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Expression of the PAX8/PPARγ Fusion Protein Is Associated with Decreased Neovascularization In Vivo: Impact on Tumorigenesis and Disease Prognosis.

ABSTRACT: 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.

SUBMITTER: Reddi HV

PROVIDER: S-EPMC2934914 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLupus pathogenesis is closely associated with interferon gamma (IFN-γ), which plays a central role in innate and adaptive immunity. The aim of this study was to evaluate the ex vivo production of IFN-γ after stimulation of peripheral blood mononuclear cells with phytohemagglutinin (PHA) in patients with lupus, according to disease activity.MethodsThis study included 118 patients with lupus who had undergone IFN-γ-releasing assays (IGRAs) to screen for tuberculosis. Data on IFN-γ production in negative (nil) and positive (mitogen with PHA) controls were collected and analysed. The difference (mitogen minus nil) was used to calculate ex vivo IFN-γ production. Disease activity was evaluated using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K). Poor hospitalisation outcome was defined as in-hospital mortality or intensive care unit admission. Associations among disease activity, poor hospitalisation outcome, and ex vivo IFN-γ production were assessed.ResultsThe level of ex vivo IFN-γ production was significantly lower in patients with active systemic lupus erythematosus (SLE) (n = 64) than in those with inactive SLE (n = 54) (median 0.92 vs. 11.06 IU/mL, p < 0.001). Ex vivo IFN-γ production was correlated with the SLEDAI-2 K (r = - 0.587, p < 0.001). Results of multivariate logistic regression analysis showed that ex vivo IFN-γ production ≤ 7.19 IU/mL was an independent predictor for discriminating active and inactive lupus. In addition, patients with ex vivo IFN-γ production ≤ 0.40 IU/mL had more frequent poor hospitalisation outcomes than those with ex vivo IFN-γ production > 0.40 (40.0% vs. 9.3%, p = 0.001). The proportion of indeterminate IGRA results was higher in patients with active lupus than in those with inactive lupus (45.3% vs. 0.0%, p < 0.001) because of decreased ex vivo IFN-γ production.ConclusionsEx vivo IFN-γ production is a useful biomarker for assessing disease activity and predicting poor clinical outcomes of SLE.

Project description:BackgroundPAX8/PPARγ rearrangement is a common genetic alteration in follicular thyroid carcinoma (FTC) and has been reported with variable frequency in papillary thyroid carcinoma (PTC). The diagnostic and phenotypic features of thyroid nodules positive for PAX8/PPARγ on preoperative examination are not well understood.MethodsThe prevalence of PAX8/PPARγ rearrangement was analyzed in a series of 2015 consecutive thyroid nodules that underwent molecular analysis on cytology specimens and in 446 surgically removed PTCs. For all PAX8/PPARγ positive cases, cytology and surgical pathology slides were examined and the available clinical records were reviewed.ResultsTwenty-two PAX8/PPARγ rearrangements were identified, including 16 detected preoperatively and 6 postoperatively. The incidence of PAX8/PPARγ in PTC was 1.1%. Cytologically, most of these nodules were diagnosed as a follicular neoplasm (73%), followed by the diagnosis of atypia of undetermined significance (19%), and none of the cases was diagnosed as cytologically malignant. All nodules with PAX8/PPARγ detected preoperatively and surgical follow-up available were found to be malignant, among which the most common diagnosis was the encapsulated follicular variant of PTC. Overall, among 20 PAX8/PPARγ-positive tumors that were surgically excised, 17 (85%) were PTC and 3 (15%) were FTC. On follow-up available for 17 patients (mean, 22.4 months), 16 PAX8/PPARγ-positive cancers showed no evidence of biochemical or structural recurrence, whereas 1 patient with FTC developed bone metastasis.ConclusionsIn this series, PAX8/PPARγ rearrangement found in thyroid nodules had a 100% predictive value for differentiated thyroid cancer, and was more predictive of PTC than FTC. However, almost all PTC carrying PAX8/PPARγ were encapsulated follicular-pattern tumors, distinguished from FTC only by nuclear features. Although most tumors carrying this mutation appear to be clinically indolent, at least on short-term follow-up, distant metastasis can develop from FTC positive for PAX8/PPARγ.

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Expression of the PAX8/PPARγ Fusion Protein Is Associated with Decreased Neovascularization In Vivo: Impact on Tumorigenesis and Disease Prognosis.

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