SNRPB/CCNB1 axis promotes hepatocellular carcinoma progression and cisplatin resistance through enhancing lipid metabolism reprogramming.

IF 12.8 1区 医学 Q1 ONCOLOGY
Xin Jin, Xigan He, Runze Huang, Qinyu Liu, Lei Wang, Xuanci Bai, Yibin Wu, Yixiu Wang, Ziting Jiang, Yi Shi, Gautam Sethi, Lu Wang, Weiping Zhu
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引用次数: 0

Abstract

Background: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality globally, significantly impacting worldwide health. Hence, identifying key molecular drivers of HCC progression is crucial for enhancing treatment options and prognostic methods. This study explores the function of Small Nuclear Ribonucleoprotein Polypeptides B and B1 (SNRPB) in HCC, unveiling critical pathways that affect the progression of the disease.

Methods: Utilizing multi-dimensional data that integrates bulk RNA sequencing (bulk RNA-seq), single-cell RNA sequencing (scRNA-seq), and spatial transcriptomics (ST) from HCC patients, we have identified SNRPB as a pivotal gene associated with the spliceosome, playing a central role in both tumor initiation and progression. We also investigated the intricate process by which SNRPB influences cyclin B1 (CCNB1) expression through FOXM1-mediated activation, using a combination of bioinformatics, functional assays, Chromatin Immunoprecipitation (ChIP), and Co-Immunoprecipitation (Co-IP) studies. Complementary in vivo experiments and metabolic assays were conducted to explore the relationship between tumor growth and lipid metabolism further. Additionally, evaluations of cisplatin sensitivity were performed, providing an in-depth analysis of influence of SNRPB on HCC.

Results: Across multiple cohorts, SNRPB exhibited a marked upregulation within tumors, correlating significantly with poor prognosis. Knockdown of SNRPB suppressed HCC cell proliferation and migration, while promoting apoptosis. Mechanistically, SNRPB regulated CCNB1 expression via FOXM1-mediated transcription, and SNRPB overexpression enhanced lipid metabolism and cisplatin resistance. This increase in drug sensitivity was mediated through alterations in lipid metabolism and the regulatory effects on CCNB1, providing a comprehensive insight into multifaceted role of SNRPB in HCC pathology and potential therapeutic targets. Finally, CCNB1 knockdown reversed the proliferative and tumorigenic effects of SNRPB overexpression in a preclinical HCC model.

Conclusions: SNRPB promoted HCC progression by modulating the FOXM1-CCNB1 axis and lipid metabolism, and could act as a potential therapeutic target to augment chemotherapy sensitivity in HCC.

SNRPB/CCNB1轴通过增强脂质代谢重编程促进肝癌进展和顺铂耐药。
背景:肝细胞癌(HCC)是全球癌症相关死亡的主要原因,严重影响着全世界的健康。因此,确定HCC进展的关键分子驱动因素对于提高治疗选择和预后方法至关重要。本研究探讨了小核糖核蛋白多肽B和B1 (SNRPB)在HCC中的功能,揭示了影响疾病进展的关键途径。方法:利用整合了大量RNA测序(bulk RNA-seq)、单细胞RNA测序(scRNA-seq)和来自HCC患者的空间转录组学(ST)的多维数据,我们已经确定SNRPB是与剪接体相关的关键基因,在肿瘤的发生和发展中发挥核心作用。我们还研究了SNRPB通过foxm1介导的激活影响细胞周期蛋白B1 (CCNB1)表达的复杂过程,使用生物信息学、功能测定、染色质免疫沉淀(ChIP)和共免疫沉淀(Co-IP)研究相结合。为了进一步探讨肿瘤生长与脂质代谢的关系,我们进行了补充体内实验和代谢分析。此外,我们还进行了顺铂敏感性评估,深入分析了SNRPB对HCC的影响。结果:在多个队列中,SNRPB在肿瘤中表现出明显的上调,与不良预后显著相关。敲低SNRPB抑制HCC细胞增殖和迁移,促进细胞凋亡。机制上,SNRPB通过foxm1介导的转录调控CCNB1表达,SNRPB过表达增强脂质代谢和顺铂耐药。这种药物敏感性的增加是通过脂质代谢的改变和对CCNB1的调节作用介导的,这为SNRPB在HCC病理和潜在治疗靶点中的多方面作用提供了全面的见解。最后,在临床前HCC模型中,CCNB1敲低逆转了SNRPB过表达的增殖和致瘤作用。结论:SNRPB通过调节FOXM1-CCNB1轴和脂质代谢促进HCC进展,可能作为增加HCC化疗敏感性的潜在治疗靶点。
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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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