凝血酶調節素(Thrombomodulin, TM)是一個調控上皮細胞連接的第一型穿膜醣蛋白。TM的轉錄在上皮間質轉化(epithelial-mesenchymal transition, EMT)的過程中受到Snail的抑制。α-actinin-4 (ACTN4)是一種絲狀肌動蛋白的結合銜接子，在子宮頸癌細胞中大量表達ACTN4會透過調節Snail表達而誘導細胞進行上皮間質轉化。先前，我們發現TM在上皮細胞與細胞間的連接處與ACTN4有相互作用。然而，關於上皮連接處的TM-ACTN4相互作用在上皮間質轉化的過程中其生物學意義仍不清楚。因此，本篇研究主要探討TM是否可能透過控制ACTN4來抑制上皮間質轉化。我們利用西方墨點法和螢光染色研究TM和ACTN4在上皮間質轉化期間的表達與細胞內之分佈。另外我們也利用功能增益(gain of function)和功能喪失(loss of function)來觀察TM和ACTN4之相互作用在調控形態變化上的生物學意義。首先，我們使用A431細胞（一種表皮樣癌細胞）來觀察TM和ACTN4在上皮間質轉化中的變化。轉化生長因子β(TGF-β)和表皮生長因子(EGF)共同刺激後，A431細胞有明顯的上皮間質轉化以及大量表現ACTN4。單獨使用TGF-β刺激則使得TM表現量降低而vimentin（一種間質指標蛋白）表現量增加。於細胞間連接處與TM有相同分佈的ACTN4在TGF-β和EGF共同刺激時會被釋放至細胞質。在A431細胞中抑制ACTN4的表現並不會改變TM的表達量或其細胞內位置，而在抑制ACTN4表現之後，可以使得細胞在使用TGF-β和EGF刺激誘導上皮間質轉化的情形被抑制。相反地，抑制TM表達會導致細胞形態的改變以及vimentin表達、occludin和上皮鈣黏蛋白(E-cadherin)的位置改變;但同時抑制TM和ACTN4表現則可以減少EMT。另外在A2058黑色素瘤細胞中表達TM會促使細胞呈現聚集生長的細胞型態以及ACTN4的表現位置再重回至細胞與細胞連接處，並且使得vimentin表現量降低、E-cadherin的表現量增加，顯示細胞經歷間質上皮轉化(MET)。相反地，A2058細胞表達TM細胞質功能區(cytoplasmic domain)中和ACTN4結合的序列帶有突變(TM-522RKK524/AAA)的基因則會破壞聚集生長的細胞型態，並使得vimentin表現而E-cadherin減少。因此根據以上的實驗結果，我們認為TM會穩定上皮細胞與細胞間的連接並透過牽制ACTN4於細胞與細胞間的連結處而抑制上皮間質轉化。

Thrombomodulin (TM) is a type I transmembrane glycoprotein that mediates epithelial cell-to-cell interaction. The transcription of TM is suppressed by Snail during epithelial-mesenchymal transition (EMT). Alpha-actinin-4 (ACTN4) is a filamentous actin-binding adaptor protein that induces EMT by induction of Snail expression when overexpressed ACTN4 in cervical cancer cells. Previously, we showed that TM could interact with ACTN4 at cell junctions of epithelial cells. However, the contribution of TM-ACTN4 interaction at epithelial junctions in EMT remains unclear. Therefore, we investigated whether TM might suppress EMT through control the distribution of ACTN4 in cytosol. The distribution of TM and ACTN4 in cells before and after EMT was investigated using western blot analysis and immunofluorescence microscopy. The biological significance of TM and ACTN4 interaction in regulation of morphological changes was evaluated using gain-of-function and loss-of-function strategies. First, we use A431 cells, an epidermoid carcinoma cell to investigate the role of TM and ACTN4 in EMT. A431 cells exhibited profound EMT phenotype and upregulation of ACTN4 by co-stimulation with transforming growth factor beta (TGF-β) and epidermal growth factor (EGF). TGF-β alone caused TM downregulation along with upregulation of vimentin, a mesenchymal marker. ACTN4, which is co-localized with TM at cell-cell junctions, was released to cytoplasm upon TGF-β and EGF co-stimulation. Knockdown of ACTN4 in A431 cells did not alter either TM expression or subcellular location. However, EMT induced by TGF-β/EGF was suppressed in the cells if ACTN4 expression was knockdown. Conversely, knockdown of TM altered the epithelial cell morphology, vimentin expression, and caused dislocation of occludin and E-cadherin from cell-cell junction to cytoplasm; whereas, knockdown of TM and ACTN4 at the same time reduced EMT phenotype. On the other hand, overexpression of TM in A2058 melanoma cells led to clustering growth phenotype along with concentration of ACTN4 at cell-cell junctions, downregulation of vimentin and upregulation of E-cadherin, suggesting that cells undergo a mesenchymal-to-epithelial transition progress. Reversely, transfection of TM gene with mutation in a putative ACTN4-binding motif in TM cytoplasmic domain disrupted clustering growth phenotype along with upregulation of vimentin and downregulation of E-cadherin. Taken together, these results indicated that TM stabilized epithelial junctions and control the ACTN4 distribution at cell-cell junctions to block EMT.

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