在代谢组学分析的辅助下,转录组学提供了对水动力转染肝癌模型中致癌过程中的调节机制的见解。

IF 6 2区 医学 Q1 ONCOLOGY
Qi Zhang, Yongfeng Li, Xiaojing Cheng, Zhouxiang Liao, Sha Wen, Xuejing Huang, Zhenyu Song, Min He, Lichao Yang
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引用次数: 0

摘要

背景:肝细胞癌(HCC)是最常见的恶性肿瘤之一,死亡率很高,其发病机制相对复杂。动物模型为探索恶性肿瘤的原因和机制提供了有价值的工具。本研究采用一种新型的流体动力学转染小鼠模型来研究HCC发展过程中关键基因和代谢物的变化。通过结合代谢组学辅助转录组学分析,本研究旨在为HCC的发展提供新的见解。方法:采用水动力转染,结合SB11转座子系统和CRISPR-Cas9系统,建立小鼠肝癌模型。以C57BL/6J小鼠为实验动物,随机分为对照组和实验组。实验组小鼠采用混合重组致癌质粒进行水动力转染,敲除抑癌基因Pten和P53,同时过表达致癌基因β-catenin和c-Met。对照组小鼠转染相应的空载体。在建模阶段监测所有小鼠的体重、活动和血液常规检查。所有小鼠在建模阶段完成后都被处死,收集肝脏标本用于病理评估和代谢组学辅助转录组学研究。结果:与对照组相比,实验组小鼠体重增加明显较小(P)。结论:在基于流体动力学转染的小鼠HCC模型中,雌性小鼠的肿瘤发生率高于雄性小鼠,肿瘤生长速度更快,病情更严重。这种基于性别的差异可能与女性肝脏中谷胱甘肽s -转移酶(GSTs)的低表达有关。靶向GST表达或活性可能为HCC预防和治疗提供性别知情方法的潜在策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Transcriptomics assisted by metabolomics analysis provides insights into regulation mechanisms during carcinogenic process in a hydrodynamically transfected liver cancer model.

Background: Hepatocellular carcinoma (HCC) ranks among the most prevalent malignancies with a substantial mortality rate, and its pathogenesis is relatively complex. Animal models provide valuable tools for exploring the causes and mechanisms of malignancy. This study uses a novel hydrodynamic transfection mouse model to investigate the changes in key genes and metabolites during the development of HCC. By combining metabolomics-assisted transcriptomics assay, this research seeks to provide new insights into HCC development.

Methods: A mouse model of HCC was established using hydrodynamic transfection coupled with the SB11 transposon system and the CRISPR-Cas9 system. C57BL/6J mice were used as experimental animals, with mice arbitrarily split into the control and experimental groups. The experimental group of mice underwent hydrodynamic transfection using mixed recombination carcinogenic plasmids that knocked out the tumor suppressor genes Pten and P53, while overexpressing the oncogenes β-catenin and c-Met. In contrast, the control group of mice was transfected with corresponding empty vectors. All mice were monitored for weight, activity, and blood routine examinations during the modeling phase. All mice were sacrificed upon completion of the modeling phase, and their liver specimens were harvested for pathological evaluations and metabolomics-assisted transcriptomics investigation.

Results: In contrast to the control group, the experimental group mice exhibited notably smaller weight gain (P < 0.01) and markedly elevated serum ALT and AST levels (P < 0.001). At the end of the modeling period, visible white nodules appeared in the liver; hematoxylin and eosin (H&E) staining, immunohistochemistry, and electron microscopy revealed pathological features of HCC in the experimental group. Transcriptome analysis ascertained 2757 differentially expressed genes (DEGs) between HCC tissues and control liver tissues, with 2273 elevated and 484 diminished genes. KEGG pathway evaluation indicated substantial clustering of DEGs in cell cycle signaling pathways. Metabolome analysis showed the enrichment of differential metabolites in pathways related to ascorbate and alternate metabolism, choline metabolism in cancer, and glycerophospholipid metabolism. Notably, we observed significant differences in HCC progression between male and female mice after modeling, with female mice showing a higher incidence of HCC, greater liver-to-body weight ratios, and larger tumors than males. Transcriptome analysis and subsequent qRT-PCR demonstrated a significant downregulation of several glutathione transferase family genes (Gata1, Gata2, Gstp1, Mgst1) in the liver tissues of female mice versus males in the experimental group. Liver metabolome analysis revealed that female mice in the experimental group had 57 metabolites that differed from those of male mice, with 24 metabolites being upregulated and 33 downregulated. In particular, female mice exhibited markedly higher levels of glutamate, alanine, L-pyroglutamic acid, and glycerophospholipids (P < 0.05), while their pyridoxine levels were notably lower (P < 0.05) compared to male mice in the liver.

Conclusions: In a hydrodynamic transfection-based mouse model of HCC, female mice showed higher tumor incidence, faster tumor growth, and more severe disease compared to male mice. This sex-based difference may be associated with lower hepatic expression of glutathione S-transferases (GSTs) in females. Targeting GST expression or activity may offer a potential strategy for sex-informed approaches to HCC prevention and therapy.

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来源期刊
CiteScore
10.90
自引率
1.70%
发文量
360
审稿时长
1 months
期刊介绍: Cancer Cell International publishes articles on all aspects of cancer cell biology, originating largely from, but not limited to, work using cell culture techniques. The journal focuses on novel cancer studies reporting data from biological experiments performed on cells grown in vitro, in two- or three-dimensional systems, and/or in vivo (animal experiments). These types of experiments have provided crucial data in many fields, from cell proliferation and transformation, to epithelial-mesenchymal interaction, to apoptosis, and host immune response to tumors. Cancer Cell International also considers articles that focus on novel technologies or novel pathways in molecular analysis and on epidemiological studies that may affect patient care, as well as articles reporting translational cancer research studies where in vitro discoveries are bridged to the clinic. As such, the journal is interested in laboratory and animal studies reporting on novel biomarkers of tumor progression and response to therapy and on their applicability to human cancers.
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