Sun Dongfeng, Chen Qingfa, Gai Zhibo, Zhang Fengxia, Yang Xiaoqing, Hu Wensi, Chen Chengyu, Yang Guangjie, Hörmann Severin, Kullak-Ublick Gerd A, Visentin Michele
Department of Thoracic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Emergency Medicine, Shandong Lung Cancer Institute, Shandong Institute of Respiratory Diseases, Jinan, China.
The Institute for Tissue Engineering and Regenerative Medicine, Liaocheng University/Liaocheng People's Hospital, Liaocheng, China.
Front Pharmacol. 2021 Sep 16;12:684545. doi: 10.3389/fphar.2021.684545. eCollection 2021.
Esophageal cancer is the ninth most common malignancy worldwide, ranking sixth in mortality. Platinum-based chemotherapy is commonly used for treating locally advanced esophageal cancer, yet it is ineffective in a large portion of patients. There is a need for reliable molecular markers with direct clinical application for a prospective selection of patients who can benefit from chemotherapy and patients in whom toxicity is likely to outweigh the benefit. The cytotoxic activity of platinum derivatives largely depends on the uptake and accumulation into cells, primarily by organic cation transporters (OCTs). The aim of the study was to investigate the impact of OCT expression on the clinical outcome of patients with esophageal cancer treated with oxaliplatin. Twenty patients with esophageal squamous cell carcinoma (SCC) were prospectively enrolled and surgical specimens used for screening OCT expression level by western blotting and/or immunostaining, and for culture of cancer cells. Sixty-seven patients with SCC who received oxaliplatin and for whom follow-up was available were retrospectively assessed for organic cation/carnitine transporter 2 (OCTN2) expression by real time RT-PCR and immunostaining. OCTN2 staining was also performed in 22 esophageal adenocarcinomas. OCTN2 function in patient-derived cancer cells was evaluated by assessing L-carnitine uptake and sensitivity to oxaliplatin. The impact of OCTN2 on oxaliplatin activity was also assessed in HEK293 cells overexpressing OCTN2. OCTN2 expression was higher in tumor than in normal tissues. In patient-derived cancer cells and HEK293 cells, the expression of OCTN2 sensitized to oxaliplatin. Patients treated with oxaliplatin who had high OCTN2 level in the tumor tissue had a reduced risk of recurrence and a longer survival time than those with low expression of OCTN2 in tumor tissue. In conclusion, OCTN2 is expressed in esophageal cancer and it is likely to contribute to the accumulation and cytotoxic activity of oxaliplatin in patients with esophageal carcinoma treated with oxaliplatin.
食管癌是全球第九大常见恶性肿瘤，死亡率排名第六。铂类化疗常用于治疗局部晚期食管癌，但在很大一部分患者中无效。需要有可靠的分子标志物用于直接临床应用，以便前瞻性地选择能够从化疗中获益以及毒性可能超过获益的患者。铂衍生物的细胞毒性活性在很大程度上取决于其进入细胞的摄取和积累，主要通过有机阳离子转运体（OCTs）。本研究的目的是调查OCT表达对接受奥沙利铂治疗的食管癌患者临床结局的影响。前瞻性纳入了20例食管鳞状细胞癌（SCC）患者，并使用手术标本通过蛋白质免疫印迹法和/或免疫染色筛选OCT表达水平，并用于癌细胞培养。对67例接受奥沙利铂治疗且有随访资料的SCC患者，通过实时逆转录聚合酶链反应和免疫染色对有机阳离子/肉碱转运体2（OCTN2）表达进行回顾性评估。还对22例食管腺癌进行了OCTN2染色。通过评估L-肉碱摄取和对奥沙利铂的敏感性来评估患者来源癌细胞中OCTN2的功能。在过表达OCTN2的人胚肾293细胞（HEK293细胞）中也评估了OCTN2对奥沙利铂活性的影响。肿瘤组织中OCTN2的表达高于正常组织。在患者来源的癌细胞和HEK293细胞中，OCTN2的表达使细胞对奥沙利铂敏感。肿瘤组织中OCTN2水平高的接受奥沙利铂治疗的患者比肿瘤组织中OCTN2低表达的患者复发风险降低，生存时间更长。总之，OCTN2在食管癌中表达，并且可能有助于奥沙利铂在接受奥沙利铂治疗的食管癌患者中的积累和细胞毒性活性。
Zotero 插件
