Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Hyogo, Japan.
Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Sci Adv. 2020 Mar 18;6(12):eaay3324. doi: 10.1126/sciadv.aay3324. eCollection 2020 Mar.
Head-and-neck squamous cell carcinoma (HNSCC) is the sixth most common group of cancers in the world, and patients have a poor prognosis. Here, we present data indicating that YAP1 may be a strong driver of the onset and progression of oral SCC (OSCC), a major subtype of HNSCC. Mice with tongue-specific deletion of and thus endogenous YAP1 hyperactivation underwent surprisingly rapid and highly reproducible tumorigenesis, developing tongue carcinoma in situ within 2 weeks and invasive SCC within 4 weeks. In humans, precancerous tongue dysplasia displays YAP1 activation correlating with reduced patient survival. Combinations of molecules mutated in OSCC may increase and sustain YAP1 activation to the point of oncogenicity. Strikingly, siRNA or pharmacological inhibition of YAP1 blocks murine OSCC onset in vitro and in vivo. Our work justifies targeting YAP1 as therapy for OSCC and perhaps HNSCC, and our mouse model represents a powerful tool for evaluating these agents.
头颈部鳞状细胞癌（HNSCC）是世界上第六大常见癌症类型，患者预后不良。在这里，我们提供的数据表明，YAP1 可能是口腔鳞状细胞癌（OSCC）发生和进展的主要驱动因素，OSCC 是 HNSCC 的主要亚型之一。在舌特异性缺失 和因此内源性 YAP1 过度激活的小鼠中，令人惊讶的是，它们发生了快速且高度可重复的肿瘤发生，在 2 周内发展为原位舌癌，在 4 周内发展为侵袭性 SCC。在人类中，癌前舌发育不良显示 YAP1 激活与患者生存时间缩短相关。OSCC 中突变的分子组合可能会增加并维持 YAP1 的激活，达到致癌性。引人注目的是，siRNA 或药理学抑制 YAP1 可阻断体外和体内的小鼠 OSCC 发病。我们的工作证明靶向 YAP1 作为 OSCC 甚至 HNSCC 的治疗方法是合理的，我们的小鼠模型代表了评估这些药物的有力工具。
