What question did this study set out to answer?

The study aims to explore BCAR3 methylation status and its functional impacts in thyroid cancer.

January 17, 2026Cancers0 citationsOpen Access

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

WYWenkang YuShanghai Municipal Center For Disease Control Prevention YMYizhu MaoNanjing Medical University YYYifei YinZhongyuan University of Technology

Key Points

The study aims to explore BCAR3 methylation status and its functional impacts in thyroid cancer.
Analyzed BCAR3 methylation using MALDI-TOF mass spectrometry in 422 thyroid cancer and 371 benign samples.
Assessed BCAR3 expression via immunohistochemistry, qPCR, and Western blot.
Conducted functional assays focusing on proliferation, migration, and invasion after BCAR3 knockdown.
Performed rescue experiments with a PI3K activator to determine mechanistic pathways.
BCAR3 was hypomethylated in thyroid cancer compared to benign tissues (p < 0.001).
The strongest association with thyroid cancer risk was observed in CpG_6 (OR = 1.73, p < 0.001).
Larger tumor size and advanced disease stage correlated with increased BCAR3 hypomethylation.
BCAR3 expression was upregulated in thyroid cancer tissues and cell lines (p < 0.05).
Knockdown of BCAR3 reduced AKT/mTOR phosphorylation and changed EMT marker expression, suppressing cell proliferation, migration, and invasion (p < 0.05).

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 CpG₆ 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.

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