STAT3/HOTAIR Signaling Axis Regulates HNSCC Growth in an EZH2-dependent Manner
STAT3/HOTAIR Signaling Axis Regulates HNSCC Growth in an EZH2-dependent Manner
复制标题
STAT3/HOTAIR 信号轴以 EZH2 依赖性方式调节 HNSCC 生长
DOI：
10.1158/1078-0432.ccr-16-2248
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发表时间：
2018-06-01
影响因子：
11.5
通讯作者：
Zhou, Xuan
中科院分区：
文献类型：
--
作者：
Sun, Shanshan;Wu, Yansheng;Zhou, Xuan
目的：PI3K 和 STAT3 在癌症进展中经常被激活。然而，人们对 PI3K 和 STAT3 调节头颈鳞状细胞癌 (HNSCC) 生长的潜在机制知之甚少。研究发现 lncRNA HOX 转录反义 RNA (HOTAIR) 可以调节 HNSCC 的进展。在本研究中，我们试图建立 PI3K/STAT3/HOTAIR 信号传导与 HNSCC 进展及其对铂类靶向抗 EGFR 联合治疗的敏感性的相关性。实验设计：我们首先分析了人类 HNSCC 样本中的 STAT3/HOTAIR 和 PI3K/AKT 水平。然后，我们激活或抑制 STAT3/HOTAIR，并确定其对体外 HNSCC 细胞增殖和 UM1 异种移植肿瘤（HNSCC 的原位模型）生长的影响。 HNSCC 细胞对顺铂和西妥昔单抗的敏感性通过体外测定确定。结果：与正常鳞状上皮相比，HNSCC 样本显示 STAT3、HOTAIR、PI3K 和 AKT 的表达/激活显着增强。 WP1066 抑制 STAT3 可降低 HOTAIR 水平并使 HNSCC 对顺铂或西妥昔单抗敏感。 STAT3 促进 HOTAIR 转录及其与 pEZH2-S21 的相互作用，从而促进 HNSCC 细胞的生长。此外，HOTAIR的过表达促进了体内UM1异种移植肿瘤的生长。结论：我们的结果表明，STAT3 信号传导通过调节 PI3K 过表达/激活的 HNSCC 中的 HOTAIR 和 pEZH2-S21 来促进 HNSCC 进展。这些发现为靶向 STAT3/HOTAIR/pEZH2-S21 调节轴治疗 HNSCC 患者提供了理论基础。临床癌症研究； 24（11）； 2665–77。 ©2018 AACR。
Purpose: PI3K and STAT3 are frequently activated in cancer progression. However, little is known about the underlying mechanisms by which PI3K and STAT3 regulate head and neck squamous cell cancer (HNSCC) growth. The lncRNA HOX transcript antisense RNA (HOTAIR) was found to modulate the progression of HNSCC. In this study, we attempted to establish the correlation of PI3K/STAT3/HOTAIR signaling with the progression of HNSCC and its sensitivity toward platinum-based and targeted anti-EGFR combination therapy. Experimental Design: We first analyzed the STAT3/HOTAIR and PI3K/AKT level in human HNSCC samples. We then activated or suppressed STAT3/HOTAIR and determined the effects on HNSCC cell proliferation in vitro and the growth of UM1 xenograft tumor, an orthotopic model of HNSCC. The sensitivity of HNSCC cells toward cisplatin and cetuximab was determined by in vitro assays. Results: HNSCC samples showed significantly robust expression/activation of STAT3, HOTAIR, PI3K, and AKT, compared with normal squamous epithelium. STAT3 inhibition with WP1066 decreased HOTAIR level and sensitized HNSCC to cisplatin or cetuximab. STAT3 promoted HOTAIR transcription and its interaction with pEZH2-S21, resulting in enhanced growth of HNSCC cells. In addition, overexpression of HOTAIR promoted the growth of UM1 xenograft tumors in vivo. Conclusions: Our results suggest that STAT3 signaling promotes HNSCC progression via regulating HOTAIR and pEZH2-S21 in HNSCC with PI3K overexpression/activation. These findings provide a rationale to target the STAT3/HOTAIR/pEZH2-S21 regulatory axis for treating patients with HNSCC. Clin Cancer Res; 24(11); 2665–77. ©2018 AACR.