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

Sep 29, 2026

Uploaded by Liam

Follicular thyroid carcinoma usually shows favorable outcomes, yet a high-risk subset develops distant metastases and poor prognosis, making reliable separation from low-risk disease critical to avoid overtreatment. Bulk RNA sequencing of high-risk tumors identified carbonic anhydrase 12 (CA12) as a candidate biomarker. Immunohistochemistry showed CA12 markedly higher in carcinomas than benign adenomas, especially invasive and encapsulated angioinvasive subtypes. Elevated CA12 independently predicted worse disease-free survival. Functional assays demonstrated CA12 promoted proliferation, invasion, and migration via matrix metalloproteinase 2 regulation, while the CA12 inhibitor U104 suppressed growth dose-dependently and enhanced lenvatinib’s antiproliferative effects.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Abstract

Study aim and rationale

Biomarker identification and validation

Prognostic impact

Functional mechanisms and therapeutic targeting

Introduction

Epidemiology and classification of FTC

Risk stratification challenges

Known clinicopathological prognostic factors

Abbreviations

Cancer Science ORIGINAL ARTICLE OPEN ACCESS Carbonic Anhydrase 12 as a Novel Prognostic Biomarker and Therapeutic Target for High-Risk Follicular Thyroid Carcinoma Masashi Tanida1,2 | Tsuyoshi Takashima1 | Shinichiro Tahara1 | Masaharu Kohara1 | Haruka Kanai2 | Masami Suzuki2 | Motoyuki Suzuki2 | Mitsuyoshi Hirokawa3 | Ayana Suzuki3 | Shinya Sato4 | Daisuke Okuzaki5 | Satoshi Nojima1 | Takahiro Matsui1 | Hidenori Inohara2 | Eiichi Morii1 1Department of Pathology, Graduate School of Medicine, The University of Osaka, Osaka, Japan | 2Department of Otorhinolaryngology-Head and Neck Surgery, Graduate School of Medicine, The University of Osaka, Osaka, Japan | 3Department of Diagnostic Pathology and Cytology, Kuma Hospital, Kobe, Japan | 4Department of Surgery, Yamashita Thyroid Hospital, Fukuoka, Japan | 5Single Cell Genomics, Human Immunology, WPI Immunology Frontier Research Center, The University of Osaka, Osaka, Japan Correspondence: Eiichi Morii ([morii.eiichi.med@osaka-u.ac.jp](morii.eiichi.med@osaka-u.ac.jp)) Received: 5 September 2025 | Revised: 22 October 2025 | Accepted: 29 October 2025 Funding: This work was supported by AMED under Grant Number JP21ae0121049 and by JSPS KAKENHI Grant Numbers T23K273910 . Keywords: biomarkers | carbonic anhydrase 12 | follicular thyroid carcinoma | lenvatinib | matrix metalloproteinase 2 ABSTRACT 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 asa novel prognostic biomarker of follicular thyroid carcinoma and a promising therapeutic target. | Abbreviations: CA12, carbonic anhydrase 12; CCLE, cancer cell line encyclopedia; CO₂, carbon dioxide; DEGs, differentially expressed genes; DFS, disease-free survival; EA, encapsulated angioinvasive (subtype of FTC); ECM, extracellular matrix; FA, follicular adenoma; FTC, follicular thyroid carcinoma; HALO, head alignment optimization (image analysis software); HE, hematoxylin and eosin; IHC, immunohistochemistry; KD, knockdown; MI, minimally invasive (subtype of FTC); MMP, matrix metalloproteinase; OS, overall survival; PTC, papillary thyroid carcinoma; RNA, messenger ribonucleic acid; RNA-seq, R

FAQs

What clinical problem does the study address in follicular thyroid carcinoma?

The study targets the difficulty of distinguishing high-risk from low-risk follicular thyroid carcinoma with current diagnostic approaches, which can lead to overtreatment of indolent disease.

How was carbonic anhydrase 12 (CA12) identified and validated as a biomarker?

Bulk RNA sequencing of high-risk tumors identified CA12, and immunohistochemical analysis then showed significantly higher CA12 expression in follicular thyroid carcinoma than in benign follicular adenomas, particularly in invasive subtypes.

Does CA12 have prognostic value and what mechanism supports its role?

High CA12 expression was an independent predictor of poor disease-free survival. Functional assays indicated CA12 promotes proliferation, invasion, and migration partly by regulating matrix metalloproteinase 2 expression.

Sep 29, 2026

Uploaded by Liam