Department of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, 3-1-1 Notame, Minamiku, Fukuoka, Fukuoka, 811-1395, Japan.
Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka, Fukuoka, 812-8582, Japan.
J Cancer Res Clin Oncol. 2019 Oct;145(10):2433-2444. doi: 10.1007/s00432-019-02995-z. Epub 2019 Sep 4.
The clinical importance of cancer stem cells (CSCs) in head and neck squamous cell carcinoma (HNSCC) is well recognized. However, a reliable method for the detection of functioning CSC has not yet been established. We hypothesized that YAP1, a transcriptional coactivator, and SOX2, a master transcription factor of SCC, may cooperatively induce stemness through transcriptional reprogramming.
We immunohistochemically examined the expression of SOX2 and YAP1 in the CD44 variant 9 (CD44v9)-positive invasion front. A CSC-inducible module was identified through a combination of siRNAs and sphere formation assays. YAP1 and SOX2 interactions were analyzed in vitro.
The triple overexpression of SOX2, YAP1, and CD44v9 was significantly associated with poor prognosis. TCGA data revealed that the CSC-inducible module, which was related to EMT and angiogenesis, was significantly correlated with poor prognosis. The KLF7 expression, representatively chosen from the module, also correlated with poor prognosis and was essential for sphere formation and CSC propagation. Sphere stress-activated YAP1 enhanced SOX2 activity.
The stress-triggered activation of YAP1/SOX2 transcriptionally reprograms HNSCC for the acquisition of stemness. Triple SOX2, YAP1, and CD44v9 immunostaining assays may be useful for the selection of high-risk patients with functioning CSCs, and YAP1 targeting may lead to the development of a CSC-targeting therapy.
癌症干细胞（CSC）在头颈部鳞状细胞癌（HNSCC）中的临床重要性已得到充分认识。然而，尚未建立用于检测功能 CSC 的可靠方法。我们假设 YAP1，一种转录共激活因子，和 SOX2，一种 SCC 的主转录因子，可能通过转录重编程协同诱导干细胞特性。
我们通过免疫组织化学检测了 CD44 变体 9（CD44v9）阳性侵袭前沿中 SOX2 和 YAP1 的表达。通过 siRNA 和球体形成测定的组合鉴定了 CSC 诱导模块。分析了体外 YAP1 和 SOX2 的相互作用。
SOX2、YAP1 和 CD44v9 的三重过表达与预后不良显著相关。TCGA 数据显示，与 EMT 和血管生成相关的 CSC 诱导模块与预后不良显著相关。该模块中代表性选择的 KLF7 表达也与预后不良相关，是球体形成和 CSC 增殖所必需的。球体应激激活的 YAP1 增强了 SOX2 的活性。
YAP1/SOX2 转录的应激触发重编程了 HNSCC 以获得干细胞特性。三重 SOX2、YAP1 和 CD44v9 免疫染色检测可能有助于选择具有功能 CSC 的高危患者，并且 YAP1 靶向可能会导致开发针对 CSC 的治疗方法。
