Chen Yun, Chen Jianliang, Guo Dainian, Yang Peixuan, Chen Shuang, Zhao Chengkuan, Xu Chengcheng, Zhang Qiuzhen, Lin Chaoxian, Zhong Shilong, Zhang Shuyao
Department of Pharmacy, Guangzhou Red Cross Hospital, Jinan University, Guangzhou, China.
Clinical Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, China.
Front Oncol. 2022 Feb 28;12:800291. doi: 10.3389/fonc.2022.800291. eCollection 2022.
Perturbation of tryptophan (TRP) metabolism contributes to the immune escape of cancer; however, the explored TRP metabolites are limited, and their efficacy in clarifying the susceptibility and progression of esophageal cancer (EC) remains ambiguous. Our study sought to evaluate the effects of the TRP metabolic profile on the clinical outcomes of EC using a Chinese population cohort; and to develop a risk prediction model targeting TRP metabolism.
A total of 456 healthy individuals as control subjects and 393 patients with EC who were followed up for one year as case subjects were enrolled. Quantification of the plasma concentrations of TRP and its metabolites was performed using HPLC-MS/MS. The logistic regression model was applied to evaluate the effects of the clinical characteristics and plasma metabolites of the subjects on susceptibility and tumor metastasis events, whereas Cox regression analysis was performed to assess the overall survival (OS) of the patients.
Levels of creatinine and liver enzymes were substantially correlated with multiple metabolites/metabolite ratios in TRP metabolism, suggesting that hepatic and renal function would exert effects on TRP metabolism. Age- and sex-matched case-control subjects were selected using propensity score matching. Plasma exposure to 5-HT was found to be elevated 3.94-fold in case subjects (N = 166) compared to control subjects (N = 203), achieving an AUC of 0.811 for predicting susceptibility event. Subsequent correlation analysis indicated that a higher plasma exposure to 5-HIAA significantly increased the risk of lymph node metastasis (OR: 2.16, = 0.0114). Furthermore, it was figured out that OS was significantly shorter for patients with elevated XA/KYN ratio (HR: 1.99, = 0.0016), in which medium and high levels of XA/KYN versus low level had a significantly lower OS (HR: 0.48, = 0.0080 and HR: 0.42, = 0.0031, respectively).
This study provides a pivotal basis for targeting endogenous TRP metabolism as a potential therapeutic intervention.
色氨酸（TRP）代谢紊乱有助于癌症的免疫逃逸；然而，已探索的TRP代谢产物有限，其在阐明食管癌（EC）易感性和进展方面的功效仍不明确。我们的研究旨在使用中国人群队列评估TRP代谢谱对EC临床结局的影响；并建立针对TRP代谢的风险预测模型。
共纳入456名健康个体作为对照，393例EC患者作为病例并随访一年。采用高效液相色谱-串联质谱法（HPLC-MS/MS）对血浆中TRP及其代谢产物浓度进行定量。应用逻辑回归模型评估受试者的临床特征和血浆代谢产物对易感性和肿瘤转移事件的影响，同时进行Cox回归分析以评估患者的总生存期（OS）。
肌酐和肝酶水平与TRP代谢中的多种代谢产物/代谢产物比值显著相关，表明肝肾功能会对TRP代谢产生影响。采用倾向得分匹配法选择年龄和性别匹配的病例对照受试者。发现病例组（N = 166）血浆中5-羟色胺（5-HT）暴露水平比对照组（N = 203）升高3.94倍，预测易感性事件的曲线下面积（AUC）为0.811。随后的相关性分析表明，血浆中5-羟吲哚乙酸（5-HIAA）暴露水平较高显著增加了淋巴结转移风险（比值比：2.16，P = = 0.0114）。此外，还发现XA/KYN比值升高的患者总生存期显著缩短（风险比：1.99，P = = 0.0016），其中XA/KYN比值中高水平与低水平相比总生存期显著降低（风险比分别为：0.48，P = = 0.0080和0.42，P = = 0.0031）。
本研究为将内源性TRP代谢作为潜在治疗干预靶点提供了关键依据。
