摘要：黑色素細胞癌是最難治療的皮膚癌，特別是轉移的階段。他的發生率在近十年來不斷的增加。因此瞭解黑色素細胞癌進展的分子機轉和找出相關分子標的對治療轉移黑色細胞癌是很重要的。HMGA2 是一個連結非組織蛋白染色質的蛋白質，可以藉由調整染色質絲的結構來調控轉錄。HMGA2 主要表現在未分化的間葉組織，會調控間葉細胞的增生和分化。HMGA2 高表現的乳癌和肺癌預後較不好。HMGA2 在黑色素細胞癌也會高表現而且和局部以及遠端轉移有關。另外HMGA2 的高表現和BRAF/NRAS 基因突變有關。我們的研究顯示IMP-3 是一個黑色素細胞癌進展的標記，IMP-3 會結合並調控HMGA2 mRNA 的穩定性而且透過HMGA2 來促進黑色素細胞癌的侵犯和轉移。IMP-3 和HMGA2 mRNA 和蛋白的表現量在黑色素細胞癌細胞株和組織呈現正相關。和初期的黑色素細胞癌相比，侵襲性高的黑色素細胞癌HMGA2 表現量較高，且史必茲母斑也會表現HMGA2。本研究將研究(1)HMGA2 在不同黑色素細胞病灶的表現，與在黑色素細胞癌的診斷和預後的應用。也會探討HMGA2 和體細胞基因突變的關係。(2)探討HMGA2 以及微小RNA 在史必茲母斑和黑色素細胞癌的角色和功能，建立史必茲母斑的動物模型。（3）分析HMGA2 影響黑色素細胞癌細胞株的mRNA 和蛋白表現形式，和黑色素細胞癌形成，惡化與轉移的關係，並進一步研究調控HMGA2 表現的分子機轉。
Abstract: Cutaneous melanoma is the most aggressive skin neoplasm refractory to traditional therapies, especiallyat the metastatic stage. Furthermore, its incidence is continuously increasing during the last decade. Becauseof the intractability of metastatic melanomas, understanding the underlying molecular mechanisms involvedin melanoma progression and also identifying molecular markers are important for improvements in therapiesfor metastatic melanomas.Insulin-like growth factor II mRNA-binding protein 3 (IMP-3) has been reported to be a novel marker ofmelanoma progression. Our previous study demonstrated that Insulin-like growth factor II mRNA-bindingprotein 3 (IMP-3) binds to High mobility group A 2 (HMGA2) mRNA and, as a consequence, regulates itsexpression. We found that IMP-3 expression stabilized mRNA of HMGA2 in A2058 cells. It was alsoconfirmed that IMP-3 played an important role in melanoma invasion and metastasis through regulatingHMGA2 mRNA expression. IMP-3 expression was positively correlated with HMGA2 expression inmelanoma cells and also in melanoma tissues. High mobility group A 2 (HMGA2) is predominantly expressedin the mesenchyme before its differentiation and a regulator of mesenchymal proliferation and differentiation.There have also been a number of intriguing observations with regard to HMGA2 in malignant epithelialtumors over the past decades. It has been demonstrated that HMGA2 is highly overexpressed in melanomaand is strongly associated with regional and distant metastases. HMGA2 overexpression has also beendemonstrated to be positively associated with BRAF/NRAS mutations.However, the mechanism of HMGA2 in the pathogenesis of melanocytic lesions is unknown. Ourpreliminary data showed that HMGA2 expression was detected in 47% of superficial melanoma and 79% ofdeep melanomas. 95 percent of the metastatic melanomas were positive for HMGA2. In addition, all Spitznevi displayed HMGA2 positivity. Melanoma cells characterized by higher migratory and invasive abilityhad increased HMGA2 expression compared with those melanoma cells having lower migratory/invasiveabilities. Transfection of shHMGA2 inhibited the migratory/invasive abilities of A2058 cells. Hence, wehypothesize that HMGA2 may perturb the function of melanocytes and melanoma cells and play a role in thepathogenesis of Spitz nevus and melanoma.To test our hypothesis, there are several aims to be achieved in this proposal: 1. To investigate theexpression of HMGA2 in a panel of melanocytic lesions and assess the diagnostic and prognostic utilityof HMGA2 in melanomas. 2. To identify the underlying molecular mechanisms of HMGA2 andmicroRNA in melanocytes differentiation and establish animal model of Spitz nevus. 3. To unravel themechanism underlying the oncogenicity of HMGA2 in melanoma.