| 1. |
- Sofiadis, Anastasios
(författare)
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In search of diagnostic and prognostic markers for thyroid cancer : a proteomics approach
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Early diagnosis of cancer can influence the therapeutic strategy increasing the chances of cure or, at least, prolonged survival. It is equally important to be able to detect prognostic signs, i.e. tumor features that characterize its behavior. In the case of thyroid tumors, which usually debut as palpable nodules, fine needle aspiration biopsy is that very stage when one should ideally set a secure diagnosis and gather prognostic information (such as tumor aggressiveness, metastatic potential, response to treatment). This sampling technique has improved its performance to a considerable degree, especially when guided by ultrasonography. Nevertheless, it still fails to conclusively diagnose certain thyroid tumors as the whole tissue structure, rather than just a few hundreds of cells, is necessary for diagnosis. Therefore, there is an imperative need for molecular diagnostic and prognostic markers, which could be easily traced on cellular material. We investigated the potential of MIB-1, an index of cellular proliferation which is part of the cytological evaluation of other tumors, in facilitating the diagnosis or prognosis of thyroid tumors (Article I). Our conclusion was that MIB-1 is not particularly effective as a diagnostic marker for thyroid tumors, but it can serve as a marker of worse prognosis for patients with papillary thyroid carcinoma. In an attempt to start exploring the field of thyroid proteomics, we began by developing a protein pre-fractionation protocol suitable for using archival frozen tissue and compatible with proteomics methodology, such as two-dimensional electrophoresis (2DE) and mass spectrometry (MS) (Article II). This protocol enables us to obtain cytosolic and nuclear/nuclear membrane enriched protein fractions which comprised the starting material in our proteomics studies. S100A6, a Ca+2-binding protein evidently associated with p53 and β-catenin, was found to be significantly over-expressed in papillary thyroid carcinomas as compared to normal tissue or follicular thyroid tumors (Article III). Besides that and by applying 2DE-coupled MS, we were able to come up with two, partly overlapping sets of proteins which seem to be robust enough in distinguishing follicular thyroid carcinoma from its benign counterpart as well as from papillary thyroid carcinoma (Article IV). This study gives new perspective in pursuing the discovery of novel thyroid cancer markers. We believe that by carrying out prospective studies particularly focused on the molecules presented in this thesis, thyroid diagnostics and prognostics can be greatly facilitated in the future for the sake of cancer patients, but also the mechanisms behind thyroid tumor development can be elucidated.
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| 2. |
- Sofiadis, Anastasios, et al.
(författare)
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Proteomic profiling of follicular and papillary thyroid tumors
- 2012
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Ingår i: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 166:4, s. 657-667
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Thyroid proteomics is a new direction in thyroid cancer research aiming at etiological understanding and biomarker identification for improved diagnosis. Methods: Two-dimensional electrophoresis was applied to cytosolic protein extracts from frozen thyroid samples (ten follicular adenomas, nine follicular carcinomas, ten papillary carcinomas, and ten reference thyroids). Spots with differential expression were revealed by image and multivariate statistical analyses, and identified by mass spectrometry. Results: A set of 25 protein spots significant for discriminating between the sample groups was identified. Proteins identified for nine of these spots were studied further including 14-3-3 protein beta/alpha, epsilon, and zeta/delta, peroxiredoxin 6, selenium-binding protein 1, protein disulfide-isomerase precursor, annexin A5 (ANXA5), tubulin alpha-1B chain, and alpha 1-antitrypsin precursor. This subset of protein spots carried the same predictive power in differentiating between follicular carcinoma and adenoma or between follicular and papillary carcinoma, as compared with the larger set of 25 spots. Protein expression in the sample groups was demonstrated by western blot analyses. For ANXA5 and the 14-3-3 proteins, expression in tumor cell cytoplasm was demonstrated by immunohistochemistry both in the sample groups and an independent series of papillary thyroid carcinomas. Conclusion: The proteins identified confirm previous findings in thyroid proteomics, and suggest additional proteins as dysregulated in thyroid tumors.
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| 3. |
- 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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