Thyroid hormone (T3) and its receptor (TR) are involved in cancer progression. While deregulation of long non-coding RNA (lncRNA) expression has been detected in many tumor types, the mechanisms underlying specific involvement of lncRNAs in tumorigenicity remain unclear. Experiments from the current study revealed negative regulation of BC200 expression by T3/TR. BC200 was highly expressed in hepatocellular carcinoma (HCC) and effective as an independent prognostic marker. BC200 promoted cell growth and tumor sphere formation, which was mediated via regulation of cell cycle-related genes and stemness markers. Moreover, BC200 protected cyclin E2 mRNA from degradation. Cell growth ability was repressed by T3, but partially enhanced upon BC200 overexpression. Mechanistically, BC200 directly interacted with cyclin E2 and promoted CDK2–cyclin E2 complex formation. Upregulation of cell cycle-related genes in hepatoma samples was positively correlated with BC200 expression. Our collective findings support the utility of a potential therapeutic strategy involving targeting of BC200 for the treatment of HCC.
Yang-Hsiang Lin, Meng-Han Wu, Ya-Hui Huang, Chau-Ting Yeh, Hsiang-Cheng Chi, Chung-Ying Tsai, Wen-Yu Chuang, Chia-Jung Yu, I-Hsiao Chung, Ching-Ying Chen and Kwang-Huei Lin
Chen-Hsin Liao, Shih-Chi Yeh, Ya-Hui Huang, Ruey-Nan Chen, Ming-Ming Tsai, Wei-Jan Chen, Hsiang-Cheng Chi, Pei-Ju Tai, Chia-Jung Liao, Sheng-Ming Wu, Wan-Li Cheng, Li-Mei Pai and Kwang-Huei Lin
The thyroid hormone 3,3′,5-triiodo-l-thyronine (T3) regulates growth, development, and differentiation processes in animals. These activities are mediated by the nuclear thyroid hormone receptors (TRs). Microarray analyses were performed previously to study the mechanism of regulation triggered by T3 treatment in hepatoma cell lines. The results showed that spondin 2 was regulated positively by T3. However, the underlying mechanism and the physiological role of T3 in the regulation of spondin 2 are not clear. To verify the microarray results, spondin 2 was further investigated using semi-quantitative reverse transcription-PCR and western blotting. After 48 h of T3 treatment in the HepG2–TRα1#1 cell line, spondin 2 mRNA and protein levels increased by 3.9- to 5.7-fold. Similar results were observed in thyroidectomized rats. To localize the regulatory region in spondin 2, we performed serial deletions of the promoter and chromatin immunoprecipitation assays. The T3 response element on the spondin 2 promoter was localized in the −1104/−1034 or −984/−925 regions. To explore the effect of spondin 2 on cellular function, spondin 2 knockdown cell lines were established from Huh7 cells. Knockdown cells had higher migration ability and invasiveness compared with control cells. Conversely, spondin 2 overexpression in J7 cells led to lower migration ability and invasiveness compared with control cells. Furthermore, this study demonstrated that spondin 2 overexpression in some types of hepatocellular carcinomas is TR dependent. Together, these experimental findings suggest that spondin 2, which is regulated by T3, has an important role in cell invasion, cell migration, and tumor progression.