作为肝细胞癌预后特征的 KIF5B 蛋白基因组鉴定与分析

IF 3.8 4区 医学 Q2 GENETICS & HEREDITY
Lishuang Qi, Yilong Tan, Yunfei Zhou, Yihong Dong, Xun Yang, Shuyuan Chang, Lei Yu, Dabin Liu
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引用次数: 0

摘要

背景:代谢紊乱是肝癌,尤其是肝细胞癌(HCC)的重要风险因素。然而,肝脏代谢重编程的分子遗传基础在很大程度上仍不确定:本研究旨在利用蛋白质基因组学和转录物组学分析研究一些新型的 HCC 预后生物标志物,并探索特定预后基因在 HCC 中的潜在作用。方法:我们在这里对 10 对 HCC 进行了蛋白质组学分析,并通过蛋白质共表达和通路分析来研究 HCC 的生物学特征。我们整合了多组HCC的蛋白质和mRNA表达谱,以检测新的HCC预后蛋白标志物。候选预后标志物的致癌作用通过 MTS 试验、集落形成、单层伤口愈合试验和异种移植模型进行了进一步评估:结果:共检测到 2086 种蛋白质在 HCC 中的表达存在显著差异。结果:共检测到 2086 个蛋白在 HCC 中的表达存在明显差异,其中与致癌信号转导和胰岛素相关代谢有关的通路在 HCC 中存在失调和差异调控。我们发现了参与肝脏代谢重编程的新型预后生物标志物 KIF5B。我们从两个独立的蛋白质组数据集(复旦队列和我们招募的队列)和TCGA mRNA数据库中使用多变量COX回归分析鉴定了这些生物标志物。研究发现,KIF5B的蛋白和mRNA上调与HCC的不良临床预后有关。胰岛素激活了KIF5B在HCC中的蛋白表达。通过sgRNA敲除KIF5B的表达可降低FASN和SCD1的蛋白表达以及细胞内甘油三酯的浓度。沉默 KIF5B 可抑制体外 HCC 细胞增殖和集落形成,也可抑制异种移植模型中 HCC 的生长:我们的研究结果表明,KIF5B 蛋白可作为一种新型的 HCC 预后生物标志物。KIF5B的表达可激活AKT/mTOR通路并重塑甘油三酯代谢,从而导致HCC的发生。靶向 KIF5B 可能是临床治疗 HCC 的有效策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Proteogenomic Identification and Analysis of KIF5B as a Prognostic Signature for Hepatocellular Carcinoma.

Background: Metabolic disorders are significant risk factors for liver cancer, particularly Hepatocellular Carcinoma (HCC). However, the molecular genetic basis of metabolic reprogramming in the liver remains largely uncertain.

Objective: This study aimed to investigate some novel prognostic biomarkers in HCC by using proteogenomic and transcriptomic analysis and explore the potential role of specific prognostic genes in HCC.

Methods: Here, we have presented a proteogenomic analysis of 10 pairs of HCC. Protein co-expression and pathway analysis were performed to investigate the biological characteristics of HCC. Protein and mRNA expression profiles of multi-cohorts were integrated to detect novel prognostic protein markers of HCC. The carcinogenic roles of candidate prognostic markers were further evaluated by MTS assay, colony formation, monolayer wound healing assay, and xenograft models.

Results: A total of 2086 proteins with significantly different expressions were detected in HCC. Pathways related to oncogenic signaling and insulin-related metabolism have been found to be dysregulated and differentially regulated in HCC. We have identified the novel prognostic biomarkers, KIF5B, involved in liver metabolic reprogramming. The biomarkers were identified using multivariable COX regression analysis from two independent proteomic datasets (Fudan Cohort and our recruited cohort) and the TCGA mRNA database. Both the protein and mRNA up-regulation of KIF5B have been found to be associated with a poor clinical outcome in HCC. Insulin activated the protein expression of KIF5B in HCC. Knocking out KIF5B expression by sgRNA decreased the protein expression of FASN and SCD1 and the intracellular triglyceride concentration. Silencing KIF5B suppressed HCC cell proliferation and colony formation in vitro, as well as HCC growth in xenograft models.

Conclusion: Our findings have suggested KIF5B protein to function as a novel prognostic biomarker in HCC. KIF5B expression has been found to activate the AKT/mTOR pathway and reprogram triglyceride metabolism, leading to HCC development. Targeting KIF5B may be an effective strategy in the clinical treatment of HCC.

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来源期刊
Current gene therapy
Current gene therapy 医学-遗传学
CiteScore
6.70
自引率
2.80%
发文量
46
期刊介绍: Current Gene Therapy is a bi-monthly peer-reviewed journal aimed at academic and industrial scientists with an interest in major topics concerning basic research and clinical applications of gene and cell therapy of diseases. Cell therapy manuscripts can also include application in diseases when cells have been genetically modified. Current Gene Therapy publishes full-length/mini reviews and original research on the latest developments in gene transfer and gene expression analysis, vector development, cellular genetic engineering, animal models and human clinical applications of gene and cell therapy for the treatment of diseases. Current Gene Therapy publishes reviews and original research containing experimental data on gene and cell therapy. The journal also includes manuscripts on technological advances, ethical and regulatory considerations of gene and cell therapy. Reviews should provide the reader with a comprehensive assessment of any area of experimental biology applied to molecular medicine that is not only of significance within a particular field of gene therapy and cell therapy but also of interest to investigators in other fields. Authors are encouraged to provide their own assessment and vision for future advances. Reviews are also welcome on late breaking discoveries on which substantial literature has not yet been amassed. Such reviews provide a forum for sharply focused topics of recent experimental investigations in gene therapy primarily to make these results accessible to both clinical and basic researchers. Manuscripts containing experimental data should be original data, not previously published.
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