LncRNA HOTTIP facilitates the stemness of breast cancer via regulation of miR-148a-3p/WNT1 pathway
LncRNA HOTTIP facilitates the stemness of breast cancer via regulation of miR-148a-3p/WNT1 pathway
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LncRNA HOTTIP 通过调节 miR-148a-3p/WNT1 通路促进乳腺癌的干细胞性
DOI：
10.1111/jcmm.15261
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发表时间：
2020-04-19
影响因子：
5.3
通讯作者：
Wei, Minjie
中科院分区：
文献类型：
--
作者：
Han, Li;Yan, Yuanyuan;Wei, Minjie
新出现的证据表明，长链非编码RNA （lncRNA）的失调在肿瘤发生中起着关键作用。据报道，lncRNA，远端HOXA转录本（HOTTIP），在包括乳腺癌在内的多种癌症中上调，并参与多种生物学过程，包括维持干性。然而，HOTTIP在乳腺癌干细胞（BCSCs）中的生物学功能和潜在的调节机制尚不清楚。在本研究中，我们发现HOTTIP在BCSCs中显著上调，并与乳腺癌进展呈正相关。功能研究显示，HOTTIP过表达可显著促进乳腺癌细胞的克隆性，增加干细胞标志物OCT4和SOX2的表达，降低分化标志物CK14和CK18的表达。敲除HOTTIP抑制了bscs的类csc特性。在人源化乳腺癌模型中，HOTTIP的缺失一致地抑制了肿瘤的生长。机制研究表明，HOTTIP直接结合miR-148a-3p，抑制WNT1的介导作用，导致Wnt/ β -catenin信号通路失活。我们的研究首次报道了HOTTIP作为miR-148a-3p的分子海绵，通过增加WNT1的表达来调节BCSCs的csc样特性，为乳腺癌治疗提供了新的靶点。
Emerging evidence suggests that dysregulation of long non-coding RNA (lncRNA) plays a key role in tumorigenesis. The lncRNA, HOXA transcript at the distal tip (HOTTIP), has been reported to be up-regulated in multiple cancers, including breast cancer, and is involved in various biological processes, including the maintenance of stemness. However, the biological function and underlying modulatory mechanism of HOTTIP in breast cancer stem cells (BCSCs) remains unknown. In this study, we found that HOTTIP was markedly up-regulated in BCSCs and had a positive correlation with breast cancer progression. Functional studies revealed that overexpression of HOTTIP markedly promoted cell clonogenicity, increased the expression of the stem cell markers, OCT4 and SOX2, and decreased the expression of the differentiation markers, CK14 and CK18, in breast cancer cells. Knockdown of HOTTIP inhibited the CSC-like properties of BCSCs. Consistently, depletion of HOTTIP suppressed tumour growth in a humanized model of breast cancer. Mechanistic studies demonstrated that HOTTIP directly binds to miR-148a-3p and inhibits the mediation of WNT1, which leads to inactivation of the Wnt/beta-catenin signalling pathway. Our study is the first to report that HOTTIP regulates the CSC-like properties of BCSCs by as a molecular sponge for miR-148a-3p to increase WNT1 expression, offering a new target for breast cancer therapy.