RESUMO
The present study investigated whether the efficacy of radioiodine therapy towards aggressive thyroid cancer cells was affected by ß-catenin activity and associated with sodium/iodine symporter (NIS) localization. Human thyroid cancer cell line follicular thyroid carcinoma (FTC) 133 was endowed with aggressiveness by HIF-1α or ß-catenin overexpression. The protein amount and subcellular localization of NIS, and the radioiodine uptake capacity were detected in the cells, as well as in cells subsequently undergoing ß-catenin knockdown. Xenograft experiments were conducted to compare the tumor growth ability and responsiveness to radioactive treatment among HIF-1α and ß-catenin overexpressing FTC cells, respectively with or without ß-catenin knockdown. ß-catenin increased upon HIF-1α overexpression, but not vice versa. This signal axis would prompt metastatic propensity in FTC cells, and translocate NIS from cytomembrane to cytoplasm. Consistently the radioiodine uptake capacity in the cells decreased obviously. Knockdown of ß-catenin reversed all these changes. Furthermore, the xenograft experiments showed that radioiodine treatment could thoroughly suppress tumor growth ability of aggressive FTC cells only if the HIF-1α-induced ß-catenin activation was disrupted by ß-catenin knockdown. ß-catenin nuclear translocation in tumor cells was accompanied by abnormal subcellular localization of NIS. Moreover, we found that only after inhibiting ß-catenin expression, can the radioiodine treatment promote apoptosis other than repress proliferation and survival in xenograft tumor cells. In conclusion, aggressive FTC cells overexpressing HIF-1α will be fully cracked down by radioiodine therapy once ß-catenin expression is inhibited, and regulated localization of NIS may account for underlying mechanisms.
Assuntos
Adenocarcinoma Folicular/metabolismo , Radioisótopos do Iodo/uso terapêutico , Tolerância a Radiação/genética , Simportadores/metabolismo , beta Catenina/genética , Adenocarcinoma Folicular/genética , Adenocarcinoma Folicular/patologia , Adenocarcinoma Folicular/radioterapia , Animais , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Radioisótopos do Iodo/farmacocinética , Masculino , Camundongos , Camundongos SCID , Invasividade Neoplásica , Transdução de Sinais/genética , Transdução de Sinais/efeitos da radiação , Ensaios Antitumorais Modelo de Xenoenxerto , beta Catenina/antagonistas & inibidores , beta Catenina/metabolismoRESUMO
All-trans-retinoic acid (ATRA) can enhance iodine uptake capability of thyroid tumors, but the mechanisms remain poorly understood. The aim of the present study was to investigate the effects of ATRA on isotope susceptibility, proliferation and invasion of anaplastic thyroid carcinoma (ATC) and potential mechanisms. SW1736 cells were treated with 1 µmol/l ATRA or 1% ethanol for 5 days. A cell line stably expressing ß-catenin-shRNA was established. An iodine uptake assay was performed using 125I. Proliferation and invasiveness were tested using MTT and Transwell assays, respectively. Western blotting was used to assess the expression of ß-catenin, glycogen synthase kinase-3ß (GSK-3ß), sodium/iodine symporter (NIS) and proteins involved in epithelial-mesenchymal transition. Cells pretreated with ATRA were injected subcutaneously into SCID mice. Mice were intraperitoneally injected with 131I once on the first day of treatment, and tumor growth was then assessed. After 35 days of 131I treatment, ATRA-pretreated tumor volume and weight were decreased compared with the 131I alone group (163.32±19.57 vs. 332.06±21.37 mm3; 0.35±0.14 vs. 0.67±0.23 g, both P<0.05). Similar results were observed in the ß-catenin shRNA-pretreated tumors. ATRA also increased the uptake of iodine by SW1736 cells (P<0.01), and similar results were observed in ß-catenin shRNA cells. ATRA treatment decreased the cell proliferation and invasion compared with control cells (all P<0.05), similar to ß-catenin shRNA. ATRA treatment decreased the expression of phosphorylated (p-)ß-catenin, p-GSK-3ß, vimentin, and fibronectin, and increased the expression of NIS and E-cadherin, compared with the control. ATRA increased the iodine uptake and inhibited the proliferation and invasion of SW1736 cells, involving ß-catenin phosphorylation. In conclusion, ATRA could be used to improve the isotope sensitivity of ATC.