Clinical Impact of Androgen Receptor–Suppressing miR-146b Expression in Papillary Thyroid Cancer Aggressiveness

• Published in: The journal of clinical endocrinology and metabolism Vol. 108; no. 11; pp. 2852 - 2861
• Main Authors: Chou, Chen-Kai, Chi, Shun-Yu, Hung, Yi-Yung, Yang, Yi-Chien, Fu, Hung-Chun, Wang, Jia-He, Chen, Chueh-Chen, Kang, Hong-Yo
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 18.10.2023
• Subjects: Androgen receptors; Androgens; Carcinoma, Papillary - genetics; Carcinoma, Papillary - metabolism; Cell Line, Tumor; Chromatin; Correlation analysis; Gene Expression Regulation, Neoplastic; Gene silencing; Humans; Immunoprecipitation; Lymph nodes; Malignancy; Metastases; MicroRNAs - metabolism; miRNA; Papillary thyroid cancer; Papillary thyroid carcinoma; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; Thyroid cancer; Thyroid Cancer, Papillary - genetics; Thyroid Cancer, Papillary - pathology; Thyroid Neoplasms - genetics; Thyroid Neoplasms - pathology; Tumor cell lines; Tumorigenesis; microRNA; neoplasm; steroid hormone receptor; tumor prognosis
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/clinem/dgad279

Abstract Context Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy. Dysregulated expression of miR-146b and androgen receptor (AR) has been shown to play critical roles in tumorigenesis in PTC. However, the mechanistic and clinical association between AR and miR-146b is not fully understood. Objective The purpose was to investigate miR-146b as the potential AR target miRNA and its involvement in advanced tumor characteristics of PTC. Methods Expression of AR and miR-146b were assessed in frozen and formalin-fixed paraffin-embedded tissue samples from PTC and adjacent normal thyroid specimens by quantitative real-time polymerase chain reaction, and their correlation was examined. Human thyroid cancer cell lines BCPAP and TPC-1 were used to evaluate the effect of AR on miR-146b signaling. Chromatin immunoprecipitation (ChIP) assays were performed to determine whether AR binds to the miR-146b promoter region. Results Pearson correlation analysis confirmed significant inverse correlation between miR-146b and AR expression. Overexpressing AR BCPAP and TPC-1 cells showed relatively lower miR-146b expression. ChIP assay revealed that AR might bind to the androgen receptor element located on the promoter region of miRNA-146b gene, and overexpression of AR suppresses miR-146b-mediated tumor aggressiveness. The low AR/high miR-146b PTC patient group was associated with advanced tumor characteristics, including higher tumor stage, lymph node metastasis, and worse treatment response. Conclusion To sum up, miR-146b is a molecular target of AR transcriptional repression; therefore, AR suppresses miR-146b expression to reduce PTC tumor aggressiveness.