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- Brown, TC, et al.
(författare)
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Recurrent Amplification of the Osmotic Stress Transcription Factor NFAT5 in Adrenocortical Carcinoma
- 2020
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Ingår i: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 4:7, s. bvaa060-
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Tidskriftsartikel (refereegranskat)abstract
- Tumorigenesis requires mitigation of osmotic stress and the transcription factor nuclear factor of activated T cells 5 (NFAT5) coordinates this response by inducing transcellular transport of ions and osmolytes. NFAT5 modulates in vitro behavior in several cancer types, but a potential role of NFAT5 in adrenocortical carcinoma (ACC) has not been studied. A discovery cohort of 28 ACCs was selected for analysis. Coverage depth analysis of whole-exome sequencing reads assessed NFAT5 copy number alterations in 19 ACCs. Quantitative real-time PCR measured NFAT5 mRNA expression levels in 11 ACCs and 23 adrenocortical adenomas. Immunohistochemistry investigated protein expression in representative adrenal samples. The Cancer Genome Atlas database was analyzed to corroborate NFAT5 findings from the discovery cohort and to test whether NFAT5 expression correlated with ion/osmolyte channel and regulatory protein expression patterns in ACC. NFAT5 was amplified in 10 ACCs (52.6%) and clustered in the top 6% of all amplified genes. mRNA expression levels were 5-fold higher compared with adrenocortical adenomas (P < 0.0001) and NFAT5 overexpression had a sensitivity and specificity of 81.8% and 82.7%, respectively, for malignancy. Increased protein expression and nuclear localization occurred in representative ACCs. The Cancer Genome Atlas analysis demonstrated concomitant NFAT5 amplification and overexpression (P < 0.0001) that correlated with increased expression of sodium/myo-inositol transporter SLC5A3 (r2 = 0.237, P < 0.0001) and 14 other regulatory proteins (P < 0.05) previously shown to interact with NFAT5. Amplification and overexpression of NFAT5 and associated osmotic stress response related genes may play an important role adrenocortical tumorigenesis.
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- Nicolson, NG, et al.
(författare)
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Transcription Factor Profiling Identifies Spatially Heterogenous Mediators of Follicular Thyroid Cancer Invasion
- 2020
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Ingår i: Endocrine pathology. - : Springer Science and Business Media LLC. - 1559-0097 .- 1046-3976. ; 31:4, s. 367-376
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Tidskriftsartikel (refereegranskat)abstract
- While minimally invasive follicular thyroid cancer (miFTC) generally has low risk of recurrence or death, encapsulated angioinvasive (eaFTC) or widely invasive (wiFTC) histological subtypes display significantly worse prognosis. Drivers of invasion are incompletely understood. Therefore, tissue samples including miFTC, eaFTC, and wiFTC tumors, as well as histologically normal thyroid adjacent to benign follicular adenomas, were selected from a cohort (n = 21) of thyroid tumor patients, and the gene expression of selected transcription factors was characterized with quantitative PCR. Invasion-relevant spatial expression patterns of selected transcription factors were subsequently characterized with immunohistochemistry. E2F1 was over-expressed in all 3 subtypes (p<0.01). SP1 was differentially expressed in eaFTC and wiFTC compared with normal (p=0.01 and 0.04, respectively). TCF7L2 was significantly upregulated in wiFTC specifically (p<0.05). While these findings were mRNA specific, immunohistochemistry of additional cancer-associated transcription factors revealed differential expression along the tumor invasive front relative to the central tumor, and histone acetylation modulators emerged as putative invasion markers. These findings may have significant implications for the interpretation of bulk gene expression analysis of thyroid tumor samples or for the development of targeted therapeutics for this rare but aggressive thyroid cancer variant.
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