Coordinated disruption of thyroid hormone signaling in high-grade serous ovarian cancer

Introduction Thyroid hormone signaling regulates cellular proliferation, differentiation and metabolism, yet its contribution to high-grade serous ovarian cancer (HGSOC) remains poorly understood. Methods and results Here, we demonstrate that HGSOC is characterized by coordinated disruption of the thyroid hormone signaling axis through simultaneous impairment of hormone transport, receptor expression and receptor localization. Bioinformatics analyses of clinical datasets revealed that the thyroid hormone receptor alpha (THRA) and the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) are significantly downregulated in ovarian cancer and that high expression of both genes is associated with improved patient survival. These findings were confirmed at the protein level in normal ovary and fallopian tube (FT) tissues and in HGSOC tumors from patients. Immunohistochemical analysis further identified a marked redistribution of THRA from the nucleus to the cytoplasm in HGSOC, with preservation of nuclear THRA correlating with a more favorable clinical outcome. Mechanistically, we identify the thyroid hormone-inactivating enzyme DIO3 as a potential regulator of THRA expression and intracellular distribution. DIO3 depletion in FT and HGSOC cell lines preferentially reduced membrane and cytoplasmic THRA while promoting relative nuclear retention of the remaining receptor, which may be associated with restoration of canonical thyroid hormone receptor signaling. Finally, restoration of MCT8 expression suppressed ovarian cancer cell growth, increased apoptosis and enhanced cellular responsiveness to triiodothyronine (T3). Conclusions Collectively, our study identifies coordinated disruption of the thyroid hormone axis as a previously unrecognized feature of HGSOC and provides a mechanistic rationale for therapeutic strategies aimed at restoring thyroid hormone signaling through targeting DIO3 and thyroid hormone transport.