凝血酶調節素(thrombomodulin，TM)是一種表現於細胞膜上的醣蛋白，透過與凝血酶(thrombin)形成複合體能達到抗凝血的功能。除了廣被人知的抗凝血功能之外，近年來研究指出TM表現量的高低與腫瘤的發展和轉移有關。除此之外，TM能透過其類凝集素功能區(lectin-like domain)調節鈣離子依賴型的細胞貼附，並且在上皮鈣黏蛋白(E-cadherin)所調節的細胞接觸中扮演一個重要的角色。但是對於TM如何去調控腫瘤細胞生長的詳細機制至今仍不甚清楚。從過去的文獻指出，上皮細胞會透過細胞接觸性抑制生長作用(cell contact inhibition)來調控生長，一旦細胞失去細胞接觸性抑制生長作用，生長便會失去調控並且可能導致腫瘤的發生。此外許多的細胞黏著分子也扮演著腫瘤抑制者的角色，並且是透過細胞接觸性抑制生長作用來達成。因此在本篇研究主要去探討TM是否會經由細胞接觸性抑制生長作用，去抑制細胞的生長且了解其相關分子機制。由實驗結果得知在正常人類角質細胞HaCaT和人類上皮癌細胞A431中，隨著細胞密度的增加，TM大量表現於細胞之間的連結上並使得細胞的生長被抑制，其中細胞週期停滯於G0/G1時期且S時期大量下降，然而若抑制TM的表現時，則細胞接觸性抑制生長作用便會減弱而使得細胞持續增生。為了進一步證實TM的角色，我們將TM表現於沒有內生性TM表現且喪失細胞接觸性抑制生長作用的人類黑色素瘤細胞A2058中，並且觀察TM使否會藉由細胞接觸性抑制生長作用讓細胞生長降低，結果得知不論是在細胞增生或腫瘤生長上，TM都具有明顯抑制腫瘤細胞生長的效果並且是與它的細胞質功能區(cytoplasmic domain，TMD5)有關。我們接著發現TMD5會與細胞中的蛋白激酶A(protein kinase A，PKA)作用，一旦將此功能區截斷，會造成PKA活性大幅上升並且持續活化下游胞外調節激酶(pERK)，促使細胞的生長速率變快。此外我們還觀察到當細胞密度提升時，PKA的調節次單元I (regulatory subunit I, RI)表現量會下降，而調節次單元II (RII)與催化次單元(catalytic subunit)表現量則沒有太大的差異。因此根據以上的結果，我們提出了TM會透過活化PKA路徑來執行細胞接觸性抑制生長作用調節細胞的生長並且藉由PKA RI與RII的轉換來維持細胞中功能。

Thrombomodulin (TM), a cell surface-expressed glycoprotein, is known as an anticoagulant which functions through the formation of thrombin–TM complex. Recently, it has been shown that loss of TM expression in tumor cells is associated with tumor progression and metastasis. Furthermore, TM can mediate Ca2+-dependent cell adhesion through its lectin-like domain and plays a vital role in E-cadherin mediated cell contact. However, the detailed mechanism of TM in regulating tumor growth is still unknown. Cell contact inhibition constrains epithelial cells growth, and loss of cell contact inhibition can lead to dysregulated growth and tumor formation. Additionally, many cell adhesion molecules act as tumor suppressors through cell contact inhibition. In this study, we explored the role of TM in cell contact inhibition. When HaCaT keratinocytes and epidermoid carcinoma A431 cells were reaching confluence, the expression of TM at cell-cell contact was up-regulated; concurrently the cell growth was inhibited, including cell cycle arrest at the G0/G1 phase and a decrease in S phase. However, knockdown of TM expression in epithelial cells lost cell contact inhibition. To further confirm the inhibitory effect of TM, we transfected TM gene into melanoma A2058 cells, which did not express TM and observed cell contact inhibition. The results showed that transfection of TM in A2058 cells suppressed cell growth in vitro and in vivo, and the inhibitory effects were due to the presence of the cytoplasmic domain (TMD5). We also found that TMD5 could interact with protein kinase A (PKA). Cytoplasmic domain truncated TM-expressing A2058 cells had no suppressive effect on the PKA activity and the activation of downstream extracellular signal-regulated kinase (ERK). Moreover, we found that the expression of PKA regulatory subunit I (PKA-RI) decreased at a high cell density, but PKA RII and catalytic subunits did not change. Taken together, these findings suggest that TM is involved in cell contact inhibition on cell growth through PKA signaling pathway, and the expression of cellular PKA-RI and PKA-RII is modulated to regulate catalytic subunits which are involved in the cell proliferation and differentiation.

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