Liganded-thyroid hormone receptor induces anaplastic thyroid cancer cell death via activation of the RhoB signaling pathway

Program: Late-Breaking Abstracts
Session: SUN-LB-Late-Breaking Poster Session 2
Bench to Bedside
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-LB-01
Sayaka Ichijo*1, Fumihiko Furuya1, Masashi Ichijo1, Hiroki Shimura1, Yoshitaka Hayashi2 and Tetsuro Kobayashi1
1University of Yamanashi, Chuo, Yamanashi, Japan, 2Nagoya Univ Res Inst of Environm, Nagoya, Japan
Thyroid hormone receptor (TR) mediates the crucial effects of the thyroid hormone (T3) on growth, development, and differentiation. Several reports indicated that decreased expression or inactivating somatic mutations of TRs have been shown in human cancers including liver, breast, lung, and thyroid. The knock-in mouse harboring a dominant negative TRβ mutation develops poorly differentiated thyroid cancer strongly suggests the involvement of TRβ in carcinogenesis. These results indicated the hypothesis that TRβ might act as a tumor suppressor in several types of cancer. The aim of this study is to identify the role of TRβ in the proliferation of thyroid cancer cells and cell cycle regulation. We first analyzed the expression profile of TRβ or other cell cycle-related genes in 27 of human thyroid cancer tissues. We constructed a recombinant adenovirus vector, AdTRβ, which expresses human TRβ cDNA driven by the cytomegalovirus promoter and analyzed the effects of AdTRβ on cell cycle or proliferation of WRO, FRO or ARO, anaplastic thyroid cancer cell line that expresses thyroid transcription factor, in vitro and in vivo. Real-time PCR and western blot analyses were employed for the analysis of mRNA and protein levels, respectively. The abundance of TRβ mRNA was significantly decreased in papillary thyroid cancer tissues (18 %), and anaplastic cancer tissues (1.3 %), compared with intact thyroid tissues. Furthermore, the expression levels of TRβ correlate with that of RhoB, a member of the Ras superfamily (R2=0.617, p<0.001). In AdTRβ-infected WRO and ARO cells, RhoB mRNA and protein expression were significantly enhanced in a T3-dependent manner. One-hundred nM of T3-treatment significantly increased the expression levels of p21 and cleaved caspase-3 in AdTRβ-infected cells. Consistent with these results, T3-treatment significantly enhanced the G1-phase cell numbers in AdTRβ-infected cells. When activation of RhoB was inhibited by treatment with 5 μM of GGTI-298, isoprenyl inhibitor, liganded-TRβ-associated prevention of cancer cell proliferation was diminished. The growth of ARO tumor xenografts in vivo was significantly inhibited by AdTRβ-injection, compared with the control virus-injected tumors. These results indicated TRβ prevents thyroid cancer cell proliferation via activation of the RhoB signaling pathway. Our present findings suggested that the restoration of liganded-TRβ may contribute to development of novel strategy against anaplastic thyroid cancer.

Nothing to Disclose: SI, FF, MI, HS, YH, TK

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