Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells.
Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells.
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DOI：
10.1038/onc.2011.222
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发表时间：
2012-01-12
期刊：
影响因子：
8
通讯作者：
Krueger, K.
中科院分区：
文献类型：
--
作者：
Bourguignon, L. Y. W.;Earle, C.;Wong, G.;Spevak, C. C.;Krueger, K.
MicroRNA通常与包括头颈鳞状细胞癌（HNSCC）在内的许多癌症的发病机制相关。具体而言，microRNA-21（miR-21）似乎在肿瘤细胞存活、化学抗性和HNSCC进展中起关键作用。在这项研究中，我们研究了基质透明质酸（HA）诱导的CD 44（主要HA受体）与干细胞标志物Nanog和Stat-3在HNSCC细胞（HSC-3细胞）中的相互作用。我们的研究结果表明，HA结合CD 44促进Nanog-Stat-3（也酪氨酸磷酸化的Stat-3）复合物的形成，核转位和转录激活。进一步的分析表明，miR-21受含有Stat-3结合位点的上游启动子控制，而染色质免疫沉淀（ChIP）测定表明，在HNSCC细胞中，HA/CD 44信号对miR-21表达的刺激是Nanog/Stat-3依赖性的。这一过程导致肿瘤抑制蛋白（PDCD 4）的减少，凋亡蛋白家族（IAP）抑制剂的上调以及HSC-3细胞的化学抗性。用Nanog和/或Stat-3特异性小干扰RNA（siRNA）处理HSC-3细胞有效地阻断HA介导的Nanog-Stat-3信号传导事件，消除miR-21产生并增加PDCD 4表达。随后，这种Nanog-Stat-3信号传导抑制导致存活蛋白（IAP）表达下调和化学敏感性增强。为了进一步评估miR-21在肿瘤细胞特异性功能中的作用，还用特异性抗miR-21抑制剂转染HSC-3细胞以沉默miR-21表达并阻断其靶功能。我们的结果表明，抗miR-21抑制剂不仅上调PDCD 4表达，而且降低IAP表达，并增强HA处理的HNSCC细胞的化疗敏感性。总之，这些发现表明HA诱导的CD 44与Nanog和Stat-3的相互作用在miR-21产生中起关键作用，导致HNSCC细胞中PDCD 4减少、IAP上调和化学抗性。这种新的Nanog/Stat-3信号通路特异性机制参与miR-21的产生，对于HA/CD 44激活的HNSCC治疗中未来干预策略的形成具有重要意义。
MicroRNAs are often associated with the pathogenesis of many cancers including Head and Neck Squamous Cell Carcinoma (HNSCC). In particular, microRNA-21 (miR-21) appears to play a critical role in tumor cell survival, chemoresistance and HNSCC progression. In this study we investigated matrix hyaluronan (HA)-induced CD44 (a primary HA receptor) interaction with the stem cell markers, Nanog and Stat-3, in HNSCC cells (HSC-3 cells). Our results indicate that HA binding to CD44 promotes Nanog-Stat-3 (also tyrosine phosphorylated Stat-3) complex formation, nuclear translocation and transcriptional activation. Further analyses reveal that miR-21 is controlled by an upstream promoter containing Stat-3 binding site(s), while chromatin immunoprecipitation (ChIP) assays demonstrate that stimulation of miR-21 expression by HA/CD44 signaling is Nanog/Stat-3-dependent in HNSCC cells. This process results in a decrease of a tumor suppressor protein (PDCD4), and an upregulation of inhibitors of the apoptosis family of proteins (IAPs) as well as chemoresistance in HSC-3 cells. Treatment of HSC-3 cells with Nanog- and/or Stat-3-specific small interfering RNAs (siRNAs) effectively blocks HA-mediated Nanog-Stat-3 signaling events, abrogates miR-21 production and increases PDCD4 expression. Subsequently, this Nanog-Stat-3 signaling inhibition causes downregulation of survival protein (IAP) expression and enhancement of chemosensitivity. To further evaluate the role of miR-21 in tumor cell-specific functions, HSC-3 cells were also transfected with a specific anti-miR-21 inhibitor in order to silence miR-21 expression and block its target functions. Our results demonstrate that anti-miR-21 inhibitor not only upregulates PDCD4 expression, but also decreases IAP expression and enhances chemosensitivity in HA-treated HNSCC cells. Together, these findings indicate that the HA-induced CD44 interaction with Nanog and Stat-3 plays a pivotal role in miR-21 production leading to PDCD4 reduction, IAP upregulation and chemoresistance in HNSCC cells. This novel Nanog/Stat-3 signaling pathway-specific mechanism involved in miR-21 production is significant for the formation of future intervention strategies in the treatment of HA/CD44-activated HNSCC.
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影响因子：
64.5
作者：
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