Thyroid cancer (TC) is among the fastest-growing solid malignancies worldwide, with papillary thyroid carcinoma (PTC) accounting for approximately 90% of all cases. Although the prognosis for most PTC patients is favorable, a subset still faces risks of aggressive progression and recurrence, highlighting the need for deeper understanding of its molecular mechanisms and novel therapeutic strategies. In recent years, obesity-associated chronic inflammation has been recognized as a major driver of PTC development. Adipose tissue, functioning as an endocrine organ, secretes various adipokines that play critical roles in tumor immunity, metabolic reprogramming, and microenvironment modulation. Among them, adiponectin (APN) is a key anti-inflammatory adipokine with regulatory functions in metabolism, autophagy, and cellular proliferation. Through its receptors, AdipoR1 and AdipoR2, APN activates signaling pathways such as AMPK and PPAR-α, contributing to energy homeostasis, autophagy induction, and modulation of the PI3K/Akt/mTOR axis. However, the poor stability of the APN protein limits its clinical application, prompting growing interest in its small-molecule receptor agonist, AdipoRon, with high oral bioavailability and stability has shown potential in inducing apoptosis and autophagy across multiple tumor models. Recent studies also suggest an interaction between APN signaling and low-density lipoprotein (LDL) metabolism. Particularly in BRAF-mutated PTC, LDL promotes tumor progression via the MAPK/ERK pathway, while APN may counteract these effects by enhancing LDLR degradation. Thus, investigating the regulatory role of AdipoRon in PTC, especially in relation to lipid metabolism and LDL signaling, holds significant scientific and therapeutic value.
This study aims to comprehensively investigate the expression patterns, biological functions, and molecular mechanisms of APN and its receptors (AdipoR1 and AdipoR2) in TC, particularly PTC. Special emphasis is placed on the interplay between APN signaling and LDL metabolism, and the antitumor potential of AdipoRon in promoting apoptosis and/or autophagy.
A combination of bioinformatics and cell-based functional experiments was employed to explore the role of APN signaling in PTC. Public databases including TCGA, GTEx, and GEO were utilized to analyze the differential expression of APN receptor-related genes (ADIPOR1, ADIPOR2) across normal thyroid tissue, benign tumors, and PTC, along with correlations with clinicopathological parameters and prognosis. Two thyroid cancer cell lines with distinct mutational backgrounds (BRAFV600E BCPAP and RET/PTC1-rearranged TPC-1) were treated with AdipoRon to evaluate its effects on cell proliferation and migration. Western blotting was used to assess the expression of key proteins involved in apoptosis, autophagy, and relevant signaling pathways (AKT, mTOR, ERK). Furthermore, combined treatment with LDL and AdipoRon was applied to examine the modulation of LDL-induced tumor-promoting effects and explore the potential synergistic mechanisms under dysregulated lipid metabolism conditions.
Our findings reveal a significant role of APN signaling in the pathogenesis and progression of PTC. APN and its receptors (ADIPOR1/2) are differentially expressed in PTC compared to benign thyroid tissues, with functional divergence: ADIPOR1 is mainly involved in cell death and immune regulation, whereas ADIPOR2 is closely linked to metabolic remodeling. In PTC patients, perithyroidal adipose tissue exhibited elevated APN secretion along with altered inflammatory cytokine profiles, suggesting its contribution to tumor transformation via the local inflammatory microenvironment. AdipoRon effectively inhibited proliferation and migration of PTC cells, induced apoptosis and autophagy, and showed mutation-dependent activity. Under high LDL conditions, AdipoRon suppressed LDLR expression and interfered with AKT/mTOR/ERK signaling, reversing LDL-induced proliferative effects. Collectively, these findings highlight the critical role of the APN–LDL axis in metabolic regulation of PTC and support the therapeutic potential of AdipoRon as a targeted intervention in metabolically dysregulated TC.
| Date of Award | 7 Oct 2025 |
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| Original language | English |
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| Awarding Institution | - Universitat Autònoma de Barcelona (UAB)
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| Supervisor | Joan Carles Escola Gil (Director) & Eugènia Mato Matute (Director) |
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