SEMA4F在肝细胞癌中的促癌功能及其潜在治疗靶点价值

SEMA4F: an oncogenic factor and potential therapeutic target identified in hepatocellular carcinoma

摘要

目的 肝细胞癌(Hepato cellular carcinoma,HCC)是全球高致死性恶性肿瘤,其发病机制复杂且缺乏有效靶点。本研究旨在探究Semaphorin家族成员SEMA4F(既往功能主要见于神经系统)在HCC中的作用与机制。方法 整合公共数据库(TCGA、ICGC、GEO、GEPIA)分析SEMA4F在消化道肿瘤(尤其HCC)中的表达及预后价值;结合空间转录组学和HPA数据库解析其组织定位及其与免疫微环境的空间关联;利用GSVA预测其相关功能通路;在肝癌细胞系中敲低SEMA4F,评估其对细胞增殖的影响。结果 SEMA4F在多种消化道肿瘤中显著高表达(P<0.001),尤其在HCC中,其高表达与患者不良预后(P=0.011)及晚期临床分期显著相关(P=0.019)。免疫组化证实SEMA4F在HCC肿瘤区域特异性高表达。GSVA富集分析揭示SEMA4F高表达样本中多个细胞增殖相关通路被显著激活(P<0.001)。体外实验证实,敲低SEMA4F可显著抑制肝癌细胞的增殖活力与克隆形成能力(P<0.001),以及与巨噬细胞共培养后上清液中TNF-α水平升高,IL-10水平降低。结论 SEMA4F在HCC中发挥促癌作用,其机制可能涉及调控细胞增殖通路。该分子在HCC中的特异性高表达、预后关联及促增殖功能,凸显其作为HCC潜在诊断/预后生物标志物及治疗干预靶点的重要研究价值。

Abstract

Objective Hepatocellular carcinoma (HCC) is a highly lethal malignancy worldwide, characterized by complex pathogenesis and a lack of effective specific therapeutic targets. This study aimed to investigate the role and underlying mechanisms of SEMA4F, a member of the Semaphorin family (previously mainly implicated in the nervous system), in HCC. Methods Public databases (TCGA, ICGC, GEO, GEPIA) were utilized to analyze SEMA4F expression and its prognostic value in gastrointestinal tumors. Spatial transcriptomics and the HPA database were integrated to examine its tissue localization and relationship with the immune microenvironment. Gene Set Variation Analysis (GSVA) was employed to predict functional pathways associated with SEMA4F. SEMA4F was knocked down in HCC cell lines to assess its impact on cell proliferation. Results SEMA4F was significantly overexpressed in multiple gastrointestinal tumors, especially in HCC, where its high expression strongly correlated with poor prognosis and advanced clinical stages. Spatial transcriptomics and immunohistochemistry revealed tumor-specific overexpression of SEMA4F in HCC tissues, with its expression pattern linked to spatial distribution of immune cells. GSVA enrichment analysis demonstrated significant activation of multiple proliferation-related signaling pathways in SEMA4F-high HCC samples. In vitro experiments demonstrated that SEMA4F knockdown significantly inhibited the proliferation and colony formation ability of HCC cells, and in co-culture with macrophages, resulted in increased TNF-α and decreased IL-10 levels in the supernatant. Conclusion SEMA4F exerts an oncogenic role in HCC, potentially by regulating proliferation-related pathways. Its tumor-specific overexpression, prognostic relevance, and pro-proliferative function highlight SEMA4F as a promising diagnostic/prognostic biomarker and therapeutic target for HCC.

关键词

肝细胞癌 / SEMA4F / 增殖 / 预后 / 治疗靶点

Key words

hepatocellular carcinoma / SEMA4F / proliferation / prognosis / therapeutic target

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基金资助

新疆维吾尔自治区“天山英才”科技创新团队项目(2023TSYCTD0020),新疆生产建设兵团指导性科技计划项目(2022ZD041)