RAB GTP酶在预测胰腺癌预后和治疗反应中的作用。
The role of RAB GTPases in predicting prognosis and therapy response in pancreatic cancer.
作者信息
Wang Jiayi, Ma Jiayao, Lei Shiying, Zhai Yulei, Liao Yangjie, Hu Chongrong, Li Jingbo
机构信息
Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, 410013, China.
Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
出版信息
Discov Oncol. 2025 Jul 21;16(1):1383. doi: 10.1007/s12672-025-03209-4.
BACKGROUND
The Rab family of small GTPases (RABs) regulates membrane trafficking and is implicated in tumor progression. Pancreatic cancer (PC), a highly aggressive malignancy, lacks effective therapeutic strategies. Using bioinformatics and experimental validation, we identified five RABs (RAB10, RAB11A, RAB39B, RAB28, and RAB11B) to construct a RAB prognostic model (RPM) for PC.
METHODS
Datasets from TCGA and GEO were analyzed using Cox and LASSO regression to establish RPM. A prognostic nomogram integrating RPM with clinical features was developed. Microenvironment and drug sensitivity analysis were performed to predict the relationship between RPM score and therapy response. In vitro experiments (CCK8, MDA assays, lentiviral knockdown, qPCR, and western blot) were performed to validate RAB39B’s role in autophagy-dependent ferroptosis.
RESULTS
RPM stratified patients into high- and low-risk groups, with high-risk patients showing poorer overall survival. The low-risk group exhibited enriched immune infiltration, elevated HLA expression, higher dysfunctional T-cell scores, and lower tumor mutation burden, suggesting an exhausted tumor immune microenvironment which could benefit from immunotherapy. The high-risk cohort exhibited markedly reduced responsiveness to axitinib, gefitinib, imatinib, methotrexate, nilotinib, and sunitinib, while demonstrating enhanced sensitivity to erlotinib, lapatinib, and sorafenib. Correlation analysis further identified RAB39B as a critical modulator of treatment response. In experiments demonstrated that RAB39B knockdown reduced ferroptosis inducibility and suppressed LC3-II accumulation, implicating RAB39B’s role in autophagy-dependent ferroptosis.
CONCLUSIONS
RPM serves as a robust prognostic tool for PC. RAB39B drives autophagy-dependent ferroptosis and influences drug sensitivity, offering therapeutic insights for PC.
SUPPLEMENTARY INFORMATION
The online version contains supplementary material available at 10.1007/s12672-025-03209-4.
背景
小GTP酶（RABs）的Rab家族调节膜运输，并与肿瘤进展有关。胰腺癌（PC）是一种高度侵袭性的恶性肿瘤，缺乏有效的治疗策略。通过生物信息学和实验验证，我们鉴定出五个RABs（RAB10、RAB11A、RAB39B、RAB28和RAB11B）来构建PC的RAB预后模型（RPM）。
方法
使用Cox和LASSO回归分析来自TCGA和GEO的数据集以建立RPM。开发了一个将RPM与临床特征相结合的预后列线图。进行微环境和药物敏感性分析以预测RPM评分与治疗反应之间的关系。进行体外实验（CCK8、MDA测定、慢病毒敲低、qPCR和蛋白质印迹）以验证RAB39B在自噬依赖性铁死亡中的作用。
结果
RPM将患者分为高风险和低风险组，高风险患者的总生存期较差。低风险组表现出丰富的免疫浸润、升高的HLA表达、更高的功能失调T细胞评分和更低的肿瘤突变负担，表明肿瘤免疫微环境耗竭，这可能从免疫治疗中受益。高风险队列对阿昔替尼、吉非替尼、伊马替尼、甲氨蝶呤、尼洛替尼和舒尼替尼的反应明显降低，而对厄洛替尼、拉帕替尼和索拉非尼的敏感性增强。相关性分析进一步确定RAB39B是治疗反应的关键调节因子。体外实验表明，RAB39B敲低降低了铁死亡诱导能力并抑制了LC3-II积累，这表明RAB39B在自噬依赖性铁死亡中的作用。
结论
RPM是PC的一种强大的预后工具。RAB39B驱动自噬依赖性铁死亡并影响药物敏感性，为PC提供了治疗见解。
补充信息
在线版本包含可在10.1007/s12672-025-03209-4获取的补充材料。
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