Single-cell and spatial transcriptomics reveal apelin/APJ pathway's role in microvessel formation and tumour progression in hepatocellular carcinoma

Yongfu Zhu, Pengcheng Zhang, Xingxing Huo, Yi Ling, Xiang Lv, Shengyou Lin, Hang Song
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Abstract

The apelin receptor (APJ) is a key player in tumour angiogenesis, but its role in hepatocellular carcinoma (HCC) remains unclear. This study aims to elucidate the function of the apelin/APJ pathway in HCC using a multi-omics approach and identify potential therapeutic biomarkers. Differentially expressed genes related to the apelin/APJ axis were identified from bulk transcriptomics to reveal HCC-associated disparities. Single-cell and spatial transcriptomics were used to localize and analyse the function of these genes. Machine learning models were constructed to predict outcomes based on apelin/APJ expression, and experimental validation was conducted to explore the pathway's impact on HCC angiogenesis. Single cell analysis revealed an overexpression of APJ/Aplin in the endothelium. The stemness of endothelial cell (EC) with high apelin/APJ was enhanced, as well as the expression of TGFb, oxidative stresses and PI3K/AKT pathway genes. Spatial transcriptomics confirmed that EC populations with high APJ scores were enriched within the tumour. Machine learning models showed high prognostic accuracy. High APJ expression was linked to worse outcomes (p = 0.001), and AUC values were high (1 year, 3 year, 5 year) (0.95, 0.97, 0.98). Immune suppression and non-responsiveness of immune therapy were also seen in high-risk groups. The experimental validation showed that silencing apelin reduced angiogenesis (p  < 0.05), endothelial proliferation, decreased expression of ANG2, KLF2, VEGFA and lower ERK1/2 phosphorylation. Apelin may serve as a potential therapeutic target in HCC, given its role in promoting tumour angiogenesis and poor patient outcomes.

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单细胞和空间转录组学揭示 apelin/APJ 通路在肝细胞癌微血管形成和肿瘤进展中的作用
凋亡素受体(APJ)是肿瘤血管生成的关键因素,但它在肝细胞癌(HCC)中的作用仍不清楚。本研究旨在利用多组学方法阐明凋亡肽/APJ通路在HCC中的功能,并确定潜在的治疗生物标记物。研究人员从大容量转录组学中鉴定了与凋亡蛋白/APJ轴相关的差异表达基因,以揭示与HCC相关的差异。单细胞和空间转录组学用于定位和分析这些基因的功能。根据apelin/APJ的表达构建了机器学习模型以预测结果,并进行了实验验证以探索该通路对HCC血管生成的影响。单细胞分析显示,APJ/Aplin在血管内皮中过度表达。高apelin/APJ的内皮细胞(EC)干性增强,TGFb、氧化应激和PI3K/AKT通路基因的表达也增强。空间转录组学证实,APJ得分高的EC群体富集在肿瘤内。机器学习模型显示了较高的预后准确性。APJ高表达与较差的预后有关(p = 0.001),AUC值较高(1年、3年、5年)(0.95、0.97、0.98)。免疫抑制和对免疫疗法无应答也见于高风险组。实验验证表明,沉默 apelin 可减少血管生成(p
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期刊介绍: The Journal of Cellular and Molecular Medicine serves as a bridge between physiology and cellular medicine, as well as molecular biology and molecular therapeutics. With a 20-year history, the journal adopts an interdisciplinary approach to showcase innovative discoveries. It publishes research aimed at advancing the collective understanding of the cellular and molecular mechanisms underlying diseases. The journal emphasizes translational studies that translate this knowledge into therapeutic strategies. Being fully open access, the journal is accessible to all readers.
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