Reddi H V, Madde P, Marlow L A, Copland J A, McIver B, Grebe S K G, Eberhardt N L
Division of Endocrinology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
Genes Cancer. 2010 May;1(5):480-492. doi: 10.1177/1947601910373545.
The PAX8/PPARγ fusion protein (PPFP) occurs in 36% of human follicular thyroid carcinoma (FTC) and is associated with favorable prognosis. To elucidate the function of PPFP in FTC, we analyzed the consequences of PPFP expression in immortalized thyrocytes in vitro and in vivo via xenograft tumorigenesis. While PPFP-expressing cells exhibited oncogenic hallmarks, including increased growth and decreased apoptosis, in vitro, xenograft tumors were initiated but not sustained in vivo. PPFP xenograft tumors exhibited reduced CD31 staining and VEGF expression, suggesting that PPFP modulates neovascularization. Microarray analysis demonstrated increased expression of tissue inhibitor of metalloproteinase (TIMP-3), an inhibitor of angiogenesis, in PPFP cells and tumors, a finding confirmed by quantitative PCR and immunohistochemistry. Immunohistochemical staining of archival human thyroid tumors demonstrates a significant decrease in CD31 staining in all adenomas and carcinomas containing the PAX8/PPARγ rearrangement. Decreased angiogenesis in PPFP-containing tumors is directly correlated with our observations in the xenograft model and provides evidence for the first time that PPFP may impact FTC tumorigenesis by modulating angiogenesis in vivo.
PAX8/PPARγ融合蛋白（PPFP）存在于36%的人类甲状腺滤泡癌（FTC）中，且与良好的预后相关。为阐明PPFP在FTC中的功能，我们通过异种移植瘤形成在体外和体内分析了PPFP在永生化甲状腺细胞中表达的后果。虽然表达PPFP的细胞在体外表现出致癌特征，包括生长增加和凋亡减少，但异种移植瘤在体内开始形成后却无法持续生长。PPFP异种移植瘤的CD31染色和VEGF表达降低，提示PPFP可调节新生血管形成。微阵列分析显示，在PPFP细胞和肿瘤中，金属蛋白酶组织抑制剂（TIMP-3，一种血管生成抑制剂）的表达增加，这一发现通过定量PCR和免疫组织化学得到证实。对存档的人类甲状腺肿瘤进行免疫组织化学染色显示，在所有含有PAX8/PPARγ重排的腺瘤和癌中，CD31染色显著减少。含PPFP肿瘤中血管生成减少与我们在异种移植模型中的观察结果直接相关，并首次为PPFP可能通过调节体内血管生成影响FTC肿瘤发生提供了证据。
