Proteomics analysis identified TPI1 as a novel biomarker for predicting recurrence of intrahepatic cholangiocarcinoma
Proteomics analysis identified TPI1 as a novel biomarker for predicting recurrence of intrahepatic cholangiocarcinoma
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DOI：
10.1007/s00535-020-01729-0
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发表时间：
2020-10-21
影响因子：
6.3
通讯作者：
Jin, Guang-Zhi
中科院分区：
文献类型：
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作者：
Yu, Wen-Long;Yu, Guanzhen;Jin, Guang-Zhi
背景肝内胆管细胞癌（ICC）是原发性肝癌中第二常见的肿瘤，但与手术切除后长期预后相关的预后因素仍不明确。本研究旨在为手术后ICC患者开发一种新型预后分类器。方法采用蛋白质组学方法筛选ICC组织中表达上调的肿瘤标志物，并通过生物信息学分析、western blot和免疫组织化学方法筛选出表达上调的肿瘤标志物。采用考克斯回归分析确定初级训练队列的预后标志物，并建立复发时间（TTR）的预测模型。在外部验证队列和前瞻性验证队列中验证预测模型的预测准确性。采用MTT法、克隆形成实验和trans-well实验观察其对ICC细胞增殖和迁移的影响。结果磷酸丙糖异构体（TPI 1）在ICC组织中表达显著上调，Kaplan-Meier分析显示TPI 1表达与ICC患者的复发率密切相关。在初级培训队列中，低风险组（TTR为26.9个月，95% CI 22.4-31.5）的平均TTR显著长于高风险组（TTR为14.5个月，95% CI 10.6-18.4）（p < 0.0001）。在两个验证队列中观察到相似的结果。此外，一个诺模图预测复发。此外，TPI 1基因在体外可抑制ICC细胞的生长、集落信息、迁移和侵袭。结论目前的预后模型可以准确预测ICC患者手术切除后的复发。
Background Intrahepatic cholangiocarcinoma (ICC) is the second most common tumor in primary liver cancer, but the prognostic factors associated with long-term outcomes after surgical resection remain poorly defined. This study aimed to develop a novel prognostic classifier for patients with ICC after surgery. Methods Using a proteomics approach, we screened tumor markers that up-regulated in ICC tissues, and narrowed down by bioinformatics analysis, western blot and immunohistochemistry. Prognostic markers were identified using Cox regression analyses in primary training cohort and the predictive models for time to recurrence (TTR) were established. The predictive accuracy of predictive model was validated in external validation cohort and prospective validation cohort. MTT assay, clonal formation assay and trans-well assays were used to verify the effect on the proliferation and migration in ICC cell line. Results Triosephosphate isomerise (TPI1) was significantly up-regulated in ICC tissues and Kaplan-Meier analysis reveals that higher TPI1 expression was strongly correlated with higher recurrence rate of ICC patients. In the primary training cohort, mean TTR was significantly longer (p < 0.0001) than in the low-risk group (26.9 months for TTR, 95% CI 22.4-31.5) than in the high-risk group (14.5 months for TTR, 95% CI 10.6-18.4). Similar results were observed in two validation cohorts. In addition, a nomogram to predict recurrence was developed. Moreover, Knockdown of TPI1 by shRNA inhibited ICC cell growth, colony information, migration, invasion in vitro. Conclusions Current prognostic models were accurate in predicting recurrence for ICC patients after surgical resection.