Abstract
Abnormally high expression of aryl hydrocarbon receptor (AhR) has been implicated in dedifferentiation of radioiodine-refractory papillary thyroid cancer (RR-PTC). This study aimed to evaluate the differentiation effect of AhR antagonist in PTC, and to explore the potential mechanism of it. Results showed that AhR antagonists promoted differentiation of PTC, as shown as increase in 125I uptake and Na/I symporter (NIS) expression level. CircRNA microarray in K1 cells treated with StemRegenin 1(SR1) revealed that hsa_circ_0006741 (circSH2B3) was down-regulated in SR1 treated K1 cells. Downregulation of circSH2B3 increased 125I uptake and NIS expression levels. CircSH2B3 acted as an endogenous sponge of hsa-miR-4640-5p and modulated IGF2BP2 expression. IGF2BP2 overexpression induced dedifferentiation of PTC, while silencing IGF2BP2 accelerated differentiation of PTC cells. Rescue studies showed that the dedifferentiation activity of AhR was modulated by the circSH2B3/miR-4640-5p/IGF2BP2 axis. Our findings confirmed for the first time that AhR antagonists promote differentiation of PTC via inhibiting the circSH2B3/miR-4640-5p/IGF2BP2 axis, offering a novel therapeutic approach and a potential marker for differentiation of PTC.
Highlights
According to the 2020 global cancer statistics, thyroid cancer is one of the most common endocrine malignancies in the worldwide, with responsible for approximately 58,600 cases, ranking in ninth place for incidence in 2020 (Sung et al, 2021)
StemRegenin 1 (SR1) or CH was administered to stimulate the differentiation of Papillary thyroid cancer (PTC) cells for 48 h. 125I uptake of BCPAP cells treated with SR1 (100 nM) or CH (20 nM) was 3.32, and 3.46-fold higher than those of control cells, and 3.02- and 2.67-fold higher in K1 cells (Figure 2B). 131I colony formation assay showed that the cell colonies in PTC cells treated with SR1 (100 nM) or CH (20 nM) were reduced (Figure 2C)
Since Na/I symporter (NIS) is the critical factor which is responsible for differentiation of PTC, the mRNA and protein levels of NIS in PTC cells treated with aryl hydrocarbon receptor (AhR) antagonists are determined
Summary
According to the 2020 global cancer statistics, thyroid cancer is one of the most common endocrine malignancies in the worldwide, with responsible for approximately 58,600 cases, ranking in ninth place for incidence in 2020 (Sung et al, 2021). Radioiodine (131I) therapy has been the standard of care for unresectable 131I -avid metastatic PTC, and 131I uptake is a good prognostic marker (Ahn, 2016). Most patients do well, the biology of PTC is extremely diverse, ranging from well 131I-responsive indolent lesions to 131I-refractory locally advanced or metastatic disease. Differentiation therapy followed by 131I is a promising alternative therapy for radioiodine refractory thyroid cancer (RR-PTC). Several differentiation therapies including retinoic acid (Schmutzler and Köhrle, 2000), tyrosine-kinase inhibitors (Oh et al, 2020), histone deacetylase inhibitors (Jang et al, 2015), peroxisome proliferator-activated receptor (PPAR)-c agonists etc
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