Jing Chao, Qu Xin, Li Zhaoqing, Wu Chuanqiang, Zhao Minghui, Wang Yu, Sun Shanshan, Zhang Shengchi, Chen Jinliang, Qiao Yu, Hu Xiaomeng, Yao Xiaofeng, Jin Rui, Wang Xudong, Zhang Lun, Zhou Xuan
Department of Maxillofacial and Otorhinolaryngological Oncology, Tianjin Medical University Cancer Institute and HospitalTianjin 300060, China.
Key Laboratory of Cancer Prevention and Therapy, Tianjin Cancer InstituteTianjin 300060, China.
Am J Cancer Res. 2017 Dec 1;7(12):2491-2502. eCollection 2017.
Patients suffered from head and neck squamous cell carcinoma (HNSCC) have an overall poor prognosis owing to proliferation and resistance to treatment. Hence, mining the underlying mechanism of malignancies above and translating the bench outcomes to clinical practice are in urgent need. Previous studies found that the epidermal growth factor receptor (EGFR) increases and co-expresses with EGFRvIII in HNSCC tissues, which indicates poor prognosis of HNSCC patients. Here, we clarify that compared with EGFRwt, EGFRwt/vIII enhances the capability of proliferation and colony formation in HNSCC cells , and reduces the sensitivity to cisplatin. Furthermore, EGFRwt/vIII induces nuclear translocation of the M2 isoform of pyruvate kinase (PKM2) in a time-dependent manner. The aberrant expression of PKM2 in HNSCC suggests unfavorable outcome. Especially, nuclear PKM2 determines the activation of β-catenin signaling and regulates the proliferation and chemo-sensitivity of HNSCC cells. Together, our findings demonstrate that EGFRwt/vIII-PKM2-β-catenin cascade controls the proliferation and chemo-sensitivity of HNSCC, thereby providing a promising strategy for diagnosis and therapy of HNSCC.
头颈部鳞状细胞癌（HNSCC）患者由于肿瘤增殖和对治疗的抵抗性，总体预后较差。因此，迫切需要深入探究上述恶性肿瘤的潜在机制，并将实验室研究成果转化为临床实践。以往研究发现，在HNSCC组织中，表皮生长因子受体（EGFR）表达增加且与EGFRvIII共表达，这表明HNSCC患者预后不良。在此，我们阐明，与野生型EGFR（EGFRwt）相比，EGFRwt/vIII增强了HNSCC细胞的增殖能力和集落形成能力，并降低了对顺铂的敏感性。此外，EGFRwt/vIII能使丙酮酸激酶M2亚型（PKM2）呈时间依赖性地发生核转位。PKM2在HNSCC中的异常表达提示预后不良。特别是，细胞核内的PKM2决定了β-连环蛋白信号通路的激活，并调节HNSCC细胞的增殖和化疗敏感性。综上所述，我们的研究结果表明，EGFRwt/vIII-PKM2-β-连环蛋白级联反应控制着HNSCC的增殖和化疗敏感性，从而为HNSCC的诊断和治疗提供了一种有前景的策略。
