García-Carracedo Darío, Villaronga Maria Ángeles, Álvarez-Teijeiro Saúl, Hermida-Prado Francisco, Santamaría Iñigo, Allonca Eva, Suárez-Fernández Laura, Gonzalez Maria Victoria, Balbín Milagros, Astudillo Aurora, Martínez-Camblor Pablo, Su Gloria H, Rodrigo Juan Pablo, García-Pedrero Juana María
Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.
Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.
Oncotarget. 2016 May 17;7(20):29780-93. doi: 10.18632/oncotarget.8957.
The PI3K/AKT/mTOR signaling pathway has emerged as one of the most frequently deregulated in head and neck squamous cell carcinomas (HNSCC). Numerous alterations of various upstream and downstream components have been described; however, their prognostic significance and impact on HNSCC patient survival remains to be established. This was addressed using an unbiased cohort of 93 consecutive and homogeneous surgically treated HNSCC patients and results confirmed in 432 HNSCC patients. Our findings reveal the high prevalence of S6 phosphorylation, a surrogate marker of mTORC1 activation, in HNSCC specimens (>70%) and, more importantly, demonstrate its relevance on clinical outcome. Phosphorylation of ribosomal protein S6 on either Ser235/236 or Ser240/244 was consistently and significantly correlated with favorable prognosis, although with differences depending on the tumor site. Thus, p-S6 expression was significantly correlated with better disease-specific survival specifically in the subgroup of laryngeal carcinoma patients (P< 0.001). In addition, multivariate regression models revealed p-S6 to be an inverse and independent predictor of lymph-node metastasis (P= 0.004) and distant metastasis (P= 0.006). Taken together, this study unveils an unprecedented correlation of mTOR activation with improved clinical outcome in patients with laryngeal carcinomas and uncovers the potential of p-S6 expression as a good prognostic biomarker and an inverse predictor of lymph node and distant metastases. These results should be of broad interest as immunohistochemical detection of p-S6 may help to stratify patients and guide treatment decisions.
PI3K/AKT/mTOR信号通路已成为头颈部鳞状细胞癌（HNSCC）中最常发生失调的信号通路之一。已经描述了各种上游和下游成分的众多改变；然而，它们的预后意义以及对HNSCC患者生存的影响仍有待确定。本研究使用了93例连续且同质的接受手术治疗的HNSCC患者组成的无偏队列进行分析，并在432例HNSCC患者中证实了结果。我们的研究结果显示，HNSCC标本中mTORC1激活的替代标志物S6磷酸化的发生率很高（>70%），更重要的是，证明了其与临床结果的相关性。核糖体蛋白S6在Ser235/236或Ser240/244位点的磷酸化始终与良好的预后显著相关，尽管因肿瘤部位而异。因此，p-S6表达与更好的疾病特异性生存显著相关，特别是在喉癌患者亚组中（P<0.001）。此外，多变量回归模型显示p-S6是淋巴结转移（P=0.004）和远处转移（P=0.006）的反向独立预测因子。综上所述，本研究揭示了mTOR激活与喉癌患者临床结果改善之间前所未有的相关性，并发现p-S6表达有可能作为良好的预后生物标志物以及淋巴结和远处转移的反向预测因子。这些结果可能会引起广泛关注，因为p-S6的免疫组化检测可能有助于对患者进行分层并指导治疗决策。
