研究背景

甲状腺激素受体相互作用蛋白13（Thyroid Hormone Receptor Interactor 13, TRIP13）参与调控细胞周期及DNA损伤应答通路，且在多种癌症中过表达。然而，目前尚未有关于TRIP13在人类癌症免疫治疗反应中作用的系统评估。为此，我们开展了一项涵盖表达水平、预后、免疫相关机制及生物标志物价值的泛癌分析，以探究TRIP13表达与免疫治疗反应之间的关联。

研究方法

研究基于TCGA（The Cancer Genome Atlas）、GTEx（Genotype-Tissue Expression）和CPTAC（Clinical Proteomic Tumor Analysis Consortium）等多组学数据库，通过TIMER2.0和GEPIA2平台评估TRIP13在泛癌中的表达谱差异。采用单变量Cox回归和Kaplan-Meier（K-M）法分析TRIP13表达与患者预后的相关性。分析TRIP13表达与肿瘤突变负荷（Tumor Mutation Burden, TMB）、微卫星不稳定性（Microsatellite Instability, MSI）及免疫检查点分子的关联探究TRIP13在免疫治疗应答中的作用，利用LASSO-Cox回归构建预后预测模型。实验验证部分包括实时荧光定量PCR（RT-qPCR）检测TRIP13 mRNA表达及免疫组化分析其蛋白定位与表达水平。

研究结果

TRIP13在乳腺癌、肺癌、肝癌等多种癌症中高表达，且与患者总生存期（Overall Survival, OS）、无病生存期（Disease-Free Survival, DFS）、无进展生存期（Progression-Free Survival, PFS）和疾病特异性生存期（Disease-Specific Survival, DSS）缩短显著相关。TRIP13基因变异以扩增为主，并且与其表达量增加相关联。其次，在多数肿瘤中TRIP13高表达常伴随高TMB和MSI，通过免疫分析发现TRIP13高表达与内皮细胞、肿瘤相关成纤维细胞等浸润增加呈正相关，这一现象可能与患者预后不良相关。此外，研究鉴定出与TRIP13相互作用的三个关键基因CDC20、RAD1和MAD2L1，这些基因通过调控细胞周期协同促进肿瘤发生和增殖。定量PCR验证显示，TRIP13在肾透明细胞癌、肝细胞癌和胰腺导管腺癌细胞中的表达水平显著高于对应正常细胞。

结论

本研究首次通过泛癌分析揭示TRIP13可作为预测免疫治疗疗效的新型生物标志物，并描述其在肿瘤中表达量、基因变异及免疫微环境特征等，为探索癌症免疫治疗提供新方向。

Background

Thyroid Hormone Receptor Interactor 13 (TRIP13) regulates the cell cycle and DNA damage response pathways and is overexpressed in various cancers. However, its role in predicting immune therapy response in human cancers has not been systematically evaluated. To investigate the association between TRIP13 expression and immune therapy efficacy, we conducted a pan-cancer analysis encompassing expression profiles, prognostic value, immune-related mechanisms, and biomarker potential.

Methods

This study systematically analyzed the expression patterns and clinical relevance of TRIP13 across cancers using multi-omics databases, including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Clinical Proteomic Tumor Analysis Consortium (CPTAC). First, differential expression profiles of TRIP13 in pan-cancer were evaluated using TIMER2.0 and GEPIA2 platforms. Second, univariate Cox regression and Kaplan-Meier (K-M) analyses were employed to assess the correlation between TRIP13 expression and patient prognosis. To explore its role in immunotherapy response, TRIP13 expression was further analyzed in relation to tumor mutation burden (TMB), microsatellite instability (MSI), and immune checkpoint molecules. A prognostic prediction model was constructed using LASSO-Cox regression. Experimental validation included RT-qPCR for TRIP13 mRNA expression and immunohistochemistry (IHC) for protein localization and expression levels.

Results

TRIP13 was highly expressed in breast, lung, liver, and other cancers, and its overexpression was significantly associated with shortened overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and disease-specific survival (DSS). Genetic alterations in TRIP13, primarily amplifications, correlated with increased expression. In most tumors, high TRIP13 expression coincided with elevated TMB and MSI. Immune infiltration analysis revealed that TRIP13 upregulation positively correlated with increased infiltration of endothelial cells and cancer-associated fibroblasts, potentially linked to poor prognosis. Three key TRIP13-interacting genes CDC20, RAD1, and MAD2L1 were identified, which synergistically promote tumorigenesis and proliferation by regulating the cell cycle. RT-qPCR confirmed significantly higher TRIP13 mRNA levels in clear cell renal carcinoma, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma cells compared to normal counterparts.

Conclusion

This study is the first pan-cancer analysis to reveal TRIP13 as a novel biomarker for predicting immune therapy efficacy. It delineates the aberrant expression, genetic alterations, and immune microenvironment features of TRIP13, providing new directions for exploring cancer immunotherapy strategies.