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      MALAT1 Long Non-coding RNA Expression in Thyroid Tissues: Analysis by In Situ Hybridization and Real-Time PCR

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          Abstract

          <p class="first" id="P1">Long noncoding RNAs (lncRNAs) are important for transcription and for epigenetic or posttranscriptional regulation of gene expression, and may contribute to carcinogenesis. MALAT1 (Metastasis Associated Lung Adenocarcinoma Transcript 1), a lncRNA involved in the regulation of the cell cycle, cell proliferation and cell migration, is known to be deregulated in multiple cancers. Here we analyzed the expression of MALAT1 on 195 cases of benign and malignant thyroid neoplasms by using tissue microarrays for RNA in-situ hybridization (ISH) and real-time PCR. MALAT1 is highly expressed in normal thyroid tissues (NT) and thyroid tumors, with increased expression during progression from NT to papillary thyroid carcinomas (PTCs), but is downregulated in poorly differentiated thyroid cancers (PDCs) and anaplastic thyroid cancers (ATCs) compared to NT. Induction of epithelial to mesenchymal transition (EMT) by TGF beta in a PTC cell line (TPC1) led to increased MALAT1 expression, supporting a role for MALAT1 in EMT in thyroid tumors. This is the first ISH study of MALAT1 expression in thyroid tissues. It also provides the first piece of evidence suggesting MALAT1 downregulation in certain thyroid malignancies. Our findings support the notion that ATCs may be molecularly distinct from low grade thyroid malignancies, and suggest that MALAT1 may function both as an oncogene and as a tumor suppressor in different types of thyroid tumors. </p>

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          Most cited references17

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          Molecular genetics and diagnosis of thyroid cancer.

          Thyroid cancer is a common type of endocrine malignancy, and its incidence has been steadily increasing in many regions of the world. Initiation and progression of thyroid cancer involves multiple genetic and epigenetic alterations, of which mutations leading to the activation of the MAPK and PI3K-AKT signaling pathways are crucial. Common mutations found in thyroid cancer are point mutation of the BRAF and RAS genes as well as RET/PTC and PAX8/PPARγ chromosomal rearrangements. The mutational mechanisms seem to be linked to specific etiologic factors. Chromosomal rearrangements have a strong association with exposure to ionizing radiation and possibly with DNA fragility, whereas point mutations probably arise as a result of chemical mutagenesis. A potential role of dietary iodine excess in the generation of BRAF point mutations has also been proposed. Somatic mutations and other molecular alterations have been recognized as helpful diagnostic and prognostic markers for thyroid cancer and are beginning to be introduced into clinical practice, to offer a valuable tool for the management of patients with thyroid nodules.
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            Specific microRNAs are downregulated in human thyroid anaplastic carcinomas.

            Thyroid carcinomas comprise a broad spectrum of tumors with different clinical behaviors. On the one side, there are occult papillary carcinomas (PTC), slow growing and clinically silent, and on the other side, rapidly growing anaplastic carcinomas (ATC), which are among the most lethal human neoplasms. We have analysed the microRNA (miR) profile of ATC in comparison to the normal thyroid using a microarray (miRNACHIP microarray). By this approach, we found an aberrant miR expression profile that clearly differentiates ATC from normal thyroid tissues and from PTC analysed in previous studies. In particular, a significant decrease in miR-30d, miR-125b, miR-26a and miR-30a-5p was detected in ATC in comparison to normal thyroid tissue. These results were further confirmed by northern blots, quantitative reverse transcription-PCR analyses and in situ hybridization. The overexpression of these four miRs in two human ATC-derived cell lines suggests a critical role of miR-125b and miR-26a downregulation in thyroid carcinogenesis, since a cell growth inhibition was achieved. Conversely, no effect on cell growth was observed after the overexpression of miR-30d and miR-30a-5p in the same cells. In conclusion, these data indicate a miR signature associated with ATC and suggest the miR deregulation as an important event in thyroid cell transformation.
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              Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas.

              Anaplastic thyroid carcinomas (ATCs) arise from epithelial thyroid cells by mesenchymal de-/transdifferentiation and rapidly invade the adjacent tissue. Specific microRNA signatures were suggested to distinguish ATCs from normal thyroid tissue and other thyroid carcinomas of follicular origin. Whether distinct microRNA patterns correlate with de-/transdifferentiation and invasion of ATCs remained elusive. We identified two significantly decreased microRNA families that unambiguously distinguish ATCs from papillary and follicular thyroid carcinomas: miR-200 and miR-30. Expression of these microRNAs in mesenchymal ATC-derived cells reduced their invasive potential and induced mesenchymal-epithelial transition (MET) by regulating the expression of MET marker proteins. Supporting the role of transforming growth factor (TGF)beta signaling in modulating MET/epithelial-mesenchymal transition (EMT), expression of SMAD2 and TGFBR1, upregulated in most primary ATCs, was controlled by members of the miR-30 and/or miR-200 families in ATC-derived cells. Inhibition of TGFbeta receptor 1 (TGFBR1) in these cells induced MET and reduction of prometastatic miR-21, but caused an increase of the miR-200 family. These findings identify altered microRNA signatures as potent markers for ATCs that promote de-/transdifferentiation (EMT) and invasion of these neoplasias. Hence, TGFBR1 inhibition could have a significant potential for the treatment of ATCs and possibly other invasive tumors.
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                Author and article information

                Journal
                Endocrine Pathology
                Endocr Pathol
                Springer Nature
                1046-3976
                1559-0097
                March 2017
                September 2016
                : 28
                : 1
                : 7-12
                Article
                10.1007/s12022-016-9453-4
                5313332
                27696303
                3af8d5f1-ab45-4cb9-a9ca-f052d3904e7b
                © 2017
                History

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