Identification of Functional Thyroid Stimulating Hormone Receptor and TSHR Gene Mutations in Hepatocellular Carcinoma.

Abstract

Extra-thyroid expression of thyroid stimulating hormone (TSH) receptor (TSHR) has been reported in normal liver tissues, but never assessed in hepatocellular carcinoma (HCC). Paired cancerous and non-cancerous HCC tissues were analyzed with TSHR expression assays. TSHR functional assessments and sequence analysis for the TSHR exon-10 were performed. TSHR overexpression was found in 150/197 (76.1%) HCCs. Higher TSHR expression was associated with unfavorable postoperative outcomes. Immunohistochemical analysis revealed predominantly nuclei/peri-nuclei localization of TSHR in cancerous tissues but cell membrane localization in non-cancerous parts. TSH stimulation on hepatoma cells resulted in increased cyclic adenosine monophosphate levels with altered cell sensitivity to cisplatin. Gene mutations leading to TSHR truncation were detected in 8/81 (9.9%) HCC tissues. Overexpression of TSHR was found in a great majority of HCC tissues and associated with unfavorable prognosis. Cell-based experiments and gene mutation analysis suggested that TSHR in HCCs was functional.