转录因子 FOSB 在肺癌进展和预后中的两极作用:取决于 p53 状态。

IF 11.4 1区 医学 Q1 ONCOLOGY Journal of Experimental & Clinical Cancer Research Pub Date : 2024-08-21 DOI:10.1186/s13046-024-03161-1
Hongchao Zhang, Guopei Zhang, Mingyang Xiao, Su Cui, Cuihong Jin, Jinghua Yang, Shengwen Wu, Xiaobo Lu
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引用次数: 0

摘要

背景:激活蛋白-1(AP-1)是一个转录因子家族,因其广泛参与肿瘤生物学而日益受到关注。然而,AP-1 家族在肺癌演化过程中的作用仍然鲜为人知。FBJ Murine Osteosarcoma Viral Oncogene Homolog B(FOSB)是典型的AP-1家族成员,之前有报道称它在非小细胞肺癌(NSCLC)中扮演着令人困惑的两极角色,是一把神秘的双刃剑,其原因和意义值得进一步阐明:基于对 TCGA 数据库中一个大型 NSCLC 队列的生物信息学分析,我们目前的工作发现,著名的肿瘤抑制基因 TP53 是破译 FOSB 两面性的关键代码--其表达在携带野生型 TP53 的 NSCLC 患者中显示出积极的预后,而在携带突变型 TP53 的患者中则显示出消极的预后。通过构建一个在不同状态下表达 p53 的合成基因衍生 NSCLC 细胞面板,验证了 FOSB 表达在 NSCLC 群体中截然相反的预后效果,其中 TP53-R248Q 突变位点的表达尤为重要。转录组测序显示,FOSB的过表达在具有不同TP53遗传背景的NSCLC细胞中引起了多样化的转录组景观,结合RT-qPCR的验证,PREX1(TP53-Null)、IGFBP5(TP53-WT)、AKR1C3和ALDH3A1(TP53-R248Q)分别被确定为FOSB的p53依赖性转录靶标。随后,在体外和体内证实了FOSB通过上述选择性转录靶点对NSCLC细胞肿瘤生物学的不同影响。机理研究发现,野生型或突变型p53可能通过蛋白-蛋白相互作用引导FOSB识别并结合到不同的启动子序列,转录激活特定的靶基因,从而对NSCLC的进展和预后产生不同的影响:结论:结合特定的TP53遗传背景,FOSB的表达有望成为NSCLC的新型预后生物标志物,FOSB与p53之间的独特相互作用可能成为NSCLC的潜在干预靶点。
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Two-polarized roles of transcription factor FOSB in lung cancer progression and prognosis: dependent on p53 status.

Background: Activator protein-1 (AP-1) represents a transcription factor family that has garnered growing attention for its extensive involvement in tumor biology. However, the roles of the AP-1 family in the evolution of lung cancer remain poorly characterized. FBJ Murine Osteosarcoma Viral Oncogene Homolog B (FOSB), a classic AP-1 family member, was previously reported to play bewilderingly two-polarized roles in non-small cell lung cancer (NSCLC) as an enigmatic double-edged sword, for which the reasons and significance warrant further elucidation.

Methods and results: Based on the bioinformatics analysis of a large NSCLC cohort from the TCGA database, our current work found the well-known tumor suppressor gene TP53 served as a key code to decipher the two sides of FOSB - its expression indicated a positive prognosis in NSCLC patients harboring wild-type TP53 while a negative one in those harboring mutant TP53. By constructing a panel of syngeneically derived NSCLC cells expressing p53 in different statuses, the radically opposite prognostic effects of FOSB expression in NSCLC population were validated, with the TP53-R248Q mutation site emerging as particularly meaningful. Transcriptome sequencing showed that FOSB overexpression elicited diversifying transcriptomic landscapes across NSCLC cells with varying genetic backgrounds of TP53 and, combined with the validation by RT-qPCR, PREX1 (TP53-Null), IGFBP5 (TP53-WT), AKR1C3, and ALDH3A1 (TP53-R248Q) were respectively identified as p53-dependent transcriptional targets of FOSB. Subsequently, the heterogenous impacts of FOSB on the tumor biology in NSCLC cells via the above selective transcriptional targets were confirmed in vitro and in vivo. Mechanistic investigations revealed that wild-type or mutant p53 might guide FOSB to recognize and bind to distinct promoter sequences via protein-protein interactions to transcriptionally activate specific target genes, thereby creating disparate influences on the progression and prognosis in NSCLC.

Conclusions: FOSB expression holds promise as a novel prognostic biomarker for NSCLC in combination with a given genetic background of TP53, and the unique interactions between FOSB and p53 may serve as underlying intervention targets for NSCLC.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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