K-Ras-luc)，並再透過lentivirus建立大量表達miR-146a的細胞株(CE81FN+K-Ras-luc-146a)進行研究。免疫缺陷小鼠尾靜脈轉移實驗的結果顯示CE81FN+K-Ras-luc與CE81FN+K-Ras-luc-146a相較下表現出較強的轉移能力，並且CE81FN+K-Ras-luc相較於CE81FN+形成腫瘤的時間相較於先前的四個月縮短至約兩個月。然而我們卻在後續建立回補纖維蛋白的細胞株及動物實驗中發現喪失了K-Ras轉植基因的表現。為了克服此困難，我們轉而使用替代性的短暫轉染方法回補K-Ras轉植基因的表現。結果顯示過量表達野生型K-Ras外源基因能增強細胞增生、群落生成、細胞爬行與侵襲等癌化特性。此外源K-Ras亦能造成鈣粘蛋白(E-cadherin)表現量下降伴隨著纖維蛋白 (Vimentin)、轉錄因子Snail、Slug與MED28蛋白表現量上升，顯示與促進上皮間質轉型(EMT)可能有關。若在上述K-Ras外源基因細胞中，過量表達miR-146a的情況下，細胞增生、群落生成、細胞爬行與侵襲等癌化特性均被抑制， 鈣粘蛋白(E-cadherin)表現量上升伴隨著纖維蛋白 (Vimentin)、轉錄因子Slug與MED28蛋白表現量下降，。而在大量表達miR-146a的情況下回補纖維蛋白的表現，上述之癌化特性呈現不同程度之回復現象。上述之四細胞株在免疫缺陷小鼠的異種移植實驗中，腫瘤生成能力由強至弱分別為CE81FN+K-Ras-luc、CE81FN+K-Ras-luc-146a-VIM、CE81FN+K-Ras-luc-146a與CE81FN+。綜述之，本研究證實過量表達正常之K-Ras基因可顯著縮短ESCC CE81FN+細胞之致癌性及於小鼠中之成瘤時間，並揭示miR-146a經由降解目標基因Vimentin而抑制上述之癌化現象，致於EMT相關基因Med28基因在其中扮演何角色，值得進一步探討

Metastasis is a major risk factor of esophageal squamous cell carcinoma (ESCC) and associated with high mortality rate, but the underlying mechanism remains poorly understood. We previously showed that fibronectin assembly promotes ESCC metastasis accompanied with decreased expression of miR-146a, which was identified by miRNA microarray. We demonstrated that miR-146a could inhibit ESCC cell migration by targeting vimentin gene in vitro by pMIR-luciferase reporter assay. But the ESCC CE81FN+ cells display low tumorigenicity in the mouse model. The objective of this study is to enhance the tumorigenicity of CE81FN+ cells by overexpression K-Ras oncogene and clarify how miR-146a and its target gene vimentin affect metastasis in vivo. We established stable cell lines harboring wild type K-Ras transgene together with a luciferase report gene, and within or without miR-146a (CE81FN+K-Ras-luc and CE81FN+K-Ras-luc-146a). Our in vivo data show that CE81FN+K-Ras-luc cells exhibited high lung metastasis capability in NOD/SCID mice, and the time for lung metastasis of CE81FN+K-Ras-luc cells was shortened to about 2 months compared with the parental CE81FN+ cells (four months) by tail vein injection. Because the K-Ras transgene disappeared in CE81FN+K-Ras-luc related cell lines, K-Ras transgene was re-introduced into the cell lines by transient transfection. Subsequently, we reveal that overexpressing wild-type K-Ras gene enhanced cell proliferation, colony formation, cell migration and invasion in vitro by MTT assay, soft agar assay, Western blot analysis and TranswellTM. K-Ras transgene increased the expression of vimentin, Snail, Slug and MED28, a Mediator subunit but decreased the expression of E-cadherin. In contrast, miR-146a inhibited cell proliferation, colony formation, cell migration, invasion, and increased E-cadherin expression and decreased the expression of vimentin, snail, slug and MED28 through targeting vimentin gene expression. Restoring vimentin expression in CE81FN+K-Ras-luc-146a cells increased cell proliferation, colony formation, cell migration and invasion ability. Furthermore, CE81FN+K-Ras-luc cells showed high xenograft tumor formation, following by CE81FN+K-Ras-luc-146a-VIM, CE81FN+K-Ras-luc-146a and parental CE81FN+cells in NOD/SCID mice. In conclusion, we confirmed that overexpression of wild type K-Ras transgene in ESCC CE81+ cell lines could enhance the tumorigenicity and shorten the time of tumor formation, and Ras related tumorigenesis could be suppressed by miR-146a possibly through miR-146a targeting vimentin gene expression. However, the roles of EMT related genes and MED28 gene in ESCC EMT remain to be determined.

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