Thyroid hormone (T 3 ) signaling through the thyroid hormone receptor (TRa1) regulates hepatoma cell growth and pathophysiology, but the underlying mechanisms are unclear at present. Here, we have shown that the oncomir microRNA-21 (miR-21) is activated by T 3 through a native T 3 response element in the primary miR-21 promoter. Overexpression of miR-21 promoted hepatoma cell migration and invasion, similar to that observed with T 3 stimulation in hepatoma cells. In addition, anti-miR-21-induced suppression of cell migration was rescued by T 3 . The Rac-controlled regulator of invasion and metastasis, T-cell lymphoma invasion and metastasis 1 (TIAM1), was identified as a miR-21 target additionally downregulated by T 3 . Attenuation and overexpression of miR-21 induced upregulation and downregulation of TIAM1, respectively. TIAM1 attenuation, in turn, enhanced migration and invasion via the upregulation of b-catenin, vimentin, and matrix metalloproteinase-2 in hepatoma cells. Notably, correlations between TRa1, miR-21, and TIAM1 expression patterns in animal models paralleled those observed in vitro. In the clinic, we observed a positive correlation (P ¼ 0.005) between the tumor/nontumor ratios of TRa1 and miR-21 expression, whereas a negative correlation (P ¼ 0.019) was seen between miR-21 and TIAM1 expression in patients with hepatoma. Our findings collectively indicate that miR-21 stimulation by T 3 and subsequent TIAM1 suppression promotes hepatoma cell migration and invasion. Cancer Res; 73(8); 2505-17. Ó2013 AACR.

The effects of gonadal steroids on glutamate-mediated pelvic nerve-to-urethra reflex (PUR) plasticity were investigated in rats, which received a sham operation (Sham), ovariectomy (OVX), or ovariectomy with daily supplemental estrogen (50 microg/kg, OVX + E2). The magnitude of the repetitive stimulation (RS, 1 Hz)-induced potentiation in PUR activity decreased significantly in the OVX group when compared with the Sham groups (18.09 +/- 3.91 and 7.40 +/- 1.03 spikes/stimulation in Sham and OVX group; respectively, P < 0.01, n = 21). Supplemental estrogen (OVX + E2, 12.60 +/- 1.49 spikes/stimulation) significantly reversed the decrease in RS-induced PUR potentiation caused by OVX (P < 0.01, n = 21). The magnitude of the RS-induced potentiation in PUR activity decreased significantly after intrathecal 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline [(20 microm, 10 microl), from 18.09 +/- 3.91 to 10.40 +/- 0.81, from 7.40 +/- 1.03 to 3.20 +/- 0.94, and from 12.60 +/- 1.49 to 8.06 +/- 0.32 spikes/stimulation in Sham, OVX, and OVX + E2, respectively, P < 0.01, n = 18] and D-2-amino-5-phosphonoraleric acid [(100 microm, 10 microl), from 18.09 +/- 3.91 to 1.04 +/- 0.12, from 7.40 +/- 1.03 to 1.06 +/- 0.22, and from 12.60 +/- 1.49 to 0.98 +/- 0.25 spikes/stimulation in Sham, OVX, and OVX + E2, respectively, P < 0.01, n = 18]. In addition, potentiation in PUR activities was induced by intrathecal l-glutamate (0.1 mm, 10 microl, from 1.04 +/- 0.02 to 21.60 +/- 0.93, from 1.10 +/- 0.06 to 8.40 +/- 1.50, and from 1.03 +/- 0.03 to 18.04 +/- 0.84 spikes/stimulation in Sham, OVX, and OVX + E2, respectively, P < 0.01, n = 18) and N-methyl-D-aspartic acid (0.1 mm, 10 microl, from 1.04 +/- 0.02 to 14.80 +/- 0.97, from 1.10 +/- 0.06 to 4.60 +/- 0.48, and from 1.03 +/- 0.03 to 9.09 +/- 0.63 spikes/stimulation in Sham, OVX, and OVX + E2); N-methyl-D-aspartic acid-mediated PUR plasticity in female rats and may contribute to alterations in urinary dysfunction after menopause.