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- Mu, Ninni
(författare)
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Diagnostic and prognostic markers in thyroid carcinoma with focus on TERT activation
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Well-differentiated follicular cell-derived thyroid carcinomas are usually categorized into papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), which represent the most common and second most common types of thyroid carcinoma, respectively. PTC patients generally have a good prognosis, although a subset of patients progress in their disease with poor clinical outcome. Also, it remains a diagnostic challenge to differentiate FTC pre-operatively from follicular thyroid adenoma (FTA) and follicular tumor of uncertain malignant potential (FT-UMP). For both PTC and FTC, promoter mutations in the telomerase reverse transcriptase (TERT) gene have been identified as an important underlying genetic event. However, other TERT-activating alterations are less studied in thyroid carcinoma. Thus, this thesis aimed to investigate potential diagnostic and prognostic biomarkers, and TERT-activating alterations in FTC and PTC, respectively. In Paper I, we identified high cytological Ki-67 proliferation index and larger tumor size as predictors of FTC in follicular thyroid tumors using univariate and multivariate analyses. In the FTC subgroup, extrathyroidal extension and the widely invasive sub-type were associated with higher cytological Ki-67 index. Taken together, cytological Ki-67 index could potentially add pre-operative diagnostic information for a subset of patients. In Paper II, we found that TERT expression was coupled with co-existing TERT copy number gain, promoter mutation or hypermethylation in follicular thyroid tumors. Several of these alterations were observed in higher frequencies in FTC/FT-UMP and associated with poor clinical outcome in FTC. Thus, they are promising as biomarkers for diagnosis and prognostication. In Paper III, the E26 transformation-specific (ETS) transcription factor GABPA was shown to exhibit mutant TERT promoter-activating properties in thyroid carcinoma cells. In contrast, GABPA also exhibited tumor-suppressive properties in vitro and in vivo, highlighting its dual roles. In PTC tumors, low expression of GABPA was associated with poor clinical outcome. Moreover, DICER1, involved in the microRNA machinery, was identified as a potential downstream target for the GABPA-mediated tumor suppressive effect. We conclude that loss of tumor suppressive functions of GABPA is coupled to PTC progression. In Paper IV, the 28 known ETS transcription factors were analyzed in relation to clinical phenotype in PTC. EHF was found to be upregulated in PTC and associated with aggressive clinical features, BRAFV600E and TERT promoter mutation or expression. In PTC cells with concurrent BRAFV600E and TERT promoter mutations, over-expression of EHF induced an increase in TERT expression. Collectively, EHF is a potential oncogenic ETS factor in PTC. In summary, the findings in this thesis add insights into the underlying TERT-activating alterations in follicular cell-derived thyroid carcinomas. Further, several potentially clinically relevant biomarkers for diagnosis and prognostication for this patient group were identified.
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| 2. |
- Yuan, Xiaotian, et al.
(författare)
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GABPA inhibits invasion/metastasis in papillary thyroid carcinoma by regulating DICER1 expression
- 2019
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 38:7, s. 965-979
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Tidskriftsartikel (refereegranskat)abstract
- The ETS family transcription factor GABPA is suggested as an oncogenic element, which is further supported by the recent reporting of it as the sole ETS member to activate the mutant TERT promoter in thyroid carcinomas (TC). However, it remains unclear how GABPA contributes to TC pathogenesis. The present study is designed to address this issue. TERT expression was significantly diminished in TERT promoter-mutated TC cells upon GABPA inhibition. Surprisingly, GABPA depletion led to robustly increased cellular invasion independently of TERT promoter mutations and TERT expression. DICER1, a component of the microRNA machinery, was identified as a downstream effector of GABPA. GABPA facilitated Dicer1 transcription while its depletion reduced Dicer1 expression. The mutation of the GABPA binding site in the DICER1 promoter led to diminished basal levels of DICER1 promoter activity and abolishment of GABPA-stimulated promoter activity as well. The forced DICER1 expression abrogated the invasiveness of GABPA-depleted TC cells. Consistently, the analyses of 93 patients with papillary thyroid carcinoma (PTC) revealed a positive correlation between GABPA and DICER1 expression. GABPA expression was negatively associated with TERT expression and promoter mutations, in contrast to published observations in cancer cell lines. Lower GABPA expression was associated with distant metastasis and shorter overall/disease-free survival in PTC patients. Similar results were obtained for PTC cases in the TCGA dataset. In addition, a positive correlation between GABPA and DICER1 expression was seen in multiple types of malignancies. Taken together, despite its stimulatory effect on the mutant TERT promoter and telomerase activation, GABPA may itself act as a tumor suppressor rather than an oncogenic factor to inhibit invasion/metastasis in TCs and be a useful predictor for patient outcomes.
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