Department of Maxillofacial and Otorhinolaryngology Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer Institute, National Clinical Research Center of Cancer, Tianjin, China.
Department of Medicine, Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
Clin Cancer Res. 2018 Jun 1;24(11):2665-2677. doi: 10.1158/1078-0432.CCR-16-2248. Epub 2018 Mar 14.
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 () 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. 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 and the growth of UM1 xenograft tumor, an orthotopic model of HNSCC. The sensitivity of HNSCC cells toward cisplatin and cetuximab was determined by assays. 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 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. .
PI3K 和 STAT3 在癌症进展中经常被激活。然而，PI3K 和 STAT3 调节头颈部鳞状细胞癌（HNSCC）生长的潜在机制知之甚少。lncRNA HOX 转录物反义 RNA () 被发现可调节 HNSCC 的进展。在这项研究中，我们试图建立 PI3K/STAT3/HOTAIR 信号与 HNSCC 进展及其对铂类和靶向抗 EGFR 联合治疗的敏感性的相关性。我们首先分析了人 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 HNSCC 细胞增殖和 UM1 异种移植肿瘤生长的影响，UM1 是 HNSCC 的一种原位模型。通过 测定法确定 HNSCC 细胞对顺铂和西妥昔单抗的敏感性。与正常鳞状上皮相比，HNSCC 样本显示出明显强烈的 STAT3、HOTAIR、PI3K 和 AKT 的表达/激活。WP1066 抑制 STAT3 降低了 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，从而增强 HNSCC 细胞的生长。此外，HOTAIR 的过表达促进了 UM1 异种移植肿瘤的生长。我们的结果表明，STAT3 信号通过调节 HNSCC 中 PI3K 的过表达/激活的 HOTAIR 和 pEZH2-S21 促进 HNSCC 的进展。这些发现为针对 STAT3/HOTAIR/pEZH2-S21 调节轴治疗 HNSCC 患者提供了依据。
