长链非编码 RNA-H19 通过上调雌激素受体 β 促进甲状腺乳头状癌肿瘤干细胞样特性。
Estrogen receptor β upregulated by lncRNA-H19 to promote cancer stem-like properties in papillary thyroid carcinoma.
机构信息
The First Affiliated Hospital, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
出版信息
Cell Death Dis. 2018 Nov 2;9(11):1120. doi: 10.1038/s41419-018-1077-9.
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.
雌激素受体β（ERβ）在甲状腺癌的进展中起着关键作用。然而，其在甲状腺癌干细胞维持中的作用仍不清楚。在这里，我们报告 ERβ 在甲状腺癌干细胞（PTCSC）中过度表达，而 ERβ 的缺失会降低与干细胞特性相关的因子表达，减少 ALDH 细胞群，并抑制球体形成能力和肿瘤生长。在 PTC 球体细胞中筛选雌激素反应性 lncRNA 时，我们发现 lncRNA-H19 在 PTCSC 和 PTC 组织标本中高表达，与总生存期不良相关。在机制上，雌二醇（E2）通过 ERβ 显著促进 H19 的转录，并升高 H19 的表达。沉默 H19 抑制 E2 诱导的球体形成能力。此外，H19 作为竞争性内源性 RNA 可将 miRNA-3126-5p 隔离，从而释放 ERβ 的表达。在 E2 处理时，ERβ 的缺失可逆转 H19 诱导的干细胞样特性。适当的是，ERβ 在 PTC 组织标本中上调。值得注意的是，阿司匹林通过降低 H19 和 ERβ 的表达来减弱 E2 诱导的癌症干细胞样特征。综上所述，我们的研究结果表明，在 E2 处理下，ERβ-H19 正反馈环在 PTCSC 维持中起着重要作用，并为 PTC 提供了一种潜在的治疗靶向策略。
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