Haitao Xu, Dangui Chen, Jia Lu, Long Zhong, Lihong Wang, Jian Ge
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The diagnostic potential of ARF6 was assessed through receiver operating characteristic curve analysis, and logistic regression was employed to identify factors correlating with elevated ARF6 expression. Functional assays were performed to elucidate the effects of ARF6 modulation on apoptosis, cell cycle progression, and AML cell proliferation, while mechanistic investigations focused on the PI3K/AKT/mTOR signaling pathway, particularly in the context of pharmacological PI3K inhibition.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Our findings revealed a significant upregulation of ARF6 in AML compared to normal controls, with diagnostic efficacy indicated by an AUC of 0.793. Logistic regression analysis identified older age (> 60 years) and a higher white blood cell count (> 20 × 10<sup>9</sup>/L) as significant predictors of high ARF6 expression. Moreover, elevated ARF6 levels were independently associated with shorter overall survival (HR = 1.634, <i>p</i> = 0.045). Notably, ARF6 knockdown induced apoptosis and G0/G1 cell cycle arrest, whereas its overexpression yielded contrary effects. In addition, ARF6 activated the PI3K/AKT/mTOR pathway, which was abrogated by pharmacological PI3K inhibition.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>Collectively, our findings establish ARF6 as a valuable diagnostic and prognostic marker in AML, driving disease progression through the activation of the PI3K/AKT/mTOR pathway. These insights not only enhance our understanding of AML pathology but also underscore the potential of targeting ARF6 for therapeutic intervention in AML treatment paradigms. Future research should aim at evaluating the therapeutic implications of targeting ARF6 in combination with existing treatment modalities.</p>\n </section>\n </div>","PeriodicalId":139,"journal":{"name":"Cancer Medicine","volume":"14 9","pages":""},"PeriodicalIF":3.1000,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cam4.70872","citationCount":"0","resultStr":"{\"title\":\"ARF6 Promotes AML Progression via Activation of PI3K/AKT/mTOR Signaling\",\"authors\":\"Haitao Xu, Dangui Chen, Jia Lu, Long Zhong, Lihong Wang, Jian Ge\",\"doi\":\"10.1002/cam4.70872\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Acute myeloid leukemia (AML) represents a highly aggressive hematological malignancy characterized by a poor prognosis and a pressing demand for innovative diagnostic and prognostic biomarkers. Recent studies have indicated that ADP-ribosylation factor 6 (ARF6) is overexpressed across various cancer types; however, its specific role and implications in AML have yet to be thoroughly investigated.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>To elucidate the clinical relevance and functional mechanisms of ARF6 in AML, we conducted an integrated analysis utilizing RNA sequencing data from The Cancer Genome Atlas (TCGA) alongside clinical samples and AML cell lines. The diagnostic potential of ARF6 was assessed through receiver operating characteristic curve analysis, and logistic regression was employed to identify factors correlating with elevated ARF6 expression. Functional assays were performed to elucidate the effects of ARF6 modulation on apoptosis, cell cycle progression, and AML cell proliferation, while mechanistic investigations focused on the PI3K/AKT/mTOR signaling pathway, particularly in the context of pharmacological PI3K inhibition.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Our findings revealed a significant upregulation of ARF6 in AML compared to normal controls, with diagnostic efficacy indicated by an AUC of 0.793. Logistic regression analysis identified older age (> 60 years) and a higher white blood cell count (> 20 × 10<sup>9</sup>/L) as significant predictors of high ARF6 expression. Moreover, elevated ARF6 levels were independently associated with shorter overall survival (HR = 1.634, <i>p</i> = 0.045). Notably, ARF6 knockdown induced apoptosis and G0/G1 cell cycle arrest, whereas its overexpression yielded contrary effects. 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引用次数: 0
摘要
急性髓系白血病（AML）是一种高度侵袭性的血液系统恶性肿瘤，其特点是预后差，迫切需要创新的诊断和预后生物标志物。最近的研究表明，adp -核糖基化因子6 （ARF6）在各种癌症类型中过表达；然而，其在AML中的具体作用和影响尚未得到彻底研究。为了阐明ARF6在AML中的临床相关性和功能机制，我们利用来自癌症基因组图谱（TCGA）的RNA测序数据以及临床样本和AML细胞系进行了综合分析。通过受试者工作特征曲线分析评估ARF6的诊断潜力，并采用logistic回归分析确定与ARF6表达升高相关的因素。功能分析旨在阐明ARF6调节对细胞凋亡、细胞周期进展和AML细胞增殖的影响，而机制研究主要集中在PI3K/AKT/mTOR信号通路上，特别是在PI3K药理抑制的背景下。我们的研究结果显示，与正常对照相比，AML患者的ARF6显著上调，AUC为0.793。Logistic回归分析发现，年龄较大（60岁）和白细胞计数较高（20 × 109/L）是ARF6高表达的重要预测因素。此外，ARF6水平升高与总生存期缩短独立相关（HR = 1.634, p = 0.045）。值得注意的是，ARF6敲低诱导细胞凋亡和G0/G1细胞周期阻滞，而其过表达则产生相反的作用。此外，ARF6激活了PI3K/AKT/mTOR通路，该通路被PI3K药物抑制所取消。总之，我们的研究结果表明，ARF6是AML的一个有价值的诊断和预后标志物，通过激活PI3K/AKT/mTOR通路驱动疾病进展。这些发现不仅增强了我们对AML病理的理解，而且强调了靶向ARF6在AML治疗模式中进行治疗干预的潜力。未来的研究应着眼于评估靶向ARF6与现有治疗方式联合的治疗意义。
ARF6 Promotes AML Progression via Activation of PI3K/AKT/mTOR Signaling
Background
Acute myeloid leukemia (AML) represents a highly aggressive hematological malignancy characterized by a poor prognosis and a pressing demand for innovative diagnostic and prognostic biomarkers. Recent studies have indicated that ADP-ribosylation factor 6 (ARF6) is overexpressed across various cancer types; however, its specific role and implications in AML have yet to be thoroughly investigated.
Methods
To elucidate the clinical relevance and functional mechanisms of ARF6 in AML, we conducted an integrated analysis utilizing RNA sequencing data from The Cancer Genome Atlas (TCGA) alongside clinical samples and AML cell lines. The diagnostic potential of ARF6 was assessed through receiver operating characteristic curve analysis, and logistic regression was employed to identify factors correlating with elevated ARF6 expression. Functional assays were performed to elucidate the effects of ARF6 modulation on apoptosis, cell cycle progression, and AML cell proliferation, while mechanistic investigations focused on the PI3K/AKT/mTOR signaling pathway, particularly in the context of pharmacological PI3K inhibition.
Results
Our findings revealed a significant upregulation of ARF6 in AML compared to normal controls, with diagnostic efficacy indicated by an AUC of 0.793. Logistic regression analysis identified older age (> 60 years) and a higher white blood cell count (> 20 × 109/L) as significant predictors of high ARF6 expression. Moreover, elevated ARF6 levels were independently associated with shorter overall survival (HR = 1.634, p = 0.045). Notably, ARF6 knockdown induced apoptosis and G0/G1 cell cycle arrest, whereas its overexpression yielded contrary effects. In addition, ARF6 activated the PI3K/AKT/mTOR pathway, which was abrogated by pharmacological PI3K inhibition.
Conclusion
Collectively, our findings establish ARF6 as a valuable diagnostic and prognostic marker in AML, driving disease progression through the activation of the PI3K/AKT/mTOR pathway. These insights not only enhance our understanding of AML pathology but also underscore the potential of targeting ARF6 for therapeutic intervention in AML treatment paradigms. Future research should aim at evaluating the therapeutic implications of targeting ARF6 in combination with existing treatment modalities.
期刊介绍：
Cancer Medicine is a peer-reviewed, open access, interdisciplinary journal providing rapid publication of research from global biomedical researchers across the cancer sciences. The journal will consider submissions from all oncologic specialties, including, but not limited to, the following areas:
Clinical Cancer Research
Translational research ∙ clinical trials ∙ chemotherapy ∙ radiation therapy ∙ surgical therapy ∙ clinical observations ∙ clinical guidelines ∙ genetic consultation ∙ ethical considerations
Cancer Biology:
Molecular biology ∙ cellular biology ∙ molecular genetics ∙ genomics ∙ immunology ∙ epigenetics ∙ metabolic studies ∙ proteomics ∙ cytopathology ∙ carcinogenesis ∙ drug discovery and delivery.
Cancer Prevention:
Behavioral science ∙ psychosocial studies ∙ screening ∙ nutrition ∙ epidemiology and prevention ∙ community outreach.
Bioinformatics:
Gene expressions profiles ∙ gene regulation networks ∙ genome bioinformatics ∙ pathwayanalysis ∙ prognostic biomarkers.
Cancer Medicine publishes original research articles, systematic reviews, meta-analyses, and research methods papers, along with invited editorials and commentaries. Original research papers must report well-conducted research with conclusions supported by the data presented in the paper.
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