Enhancer-mediated NR2F2 recruitment activates BGN to promote tumor growth and shape tumor microenvironment in papillary thyroid cancer

Sep 28, 2026

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Study investigates Biglycan (BGN) in papillary thyroid carcinoma (PTC), focusing on endocrine and paracrine mechanisms that drive disease development. Multi-omics integration evaluates BGN expression and clinical relevance, while functional assays test proliferation, colony formation, and cell-cycle effects. RNA-seq, single-cell RNA-seq, and flow cytometry assess signaling, immune infiltration, and macrophage polarization. NR2F2 enhancer regulation is examined via CRISPRi and luciferase assays, and CIA1 therapeutic effects are evaluated in PTC models.

LanguageEnglish

CategoryHealthcare

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Pages27

Reading Time1 h 8 min

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Abstract

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Methods

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Introduction

Theranostics 2026, Vol. 16, Issue 1 298 Ivyspring International Publisher Theranostics 2026; 16(1): 298-324. doi: 10.7150/thno.113712 Research Paper Enhancer-mediated NR2F2 recruitment activates BGN to promote tumor growth and shape tumor microenvironment in papillary thyroid cancer Mei Tao1\#, Xianhui Ruan1\#, Jialong Yu1\#, Qiman Dong1, Wei Luo1, Wei Zhang1,2, Mengran Tian1,2, Xiukun Hou1, Linfei Hu1, Jingzhu Zhao1, Dapeng Li1, Jie Hao2, Songfeng Wei1􀀍, Xiangqian Zheng1􀀍, Ming Gao1,2􀀍 1. Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, 300060, China. 2. Department of Thyroid and Breast Surgery, Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, 300121, China. \# These authors contributed equally to this work 􀀍 Corresponding authors: Dr Songfeng Wei, Email: [successor317@aliyun.com](successor317@aliyun.com); Dr Xiangqian Zheng, Email: [xzheng05@tmu.edu.cn](xzheng05@tmu.edu.cn); Dr Ming Gao, E-mail: [headandneck2008@126.com](headandneck2008@126.com). © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License ([https://creativecommons.org/licenses/by/4.0/](https://creativecommons.org/licenses/by/4.0/)). See [https://ivyspring.com/terms](https://ivyspring.com/terms) for full terms and conditions. Received: 2025.03.13; Accepted: 2025.08.31; Published: 2026.01.01 Abstract Background: Biglycan (BGN), a component of the extracellular matrix, has been closely associated with tumor progression. This study aimed to investigate the endocrine and paracrine roles of BGN in papillary thyroid carcinoma (PTC) to elucidate the underlying molecular mechanisms driving PTC development. Methods: Multi-omics integration was used to assess BGN expression and its clinical relevance in PTC. Functional assays, including cell viability, colony formation, and cell cycle analysis, were used to evaluate the biological functions of BGN. RNA-seq identified key signaling pathways involved in BGN-mediated PTC progression. Immune cell infiltration and macrophage polarization were analyzed using single-cell RNA-seq and flow cytometry. CRISPR interference was employed to suppress BGN enhancer activity, while luciferase assays confirmed NR2F2’s role in regulating BGN expression. The therapeutic potential of the NR2F2-specific inhibitor CIA1 was tested in PTC cell lines and mouse models. Results: BGN overexpression in malignant PTC cells evaluated by BayesPrism deconvolution was linked to poor clinicopathological features in PTC. BGN knockdown inhibited cell proliferation and induced cell cycle arrest, which was rescued by recombinant BGN. Tumor-derived BGN activated the AKT signaling pathway, promoting tumor growth. Additionally, high BGN expression facilitated M2 macrophage polarization and immune evasion through TLR4 signaling. The NR2F2-BGN axis activated BGN transcription and AKT signaling. CIA1 treatment reduced BGN expression, suppressed cell proliferation, and modulated macrophage polarization. Conclusion: Our findings highlight the NR2F2-BGN axis as a critical regulator of PTC progression. Targeting this axis offers a promising therapeutic strategy for PTC treatment and immune microenvironment modulation. Keywords: BGN, Papillary thyroid cancer, enhancer-promoter loop, M2 macrophage, NR2F2 Introduction Biglycan (BGN), a class I small leucine-rich proteoglycan (SLRP), is an essential component of the extracellular matrix (ECM) and plays pivotal roles in tissue architecture, cell signaling, and immune regulation [1] . As a structural ECM molecule, BGN contributes to tissue homeostasis and is broadly expressed in the immune, vascular, and musculoskeletal systems [2-4] . Functionally, BGN can induce sterile inflamma

FAQs

What role does BGN play in papillary thyroid carcinoma according to the study?

BGN is associated with tumor progression in PTC, and the study aims to clarify endocrine and paracrine mechanisms that drive PTC development.

How did the researchers test BGN’s function in PTC?

They used multi-omics integration to assess expression and clinical relevance, then performed functional assays such as cell viability, colony formation, and cell-cycle analysis. RNA-seq and additional immune analyses were used to map signaling and microenvironment effects.

What is the proposed NR2F2–BGN mechanism and how was it targeted?

The NR2F2–BGN axis activates BGN transcription and AKT signaling to promote tumor growth and influences immune evasion via TLR4-related effects. The NR2F2-specific inhibitor CIA1 reduced BGN expression, suppressed proliferation, and modulated macrophage polarization in PTC models.

Sep 28, 2026

Uploaded by Hazel