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In thyroid cancer, NKX2-1 expression decreases in parallel with declined differentiation. However, the molecular pathways and mechanisms connecting NKX2-1 to thyroid cancer phenotypes are largely unknown. This study aimed to examine the effects of NKX2-1 re-expression on dedifferentiated thyroid cancer cell death and explore the underlying mechanisms. A human papillary thyroid carcinoma cell line lacking NKX2-1 expression was infected with an adenoviral vector containing <jats:italic>Nkx2-1<\/jats:italic>. Cell viability decreased after <jats:italic>Nkx2-1<\/jats:italic> transduction and apoptosis and necrosis were detected. Arginase 2 (<jats:italic>ARG2<\/jats:italic>), regulator of G protein signaling 4 (<jats:italic>RGS4<\/jats:italic>), and <jats:italic>RGS5<\/jats:italic> mRNA expression was greatly increased in <jats:italic>Nkx2-1<\/jats:italic>-transducted cells. After suppressing these genes by siRNA, cell death, apoptosis, and necrosis decreased in RGS4 knockdown cells. These findings demonstrated that cell death was induced via apoptosis and necrosis by NKX2-1 re-expression and involves RGS4.<\/jats:p>","DOI":"10.1371\/journal.pone.0259558","type":"journal-article","created":{"date-parts":[[2021,11,8]],"date-time":"2021-11-08T18:27:01Z","timestamp":1636396021000},"page":"e0259558","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["NKX2-1 re-expression induces cell death through apoptosis and necrosis in dedifferentiated thyroid carcinoma cells"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5770-6926","authenticated-orcid":true,"given":"Yuko","family":"Ito","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumihiko","family":"Furuya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7158-1653","authenticated-orcid":true,"given":"Katsumi","family":"Taki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideaki","family":"Suzuki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroki","family":"Shimura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,11,8]]},"reference":[{"issue":"1","key":"pone.0259558.ref001","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/nrendo.2014.186","article-title":"Thyroid transcription factors in development, differentiation and disease","volume":"11","author":"LP Fernandez","year":"2015","journal-title":"Nat Rev Endocrinol"},{"key":"pone.0259558.ref002","doi-asserted-by":"crossref","first-page":"710213","DOI":"10.4061\/2011\/710213","article-title":"Thyroid-specific transcription factors and their roles in thyroid cancer","volume":"2011","author":"S. 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