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Establishment of a prognostic model to predict chemotherapy response and identification of RAC3 as a chemotherapeutic target in bladder cancer

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机构: [1]Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China [2]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University,Guangzhou, PR China [3]Department of Urology, The First Affiliated Hospital of Kunming Medical University, Kunming, PR China [4]Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, PR China
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关键词: bladder cancer chemotherapy predictive signature RAC3 therapy target

摘要:
Cisplatin-based chemotherapy is considered the primary treatment option for patients with advanced bladder cancer (BCa). However, the objective response rate to chemotherapy is often unsatisfactory, leading to a poor 5-year survival rate. Furthermore, current strategies for evaluating chemotherapy response and prognosis are limited and inefficient. In this study, we aimed to address these challenges by establishing a chemotherapy response type gene (CRTG) signature consisting of 9 genes and verified the prognostic value of this signature using TCGA and GEO BCa cohorts. The risk scores based on the CRTG signature were found to be associated with advanced clinicopathological status and demonstrated favorable predictive power for chemotherapy response in the TCGA cohort. Meanwhile, tumors with high risk scores exhibited a tendency toward a "cold tumor" phenotype. These tumors showed a low abundance of T cells, CD8+ T cells and cytotoxic lymphocytes, along with a high abundance of cancer-associated fibroblasts. Moreover, they displayed higher mRNA levels of these immune checkpoints: CD200, CD276, CD44, NRP1, PDCD1LG2 (PD-L2), and TNFSF9. Furthermore, we developed a nomogram that integrated the CRTG signature with clinicopathologic risk factors. This nomogram proved to be a more effective tool for predicting the prognosis of BCa patients. Additionally, we identified Rac family small GTPase 3 (RAC3) as a biomarker in our model. RAC3 was found to be overexpressed in chemoresistant BCa tissues and enhance the chemotherapeutic resistance of BCa cells in vitro and in vivo by regulating the PAK1-ERK1/2 pathway. In conclusion, our study presents a novel CRTG model for predicting chemotherapy response and prognosis in BCa. We also highlight the potential of combining chemotherapy with immunotherapy as a promising strategy for chemoresistant BCa and that RAC3 might be a latent target for therapeutic intervention.

基金:

基金编号: 2022YFC2408300 81961128027 82173230 82273421 82072827 2023A1515012486 2023A1515010355 2021B1515020009 202102010002 2023A03J0718 23YKBJ002 2020B1111170006 2018B030317001 2020B1212060 018 2022TQ0385

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大类 | 3 区 医学
小类 | 2 区 环境科学 2 区 毒理学 2 区 水资源
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出版当年[2024]版:
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Q1 TOXICOLOGY Q1 WATER RESOURCES Q2 ENVIRONMENTAL SCIENCES

影响因子: 最新[2023版] 最新五年平均 出版当年[2024版] 出版当年五年平均 出版前一年[2023版]

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第一作者机构: [1]Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China [2]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University,Guangzhou, PR China [3]Department of Urology, The First Affiliated Hospital of Kunming Medical University, Kunming, PR China
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通讯作者:
通讯机构: [1]Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, PR China [2]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University,Guangzhou, PR China [4]Guangdong Provincial Clinical Research Center for Urological Diseases, Guangzhou, PR China [*1]Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510120, PR China.
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