Abstract 2661: Role of NKX2-1 in thyroid neoplasms induced by iodine-deficiency and radiation

The multi-step carcinogenesis model, including the adenoma-carcinoma sequence, has been proposed in many cancers including those of colon, pancreas, and thyroid. BRAF activation is among the reported gene mutations important for thyroid carcinogenesis. However, the role of NKX2-1, a master regulator of thyroid development and function, in thyroid carcinogenesis remains elusive. In this study, we investigated the role of NKX2-1 in thyroid neoplasm formation using thyroid-specific Nkx2-1 conditional KO mice, Nkx2-1(fl/fl);TPO-Cre (cKO mice). Nkx2-1(fl/fl) (WT) and cKO mice were each allotted to four groups: 1. Control Diet, 2. Control Diet + Radiation, 3. Low Iodine Diet (LID), 4. LID + Radiation. Whole body gamma-irradiation (2 Gy, 3 times every other day) was carried out at 4-8 weeks of age, followed by switching the diet to either Control Diet or LID. Thyroid histology was examined at 1.1-1.3 years after the start of the diet. In both WT and cKO mice, iodine-deficiency, regardless of radiation, induced diffuse hyperplasia (goiter) in more than 50% of the mice, and increased the incidence of focal hyperplasia considered as a preneoplastic lesion. Adenoma formation was only observed in LID-treated mice regardless of radiation, suggesting that iodine-deficiency, but not radiation, is a key factor for mouse thyroid adenoma formation. The incidence of adenoma formation was significantly higher in cKO mice than WT mice in LID + Radiation group (14% for WT vs 52% for cKO, in progress). In addition, carcinoma formation was observed only in LID + Radiation-treated mice, suggesting that radiation is necessary to proceed from adenoma to cancer in thyroid carcinogenesis. Further, there is a tendency for higher incidence of carcinoma in LID + Radiation-treated cKO mice (4% for WT vs 11% for cKO, in progress). These results suggest that the loss of Nkx2-1 can promote adenoma formation induced by iodine-deficiency, and possibly facilitate carcinogenesis induced by LID + Radiation. In summary, our results suggest that NKX2-1 may function as a tumor suppressor in thyroid carcinogenesis. We are now trying to investigate the molecular mechanisms by which loss of NKX2-1 affects thyroid proliferation and facilitates neoplasm formation by examining the molecular profiles of mouse thyroids after LID and/or radiation treatment. Citation Format: Yo-Taro Shirai, Yoshinori Takizawa, Manabu Iwadate, Jorge Paiz, Shigetoshi Yokoyama, Masaaki Miyakoshi, Jerrold M. Ward, Shioko Kimura. Role of NKX2-1 in thyroid neoplasms induced by iodine-deficiency and radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2661.