High grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy with a need for better understanding the disease pathogenesis. The biologically active thyroid hormone, T3, is considered a tumor suppressor by promoting cell differentiation and mitochondrial respiration. Tumors evolved a strategy to avoid these anticancer actions by expressing the T3 catabolizing enzyme, Deiodinase type 3 (DIO3). This stimulates cancer proliferation and aerobic glycolysis (Warburg effect). We identified DIO3 expression in HGSOC cell lines, tumor tissues from mice and human patients, fallopian tube (FT) premalignant lesion and secretory cells of normal FT, considered the disease site-of-origin. Stable DIO3 knock-down (DIO3-KD) in HGSOC cells led to increased T3 bioavailability and demonstrated induced apoptosis and attenuated proliferation, migration, colony formation, oncogenic signaling, Warburg effect and tumor growth in mice. Proteomics analysis further indicated alterations in an array of cancer-relevant proteins, the majority of which are involved in tumor suppression and metabolism. Collectively this study establishes the functional role of DIO3 in facilitating tumorigenesis and metabolic reprogramming, and proposes this enzyme as a promising target for inhibition in HGSOC.

高级别浆液性卵巢癌 (HGSOC) 是最致命的妇科恶性肿瘤，需要更好地了解该病的发病机制。具有生物活性的甲状腺激素 T3 被认为是一种肿瘤抑制因子，可促进细胞分化和线粒体呼吸。肿瘤进化出一种策略，通过表达 T3 分解代谢酶 3 型脱碘酶 (DIO3) 来避免这些抗癌作用。这会刺激癌症增殖和有氧糖酵解（Warburg 效应）。我们在 HGSOC 细胞系、小鼠和人类患者的肿瘤组织、输卵管 (FT) 癌前病变和正常 FT 的分泌细胞中鉴定了 DIO3 表达，这些被认为是疾病的起源部位。HGSOC 细胞中稳定的 DIO3 敲低 (DIO3-KD) 导致 T3 生物利用度增加，并证明诱导细胞凋亡和减弱增殖，小鼠的迁移、集落形成、致癌信号、Warburg 效应和肿瘤生长。蛋白质组学分析进一步表明一系列癌症相关蛋白发生了改变，其中大部分与肿瘤抑制和代谢有关。总的来说，这项研究确定了 DIO3 在促进肿瘤发生和代谢重编程方面的功能作用，并提出将该酶作为抑制 HGSOC 的有希望的靶标。