Carbonic Anhydrase 12 as a Novel Prognostic Biomarker and Therapeutic Target for High‐Risk Follicular Thyroid Carcinoma

Follicular thyroid carcinoma is generally associated with a favorable prognosis; however, a subset of follicular thyroid carcinoma shows poor prognosis and frequent distant metastases, and this subset is referred to as high-risk follicular thyroid carcinoma. Difficulty in distinguishing high-risk from low-risk follicular thyroid carcinoma based on current diagnostic approaches leads to the overtreatment of patients with indolent disease. Therefore, the identification of novel biomarkers capable of reliably distinguishing high-risk follicular thyroid carcinoma is essential for accurate risk stratification. Such biomarkers may serve as therapeutic targets for metastatic follicular thyroid carcinoma. This study aimed to identify novel prognostic markers and therapeutic targets for high-risk follicular thyroid carcinoma. In this study, we conducted bulk ribonucleic acid sequencing of high-risk follicular thyroid carcinoma, including widely invasive subtypes and metastatic tumors, and we identified carbonic anhydrase 12 as a candidate biomarker. Immunohistochemical analysis revealed significantly higher carbonic anhydrase 12 expression in follicular thyroid carcinoma than in benign follicular adenomas, particularly in widely invasive and encapsulated angioinvasive subtypes. High carbonic anhydrase 12 expression was an independent predictor of poor disease-free survival, surpassing conventional clinicopathological parameters. Functional assays showed that carbonic anhydrase 12 promoted follicular thyroid carcinoma proliferation, invasion, and migration partly by regulating matrix metalloproteinase 2 expression. Furthermore, carbonic anhydrase 12 inhibitor U104 suppressed follicular thyroid carcinoma cell growth in a dose-dependent manner, and its combination with lenvatinib exerted synergistic antiproliferative effects. Collectively, these findings identified carbonic anhydrase 12 as a novel prognostic biomarker of follicular thyroid carcinoma and a promising therapeutic target.