{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T14:31:44Z","timestamp":1787841104038,"version":"build-2784847793"},"reference-count":36,"publisher":"SAGE Publications","issue":"6","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2021,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>DICER1 plays a central role in microRNA biogenesis and functions as a tumor suppressor in thyroid cancer, which is the most frequent endocrine malignancy with a rapidly increasing incidence. Thyroid cancer progression is associated with loss of cell differentiation and reduced expression of thyroid differentiation genes and response to thyrotropin (TSH). Here we investigated whether a molecular link exists between DICER1 and thyroid differentiation pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We used bioinformatic tools to search for transcription factor binding sites in the\n                      <jats:italic toggle=\"yes\">DICER1<\/jats:italic>\n                      promoter. DICER1, NKX2-1, PAX8, and CREB expression levels were evaluated by gene and protein expression\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and by interrogation of The Cancer Genome Atlas (TCGA) thyroid cancer data. Transcription factor binding and activity were assayed by chromatin immunoprecipitation, band-shift analysis, and promoter\u2013reporter gene activity. Gene-silencing and overexpression approaches were used to elucidate the functional link between DICER1 and differentiation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      We identified binding sites for NKX2-1 and CREB within the\n                      <jats:italic toggle=\"yes\">DICER1<\/jats:italic>\n                      promoter and found that both transcription factors are functional in thyroid cells. TSH induced\n                      <jats:italic toggle=\"yes\">DICER1<\/jats:italic>\n                      expression in differentiated thyroid cells, at least in part, through the cAMP\/PKA\/CREB pathway. TCGA analysis revealed a significant positive correlation between CREB and DICER1 expression in human thyroid tumors. NKX2-1 overexpression increased\n                      <jats:italic toggle=\"yes\">DICER1<\/jats:italic>\n                      promoter activity and expression\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      , and this was significantly greater in the presence of CREB and\/or PAX8. Gain- and loss-of-function assays revealed that DICER1 regulates NKX2-1 expression in thyroid tumor cells and\n                      <jats:italic toggle=\"yes\">vice versa<\/jats:italic>\n                      , thus establishing a positive feedback loop between both proteins. We also found a positive correlation between NKX2-1 and DICER1 expression in human thyroid tumors. DICER1 silencing decreased PAX8 expression and, importantly, the expression and activity of the sodium iodide symporter, which is essential for the diagnostic and therapeutic use of radioiodine in thyroid cancer.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:italic toggle=\"yes\">Conclusions<\/jats:italic>\n                      :\n                    <\/jats:title>\n                    <jats:p>The differentiation transcription factors NKX2.1, PAX8, and CREB act in a positive feedback loop with DICER1. As the expression of these transcription factors is markedly diminished in thyroid cancer, our findings suggest that DICER1 downregulation in this cancer is mediated, at least partly, through impairment of its transcription.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2020.0297","type":"journal-article","created":{"date-parts":[[2020,11,12]],"date-time":"2020-11-12T01:36:13Z","timestamp":1605144973000},"page":"912-921","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":4,"title":["A Positive Feedback Loop Between DICER1 and Differentiation Transcription Factors Is Important for Thyroid Tumorigenesis"],"prefix":"10.1177","volume":"31","author":[{"given":"Julia","family":"Ram\u00edrez-Moya","sequence":"first","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas \u201cAlberto Sols,\u201d Consejo Superior Investigaciones Cient\u00edficas, and Universidad Aut\u00f3noma de Madrid (CSIC-UAM), Madrid, Spain."},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pilar","family":"Santisteban","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biom\u00e9dicas \u201cAlberto Sols,\u201d Consejo Superior Investigaciones Cient\u00edficas, and Universidad Aut\u00f3noma de Madrid (CSIC-UAM), Madrid, Spain."},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de C\u00e1ncer (CIBERONC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2021,6,8]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3932"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2005.00015.x"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-019-0804-8"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-0970"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0803785"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/MED.0000000000000359"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.30403"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M307138200"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2018.0136"},{"key":"e_1_3_5_11_2","first-page":"596","article-title":"The thyrotropin receptor and the regulation of thyrocyte function and growth","volume":"13","author":"Vassart G","year":"1992","unstructured":"Vassart G, , Dumont JE. 1992. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev, 13:596\u2013611.","journal-title":"Endocr Rev"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-0800"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2003-0028"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2014.186"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.1210\/en.2009-1017"},{"key":"e_1_3_5_16_2","first-page":"7506","article-title":"Downregulated expression of TSHR is associated with distant metastasis in thyroid cancer","volume":"14","author":"Liu T","year":"2017","unstructured":"Liu T, , Men Q, , Su X, , Chen W, , Zou L, , Li Q, , Song M, , Ouyang D, , Chen Y, , Li Z, , Fu X, , Yang A. 2017. Downregulated expression of TSHR is associated with distant metastasis in thyroid cancer. 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Expression of thyroid-specific transcription factors TTF-1 and PAX-8 in human thyroid neoplasms. 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