Hu Yong-Jie, Sun Wen-Wen, Zhao Tong-Chao, Liu Ying, Zhu Dong-Wang, Wang Li-Zhen, Li Jiang, Zhang Chen-Ping, Zhang Zhi-Yuan, Zhong Lai-Ping
Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, P.R. China.
National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, P.R. China.
Oncol Lett. 2020 Nov;20(5):154. doi: 10.3892/ol.2020.12015. Epub 2020 Aug 24.
Induction chemotherapy has been previously demonstrated to downgrade locally advanced or aggressive cancers and increase the likelihood of primary lesion eradication. Based on our previous phase 3 trial on TPF (docetaxel, cisplatin and fluorouracil) induction chemotherapy in patients with oral squamous cell carcinoma (OSCC), in which short-term prognostic and predictive values of cyclin D1 expression were reported, the present study aimed to determine the long-term predictive value of cyclin D1 expression in the same patients with OSCC who were eligible to receive TPF induction chemotherapy. In addition, the present study investigated the potential association between cyclin D1 expression and chemosensitivity to TPF agents during OSCC cell intervention, and the underlying apoptotic mechanism of action. In total, 232 patients with locally advanced OSCC from our previous trial with a median follow-up of 5 years were included for survival analysis using the Kaplan-Meier method and the log-rank test in the present study, where cyclin D1 expression in their tissues was detected by immunohistochemistry. Cyclin D1 knockdown, cytotoxicity assays assessing the efficacy of the TPF chemotherapeutic agents and measurements of caspase-3 and PARP activity in HB96, CAL27 and HN30 cell lines were performed. Patients with OSCC in the low cyclin D1 expression group exhibited significantly superior long-term clinical outcomes compared with those in patients in the high cyclin D1 expression group [overall survival (OS), P=0.001; disease-free survival, P=0.003; local recurrence-free survival, P=0.004; distant metastasis-free survival (DMFS), P=0.001]. Furthermore, patients with stage clinical nodal stage 2 (cN2) OSCC in the high cyclin D1 expression group benefitted from TPF induction chemotherapy (OS, P=0.024; DMFS, P=0.024), whilst patients with cN2 OSCC in the low cyclin D1 expression group did not benefit from this chemotherapy. Overexpression of cyclin D1 expression was found to enhance chemosensitivity to TPF chemotherapeutic agents in OSCC by mediating caspase-3-dependent apoptosis. Based on these findings, TPF induction chemotherapy can benefit patients with cN2 OSCC and high cyclin D1 expression in terms of long-term survival from compared with standard treatment. In addition, OSCC cell lines overexpressing cyclin D1 are more sensitive to TPF chemotherapeutic agents in a caspase-3-dependent manner (clinical trial. no. NCT01542931; February 2012).
诱导化疗先前已被证明可使局部晚期或侵袭性癌症降级，并增加原发性病变根除的可能性。基于我们先前对口腔鳞状细胞癌（OSCC）患者进行的TPF（多西他赛、顺铂和氟尿嘧啶）诱导化疗的3期试验，该试验报告了细胞周期蛋白D1表达的短期预后和预测价值，本研究旨在确定同一组有资格接受TPF诱导化疗的OSCC患者中细胞周期蛋白D1表达的长期预测价值。此外，本研究调查了细胞周期蛋白D1表达与OSCC细胞干预期间对TPF药物的化疗敏感性之间的潜在关联，以及潜在的凋亡作用机制。本研究共纳入了我们先前试验中的232例局部晚期OSCC患者，中位随访时间为5年，采用Kaplan-Meier方法和对数秩检验进行生存分析，通过免疫组织化学检测其组织中的细胞周期蛋白D1表达。进行了细胞周期蛋白D1敲低、评估TPF化疗药物疗效的细胞毒性试验以及对HB96、CAL27和HN30细胞系中caspase-3和PARP活性的测量。细胞周期蛋白D1低表达组的OSCC患者与高表达组患者相比，长期临床结局显著更好[总生存期（OS），P=0.001；无病生存期，P=0.003；无局部复发生存期，P=0.004；无远处转移生存期（DMFS），P=0.001]。此外，高细胞周期蛋白D1表达组的临床淋巴结分期为2期（cN2）的OSCC患者从TPF诱导化疗中获益（OS，P=0.024；DMFS，P=0.024），而低细胞周期蛋白D1表达组的cN² OSCC患者未从该化疗中获益。发现细胞周期蛋白D1表达的过表达通过介导caspase-3依赖性凋亡增强了OSCC对TPF化疗药物的化疗敏感性。基于这些发现，与标准治疗相比，TPF诱导化疗在长期生存方面可使cN2 OSCC和高细胞周期蛋白D1表达的患者获益。此外，过表达细胞周期蛋白D1的OSCC细胞系以caspase-3依赖性方式对TPF化疗药物更敏感（临床试验编号：NCT01542931；2012年2月）。
