HOTAIR maintains the stemness of ovarian cancer stem cells via the miR-206/TBX3 axis
HOTAIR maintains the stemness of ovarian cancer stem cells via the miR-206/TBX3 axis
复制标题
HOTAIR 通过 miR-206/TBX3 轴维持卵巢癌干细胞的干性
DOI：
10.1016/j.yexcr.2020.112218
复制
发表时间：
2020-10-15
影响因子：
3.7
通讯作者：
Wang, Zehua
中科院分区：
文献类型：
--
作者：
Zhang, Yifan;Guo, Jianfeng;Wang, Zehua
卵巢癌的预后差的部分原因是化疗耐药和复发，而卵巢癌干细胞（OCSCs）可能介导了这种耐药和复发。在本研究中，我们研究了OCSC干细胞的机制，重点是长的非编码RNA HOX转录反义基因间RNA（HOTAIR）。检测卵巢癌细胞的高醛脱氢酶（ALDH）活性或高体外球体形成能力，以鉴定OCSC。HOTAIR在OCSC中高度表达，其缺失导致球体形成能力降低，沿着对顺铂的耐药性降低和体内致瘤性降低。T-box转录因子3（TBX 3）在OCSC中高表达，并被证实受到HOTAIR的正调控。此外，TBX 3维持细胞的干细胞性，而升高TBX 3可以缓解由HOTAIR消耗引起的球体形成能力减弱。随后，发现miR-206通过HOTAIR介导TBX 3的表达调节，并且在功能上参与OCSC的干性调节。与这些发现一致，卵巢癌患者的循环HOTAIR表达上调。总的来说，我们的研究结果表明，HOTAIR缓解了OCSC中miR-206介导的TBX 3表达的抑制，并为卵巢癌的治疗提供了新的治疗靶点。
The poor prognosis of ovarian cancer is partly attributed to the frequent chemo-resistance and recurrence, which may be mediated by ovarian cancer stem cells (OCSCs). In the present study, we investigated the mechanisms contributing to the stemness of OCSCs, focusing on the long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR). Ovarian cancer cells were tested for high aldehyde dehydrogenase (ALDH) activity or high in vitro sphere-formation ability to identify OCSCs. HOTAIR was highly expressed in the OCSCs and its depletion caused a decrease in sphere-formation ability, along with reduced resistance to cisplatin and in vivo tumorigenicity. T-box transcription factor 3 (TBX3) was highly expressed in the OCSCs and was confirmed to be positively regulated by HOTAIR. Moreover, TBX3 maintained cell stemness, whereas elevating TBX3 could relieve the weakened sphere-formation ability caused by HOTAIR depletion. Subsequently, miR-206 was found to mediate the expression regulation of TBX3 by HOTAIR, and functionally involved in the regulation of stemness in OCSCs. In line with these findings, circulating HOTAIR expression was up-regulated in ovarian cancer patients. Collectively, our findings suggest that HOTAIR relieves the inhibition of TBX3 expression mediated by miR-206 in OCSCs and provide novel therapeutic targets for the treatment of ovarian cancer.