腫瘤內皮標誌1是屬於第一型穿膜醣蛋白並表現在周細胞、基質細胞和纖維母細胞。腫瘤內皮標誌1的高表達與器官纖維化有關，如肝纖維化，腎纖維化和特發性肺纖維化。此外，腫瘤內皮標誌1參與在纖維化惡化過程中其基質細胞和纖維母細胞的增生和遷移。然而，腫瘤內皮標誌1是否參與在皮膚纖維化(蟹足腫)，以及腫瘤內皮標誌1的增加是如何被調控的機制從未被研究過。在我們的研究中，臨床檢體顯示腫瘤內皮標誌1蛋白在蟹足腫纖維母細胞中的表達高於其對應的正常纖維母細胞。由於幾種生長因子和細胞因子，包括IGF-1，TGFβ，PDGF和TNFα，已被報導可促進蟹足腫的進程，我們研究這些與纖維化相關的因子是否可以調控NHDF中的腫瘤內皮標誌1表現，結果顯示只有IGF-1顯著增加腫瘤內皮標誌1蛋白的表現，並且出乎意料的發現腫瘤內皮標誌1 mRNA的表現不會受到IGF-1影響。此外，利用特異性抑製劑來抑制IGF-1R，Akt或mTOR後，皆可以顯著地使IGF-1誘導腫瘤內皮標誌1表達消失。放線菌酮(CHX)的刺激也可以使IGF-1誘導腫瘤內皮標誌1表達的情形消失，說明IGF-1誘導腫瘤內皮標誌1表達增加與蛋白質合成有關。此外，IGF-1對腫瘤內皮標誌1的影響在蟹足腫纖維母細胞中也可以看到，但在同一名患者組織中所分離的正常纖維母細胞中沒有看到此現象。我們目前的結果顯示在纖維母細胞中IGF-1可能透過Akt / mTOR途徑並藉由轉錄後修飾調控腫瘤內皮標誌1。先前的研究顯示腫瘤內皮標誌1可以增強PDGF和TGFβ的下游信號傳導。 因此，我們提出IGF-1轉錄後刺激腫瘤內皮標誌1的蛋白表現，並且進而增強蟹足腫纖維母細胞對PDGF和TGFβ的反應。

Tumor endothelial marker 1 (TEM1), a type I transmembrane glycoprotein, is expressed in pericytes, stromal cells and fibroblasts. The elevated TEM1 expression has been implicated in fibrogenesis such as liver fibrosis, renal fibrosis, and idiopathic pulmonary fibrosis. Moreover, TEM1 is involved in proliferation and migration of stromal cells and fibroblasts, by which TEM1 promotes progression of fibrosis. However, whether TEM1 participates in skin fibrosis and the mechanisms by which TEM1 is up-regulated have never been investigated. Our study of clinical specimens showed that TEM1 protein expression was higher in keloid fibroblasts than that in their counterpart controls. Since several growth factors and cytokines, including insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGFβ), platelet-derived growth factor (PDGF) and tumor necrosis factor alpha (TNFα) have been shown to promote keloid progression, we investigated whether those fibrosis-associated factors could regulate TEM1 expression in normal human dermal fibroblasts (NHDF). The results showed that only IGF-1 significantly increased TEM1 protein expression. Surprisingly, TEM1 mRNA was not changed with IGF-1 treatment. Furthermore, suppression of IGF-1R, Akt or mTOR with specific inhibitors significantly reversed IGF-1-induced TEM1 expression. The treatment of cycloheximide could also reverse IGF-1-induced TEM1 expression, suggesting that IGF-1-induced up-regulation of TEM1 was associated with de novo protein synthesis. In addition, the stimulation of TEM1 by IGF-1 was also demonstrated in keloid fibroblasts but not in normal fibroblasts isolated from tissues of one patient. Our current result reveals a post-transcriptional regulation of TEM1 by IGF-1 in skin fibroblasts via Akt/mTOR pathway. Previous studies show that TEM1 could enhance downstream signaling of PDGF and TGFβ. Therefore, we suggested that IGF-1 post-transcriptionally increased TEM1 protein expression, which may further enhance the response of PDGF and TGFβ in keloid fibroblasts.

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