Comprehensive phosphoproteomic profiling reveals sex-specific regulatory mechanisms in HrasG12V-driven hepatocarcinogenesis.

IF 6 2区医学 Q1 ONCOLOGY

Cancer Cell International Pub Date : 2025-10-22 DOI:10.1186/s12935-025-04015-2

Changcheng Yang, Juefu Hu, Liang Yao, Yang Yu, Xiaoying Dong, Jun Chen, Aiguo Wang, Huiling Li

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引用次数: 0

Abstract

Objective: To identify common and sex-specific phosphorylation dynamics during hepatocarcinogenesis in HrasG12V transgenic mice (Hras-Tg).

Methods: We constructed a phosphoproteomic database using male/female (M/F) tumor (T), precancerous (P), and wild-type liver tissues (W) from Hras-Tg, validated via parallel reaction monitoring (PRM). Comparative analysis and hierarchical clustering were employed to delineate shared and sex-stratified phosphorylation signatures in hepatocellular carcinoma (HCC) development.

Results: PRM-validated phosphoproteomic profiling quantified 5,410 phosphorylation sites across 2,427 proteins. Analysis of common features revealed nuclear-enriched phosphoprotein accumulation in tumors versus precancerous/wild-type tissues (T vs. P/W). KEGG pathway analysis identified consistently dysregulated pathways including MAPK signaling, focal adhesion, and protein digestion/absorption. Protein-protein interaction (PPI) network analysis of shared phosphoproteins pinpointed key regulators (Alb, Hspa5, Psn), with high connectivity, suggesting potential regulatory roles in the network. Sex-specific analyses demonstrated distinct phosphorylation patterns: males exhibited extensive membrane protein phosphorylation alterations, while females showed predominant cytoplasmic modifications. KEGG pathway mapping revealed male-biased dysregulation in Ras signaling, mTOR pathways, and actin cytoskeleton regulation. Functional annotation indicated greater complexity of phosphorylated proteins in males. Notably, phosphorylation events occurring on proteins with annotated kinase or phosphatase activity were more prevalent in males, suggesting enhanced phosphorylation-mediated signaling dynamics.

Significance: This study establishes the first sexual dimorphism-aware phosphoproteomic resource for Ras-driven hepatocarcinogenesis, systematically characterizing conserved and sex-divergent phosphorylation networks. The findings provide preliminary molecular insights into gender disparities in HCC progression and may guide future therapeutic exploration.

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综合磷蛋白组学分析揭示了hrasg12v驱动的肝癌发生的性别特异性调节机制。

目的：确定HrasG12V转基因小鼠（Hras-Tg）肝癌发生过程中常见的和性别特异性的磷酸化动力学。方法：我们利用Hras-Tg的男性/女性（M/F）肿瘤(T)、癌前组织(P)和野生型肝组织(W)构建了一个磷酸化蛋白质组学数据库，并通过平行反应监测（PRM）进行验证。采用比较分析和分层聚类来描述肝细胞癌（HCC）发展中共享的和性别分层的磷酸化特征。结果：prm验证的磷酸化蛋白质组学分析量化了2,427种蛋白质的5,410个磷酸化位点。对共同特征的分析显示，核富集的磷蛋白在肿瘤和癌前/野生型组织中积累（T vs. P/W）。KEGG通路分析发现了持续失调的通路，包括MAPK信号、局灶黏附和蛋白质消化/吸收。共享磷酸化蛋白的蛋白-蛋白相互作用（PPI）网络分析确定了具有高连通性的关键调节因子（Alb, Hspa5, Psn），提示其在网络中具有潜在的调节作用。性别特异性分析显示了不同的磷酸化模式：雄性表现出广泛的膜蛋白磷酸化改变，而雌性表现出主要的细胞质修饰。KEGG通路图谱揭示了Ras信号、mTOR通路和肌动蛋白细胞骨架调控中男性偏倚的失调。功能注释表明雄性磷酸化蛋白的复杂性更高。值得注意的是，磷酸化事件发生在带有激酶或磷酸酶活性注释的蛋白质上，在男性中更为普遍，这表明磷酸化介导的信号动力学增强。意义：本研究为ras驱动的肝癌发生建立了首个性别二态性意识磷酸化蛋白质组学资源，系统地表征了保守的和性别分化的磷酸化网络。这些发现为HCC进展中的性别差异提供了初步的分子见解，并可能指导未来的治疗探索。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Cell International ONCOLOGY-

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.