AhR Antagonists Promote the Differentiation of Papillary Thyroid Carcinoma

As one of the most common endocrine system malignancies worldwide, thyroid cancer has a high incidence rate, bringing a heavy burden to patients and society. Among them, papillary thyroid carcinoma (PTC), the most prevalent pathological subtype of thyroid cancer, accounts for 80% of all thyroid cancers. Although most PTC patients have a good prognosis after surgery, radioactive iodine-131 (¹³¹I) therapy, and thyroid-stimulating hormone (TSH) suppression therapy, some patients still experience local recurrence or metastasis. Moreover, the tumor may develop a dedifferentiated phenotype, reducing or completely losing its ability to uptake iodine, preventing patients from benefiting from ¹³¹I therapy. These patients are defined as radioactive iodine-refractory papillary thyroid carcinoma (RR-PTC). RR-PTC is highly invasive, progresses rapidly, and is difficult to manage clinically, posing a significant challenge in the current field of thyroid cancer treatment.

Overview of AhR Antagonists

In recent years, with deeper research into the differentiation mechanisms of RR-PTC, the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, has gradually entered the scientific community's spotlight. AhR is abnormally expressed in various malignancies and is involved in regulating the differentiation of tumor cells. AhR agonists and antagonists have been used to regulate the differentiation of some tumor cells, bringing new hope for the treatment of RR-PTC. As a leading global supplier of high-performance life science products, Glpbio has been committed to providing comprehensive research materials and reliable product performance for biomedical research. Its research and application in the field of AhR antagonists undoubtedly provide strong support for solving this challenging problem.

AhR antagonists have shown significant effects in inducing PTC differentiation. Researchers have found that PTC cells treated with AhR antagonists StemRegenin 1 (SR1) or CH-223191 (CH) exhibit significantly increased ¹²⁵I uptake, reduced cell clonogenicity, increased levels of NIS mRNA and protein, and localization of NIS protein to the PTC cell membrane. These results indicate that AhR antagonists can effectively promote the differentiation of PTC cells, providing new insights for the treatment of RR-PTC.

Importantly, hsa_circ_0006741 (circSH2B3), a molecule closely related to cell differentiation, is significantly downregulated in PTC cells treated with AhR antagonists. Further research found that the expression of circSH2B3 was higher in various PTC cell lines than in normal thyroid epithelial cells, suggesting that circSH2B3 might be a potential target inhibited by AhR antagonists. When circSH2B3 is knocked down in PTC cells, ¹²⁵I uptake increases, clonogenicity decreases, and levels of NIS mRNA and protein rise. Conversely, overexpressing circSH2B3 in PTC promotes dedifferentiation. These results further confirm the mechanism by which AhR antagonists promote PTC differentiation by inhibiting circSH2B3.

Role of CircSH2B3 in PTC Dedifferentiation

So how does circSH2B3 play a crucial role in PTC dedifferentiation? Researchers identified downstream target miRNAs of circSH2B3 through bioinformatics analysis and selected hsa-miR-4640-5p as the target miRNA of circSH2B3 by comparing the miRNA expression levels in PTC cells treated with AhR antagonists. Dual-luciferase reporter gene assays further confirmed the direct interaction between hsa-miR-4640-5p and circSH2B3. This indicates that circSH2B3 mediates PTC dedifferentiation by sponging hsa-miR-4640-5p, thereby upregulating the expression of its target gene IGF2BP2. On the other hand, AhR antagonists can promote PTC differentiation by inhibiting the activity of the circSH2B3/miR-4640-5p/IGF2BP2 axis.

Advantages of Glpbio's AhR Antagonists

As a leading global supplier of high-performance life science products, Glpbio has played an essential role in the research and application of AhR antagonists. Glpbio covers 20 popular research fields, including cancer, neuroscience, anti-infection, and epigenetics, spanning nearly a thousand subfields such as Akt and Jak targets. It provides more than 20,000 scientific research reagents, including chemical small molecules and peptides such as GPCR ligands, neurotransmitters, ion channels, and signal inhibitors, which are widely used in preclinical research of human diseases and have broad potential uses. Among them,  AhR antagonists, one of Glpbio's important products, possess good purity, stability, and biological activity, providing reliable research materials and performance for biomedical research.

In studies on AhR antagonists promoting papillary thyroid carcinoma differentiation, Glpbio provided high-quality AhR antagonists, offering strong tools for researchers. These AhR antagonists not only exhibit excellent biological activity but also effectively inhibit circSH2B3 expression in cell experiments, thereby inducing PTC cell differentiation. This research outcome provides a new strategy for RR-PTC treatment and opens new avenues for the application of AhR antagonists in cancer therapy.

AhR Antagonists Inducing PTC Differentiation

PTC cells treated with AhR antagonists StemRegenin 1 (SR1) or CH-223191 (CH) show increased ¹²⁵I uptake, reduced clonogenicity, significantly increased levels of NIS mRNA and protein, and localization of NIS protein to the PTC cell membrane. These results suggest that AhR antagonists promote PTC differentiation.

Expression Downregulation of Hsa_circ_0006741 in AhR Antagonist-Treated PTC Cells

After transcriptome sequencing of circRNA in the K1 cell line before and after SR1 treatment, it was found that the level of hsa_circ_0006741 (circSH2B3), associated with cell differentiation, was significantly downregulated following SR1 treatment. The expression level of circSH2B3 was higher in various PTC cell lines than in normal thyroid epithelial cells, indicating that circSH2B3 might be a potential target inhibited by SR1.

Key Role of CircSH2B3 in PTC Dedifferentiation

When circSH2B3 is knocked down in PTC cells, ¹²⁵I uptake increases, clonogenicity decreases, and levels of NIS mRNA and protein increase. Conversely, overexpression of circSH2B3 in PTC promotes dedifferentiation. These results indicate that SR1 promotes PTC differentiation by inhibiting circSH2B3.

In conclusion, AhR antagonists have shown significant effects in promoting papillary thyroid carcinoma differentiation. By inhibiting the activity of the circSH2B3/miR-4640-5p/IGF2BP2 axis, AhR antagonists effectively promote PTC cell differentiation, providing new insights for RR-PTC treatment. As a leading global supplier of high-performance life science products, Glpbio has played an essential role in the research and application of AhR antagonists, providing reliable research materials and performance for biomedical research. In future research, AhR antagonists are expected to play a more critical role in cancer treatment, bringing positive outcomes for more patients.