title: Synergistic signaling of KRAS and thyroid hormone receptor β mutants promotes undifferentiated thyroid cancer through MYC up-regulation.
abstract: Undifferentiated thyroid carcinoma is one of the most aggressive human cancers with frequent RAS mutations. How mutations of the RAS gene contribute to undifferentiated thyroid cancer remains largely unknown. Mice harboring a potent dominant negative mutant thyroid hormone receptor β, TRβPV (Thrb(PV/PV)), spontaneously develop well-differentiated follicular thyroid cancer similar to human cancer. We genetically targeted the Kras(G12D) mutation to thyroid epithelial cells of Thrb(PV/PV) mice to understand how Kras(G12D) mutation could induce undifferentiated thyroid cancer in Thrb(PV/PV)Kras(G12D) mice. Thrb(PV/PV)Kras(G12D) mice exhibited poorer survival due to more aggressive thyroid tumors with capsular invasion, vascular invasion, and distant metastases to the lung occurring at an earlier age and at a higher frequency than Thrb(PV/PV) mice did. Importantly, Thrb(PV/PV)Kras(G12D) mice developed frequent anaplastic foci with complete loss of normal thyroid follicular morphology. Within the anaplastic foci, the thyroid-specific transcription factor paired box gene 8 (PAX8) expression was virtually lost and the loss of PAX8 expression was inversely correlated with elevated MYC expression. Consistently, co-expression of KRAS(G12D) with TRβPV upregulated MYC levels in rat thyroid pccl3 cells, and MYC acted to enhance the TRβPV-mediated repression of the Pax8 promoter activity of a distant upstream enhancer, critical for thyroid-specific Pax8 expression. Our findings indicated that synergistic signaling of KRAS(G12D) and TRβPV led to increased MYC expression. Upregulated MYC contributes to the initiation of undifferentiated thyroid cancer, in part, through enhancing TRβPV-mediated repression of the Pax8 expression. Thus, MYC might serve as a potential target for therapeutic intervention.
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, US.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, US.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, US.
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, US.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, US. Electronic address: chengs@mail.nih.gov.
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D051379:Mice; D009154:Mutation; D060787:Neoplasm Grading; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D065646:Thyroid Carcinoma, Anaplastic / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D037042:Thyroid Hormone Receptors beta / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D013972:Thyrotropin / Q000378:metabolism; D014157:Transcription Factors; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; C504004:Ttf1 protein, mouse; D013972:Thyrotropin; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)