title: Thyroid Hormone Receptor-β (TRβ) Mediates Runt-Related Transcription Factor 2 (Runx2) Expression in Thyroid Cancer Cells: A Novel Signaling Pathway in Thyroid Cancer.
abstract: Dysregulation of the thyroid hormone receptor (TR)β is common in human cancers. Restoration of functional TRβ delays tumor progression in models of thyroid and breast cancers implicating TRβ as a tumor suppressor. Conversely, aberrant expression of the runt-related transcription factor 2 (Runx2) is established in the progression and metastasis of thyroid, breast, and other cancers. Silencing of Runx2 diminishes tumor invasive characteristics. With TRβ as a tumor suppressor and Runx2 as a tumor promoter, a compelling question is whether there is a functional relationship between these regulatory factors in thyroid tumorigenesis. Here, we demonstrated that these proteins are reciprocally expressed in normal and malignant thyroid cells; TRβ is high in normal cells, and Runx2 is high in malignant cells. T3 induced a time- and concentration-dependent decrease in Runx2 expression. Silencing of TRβ by small interfering RNA knockdown resulted in a corresponding increase in Runx2 and Runx2-regulated genes, indicating that TRβ levels directly impact Runx2 expression and associated epithelial to mesenchymal transition molecules. TRβ specifically bound to 3 putative thyroid hormone-response element motifs within the Runx2-P1 promoter ((-)105/(+)133) as detected by EMSA and chromatin immunoprecipitation. TRβ suppressed Runx2 transcriptional activities, thus confirming TRβ regulation of Runx2 at functional thyroid hormone-response elements. Significantly, these findings indicate that a ratio of the tumor-suppressor TRβ and tumor-promoting Runx2 may reflect tumor aggression and serve as biomarkers in biopsy tissues. The discovery of this TRβ-Runx2 signaling supports the emerging role of TRβ as a tumor suppressor and reveals a novel pathway for intervention.
authors.affiliation: Departments of Pharmacology (F.E.C., M.S.B., N.E.G., K.G.E., T.H.T., J.H.W., J.A.T.), Biochemistry (P.W.L.T., S.K.Z., J.B.L., J.L.S., G.S.S.), and Neurological Sciences (D.M.J.), College of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Carr
authors.affiliation: Departments of Pharmacology (F.E.C., M.S.B., N.E.G., K.G.E., T.H.T., J.H.W., J.A.T.), Biochemistry (P.W.L.T., S.K.Z., J.B.L., J.L.S., G.S.S.), and Neurological Sciences (D.M.J.), College of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Phillip W L
authors.initials: PW
authors.lastname: Tai
authors.affiliation: Departments of Pharmacology (F.E.C., M.S.B., N.E.G., K.G.E., T.H.T., J.H.W., J.A.T.), Biochemistry (P.W.L.T., S.K.Z., J.B.L., J.L.S., G.S.S.), and Neurological Sciences (D.M.J.), College of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Barnum
authors.affiliation: Departments of Pharmacology (F.E.C., M.S.B., N.E.G., K.G.E., T.H.T., J.H.W., J.A.T.), Biochemistry (P.W.L.T., S.K.Z., J.B.L., J.L.S., G.S.S.), and Neurological Sciences (D.M.J.), College of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Noelle E
authors.initials: NE
authors.lastname: Gillis
authors.affiliation: Departments of Pharmacology (F.E.C., M.S.B., N.E.G., K.G.E., T.H.T., J.H.W., J.A.T.), Biochemistry (P.W.L.T., S.K.Z., J.B.L., J.L.S., G.S.S.), and Neurological Sciences (D.M.J.), College of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Katherine G
authors.initials: KG
authors.lastname: Evans
authors.affiliation: Departments of Pharmacology (F.E.C., M.S.B., N.E.G., K.G.E., T.H.T., J.H.W., J.A.T.), Biochemistry (P.W.L.T., S.K.Z., J.B.L., J.L.S., G.S.S.), and Neurological Sciences (D.M.J.), College of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Taber
authors.affiliation: Departments of Pharmacology (F.E.C., M.S.B., N.E.G., K.G.E., T.H.T., J.H.W., J.A.T.), Biochemistry (P.W.L.T., S.K.Z., J.B.L., J.L.S., G.S.S.), and Neurological Sciences (D.M.J.), College of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: White
authors.affiliation: Departments of Pharmacology (F.E.C., M.S.B., N.E.G., K.G.E., T.H.T., J.H.W., J.A.T.), Biochemistry (P.W.L.T., S.K.Z., J.B.L., J.L.S., G.S.S.), and Neurological Sciences (D.M.J.), College of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Tomczak
authors.affiliation: Departments of Pharmacology (F.E.C., M.S.B., N.E.G., K.G.E., T.H.T., J.H.W., J.A.T.), Biochemistry (P.W.L.T., S.K.Z., J.B.L., J.L.S., G.S.S.), and Neurological Sciences (D.M.J.), College of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Jaworski
authors.affiliation: Departments of Pharmacology (F.E.C., M.S.B., N.E.G., K.G.E., T.H.T., J.H.W., J.A.T.), Biochemistry (P.W.L.T., S.K.Z., J.B.L., J.L.S., G.S.S.), and Neurological Sciences (D.M.J.), College of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Sayyed K
authors.initials: SK
authors.lastname: Zaidi
authors.affiliation: Departments of Pharmacology (F.E.C., M.S.B., N.E.G., K.G.E., T.H.T., J.H.W., J.A.T.), Biochemistry (P.W.L.T., S.K.Z., J.B.L., J.L.S., G.S.S.), and Neurological Sciences (D.M.J.), College of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Lian
authors.affiliation: Departments of Pharmacology (F.E.C., M.S.B., N.E.G., K.G.E., T.H.T., J.H.W., J.A.T.), Biochemistry (P.W.L.T., S.K.Z., J.B.L., J.L.S., G.S.S.), and Neurological Sciences (D.M.J.), College of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Stein
authors.affiliation: Departments of Pharmacology (F.E.C., M.S.B., N.E.G., K.G.E., T.H.T., J.H.W., J.A.T.), Biochemistry (P.W.L.T., S.K.Z., J.B.L., J.L.S., G.S.S.), and Neurological Sciences (D.M.J.), College of Medicine, University of Vermont, Burlington, Vermont 05405.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Stein
mesh_terms: D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects; D020218:Response Elements; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013961:Thyroid Gland / Q000378:metabolism; D037042:Thyroid Hormone Receptors beta / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014284:Triiodothyronine / Q000494:pharmacology
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C493709:RUNX2 protein, human; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine