2. Academic Validation
  3. BCAR3 Hypomethylation as a Potential Diagnostic Marker for Thyroid Cancer and Its Mechanism via Promoting EMT and AKT/mTOR Pathway

BCAR3 Hypomethylation as a Potential Diagnostic Marker for Thyroid Cancer and Its Mechanism via Promoting EMT and AKT/mTOR Pathway

  • Cancers (Basel). 2026 Jan 15;18(2):267. doi: 10.3390/cancers18020267.
Wenkang Yu 1 2,  Yizhu Mao 1,  Yifei Yin 3,  Jiacheng Yang 1,  Yi Zhang 4,  Xuandong Huang 3,  Yifen Zhang 4,  Chenxia Jiang 5,  Rongxi Yang 1
Affiliations

Affiliations

  • 1 Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
  • 2 Hongkou District Center for Disease Control and Prevention, Shanghai (Hongkou District Institute of Health Supervision, Shanghai), Shanghai 200434, China.
  • 3 Department of Thyroid and Breast Surgery, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an 223002, China.
  • 4 Department of Pathology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China.
  • 5 Department of Pathology, Affiliated Hospital of Nantong University, Nantong 226001, China.
PMID: 41595187 DOI: 10.3390/cancers18020267
Abstract

Background: BCAR3 has been implicated in various cancers, yet its role in thyroid Cancer (TC) remains unclear. This study aimed to investigate the methylation status, functional effects, and underlying mechanisms of BCAR3 in TC.

Methods: BCAR3 methylation was analyzed using matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) mass spectrometry in 422 TC and 371 benign thyroid nodule samples. Expression levels were assessed via immunohistochemistry, qPCR, and Western blot. Functional assays including proliferation, migration, and invasion were performed after BCAR3 knockdown. Rescue experiments using a PI3K Activator were conducted to examine pathway mechanisms.

Results: BCAR3 was significantly hypomethylated in TC compared to benign tissues (p < 0.001), with CpG_6 most strongly associated with TC risk (odds ratio, OR = 1.73, p < 0.001). Notably, BCAR3 hypomethylation was more pronounced in cases with larger tumor size and advanced disease stage. Furthermore, BCAR3 methylation showed differential patterns across TC subtypes, with medullary thyroid carcinoma exhibiting the lowest methylation levels. BCAR3 expression was upregulated in TC tissues and cell lines (p < 0.05). Mechanistically, BCAR3 knockdown reduced phosphorylation of Akt/mTOR and altered expression of epithelial-to-mesenchymal transition (EMT) marker, characterized by an increase in E-cadherin and decreases in Vimentin and N-Cadherin, and consequently suppressed proliferation, migration, and invasion (p < 0.05). Rescue experiments with a PI3K Activator showed a trend towards restoration of these effects, although not to the level of the control groups.

Conclusions: BCAR3 hypomethylation contributes to TC cells' proliferation, migration, and invasion by promoting Akt/mTOR activation and EMT. These findings highlight the potential of BCAR3 methylation as both a biomarker and a therapeutic target in TC.

Keywords

BCAR3; DNA methylation; EMT; biomarker; thyroid cancer.

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