Abstract
Estrogen receptor β (ERβ) plays critical roles in thyroid cancer progression. However, its role in thyroid cancer stem cell maintenance remains elusive. Here, we report that ERβ is overexpressed in papillary thyroid cancer stem cells (PTCSCs), whereas ablation of ERβ decreases stemness-related factors expression, diminishes ALDH+ cell populations, and suppresses sphere formation ability and tumor growth. Screening estrogen-responsive lncRNAs in PTC spheroid cells, we find that lncRNA-H19 is highly expressed in PTCSCs and PTC tissue specimens, which is correlated with poor overall survival. Mechanistically, estradiol (E2) significantly promotes H19 transcription via ERβ and elevates H19 expression. Silencing of H19 inhibits E2-induced sphere formation ability. Furthermore, H19 acting as a competitive endogenous RNA sequesters miRNA-3126-5p to reciprocally release ERβ expression. ERβ depletion reverses H19-induced stem-like properties upon E2 treatment. Appropriately, ERβ is upregulated in PTC tissue specimens. Notably, aspirin attenuates E2-induced cancer stem-like traits through decreasing both H19 and ERβ expression. Collectively, our findings reveal that ERβ-H19 positive feedback loop has a compelling role in PTCSC maintenance under E2 treatment and provides a potential therapeutic targeting strategy for PTC.
Highlights
Papillary thyroid carcinoma (PTC) is one of the most common thyroid neoplasms, which exhibits multicentricity in the thyroid gland and frequently metastasizes to the regional lymph nodes, thereby increasing both morbidity and mortality[1]
Estrogen receptor β (ERβ) contributes to papillary thyroid cancer stem cells (PTCSCs) As the effect of estrogen is predominantly mediated through estrogen receptor α (ERα) and ERβ, we first examined whether ERα and ERβ are involved in PTC stemness
In this study, we demonstrate that the induction of ERβ expression by H19-overexpressing vector (H19) is critical for PTCSC maintenance
Summary
Papillary thyroid carcinoma (PTC) is one of the most common thyroid neoplasms, which exhibits multicentricity in the thyroid gland and frequently metastasizes to the regional lymph nodes, thereby increasing both morbidity and mortality[1]. Increasing evidence indicates that papillary thyroid cancer stem cells (PTCSCs) play an Official journal of the Cell Death Differentiation Association. E2 stimulation elevates stemness-related gene expression in PTC cells and promotes motility and tumorigenicity of PTCSCs in vivo[9]. Long noncoding RNAs (lncRNAs) are a class of transcripts longer than 200 nucleotides but with no proteincoding potential, which play a crucial role in regulating cancer cell stemness. LncRNA H19 increases core pluripotency factor LIN28 expression by blocking the bioactivity of let-7 to promote breast cancer stem cell maintenance[11]. Accumulating studies have indicated lncRNAs play important roles in maintaining CSCs and could be regulated by estrogen signaling in diverse cancers, little is known about the mechanism by which lncRNAs modulate E2-induced PTCSCs
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