Hepatic stellate cells promote hepatocellular carcinoma development by regulating histone lactylation: Novel insights from single-cell RNA sequencing and spatial transcriptomics analyses

IF 9.1 1区 医学 Q1 ONCOLOGY Cancer letters Pub Date : 2024-09-10 DOI:10.1016/j.canlet.2024.217243
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Abstract

This study evaluated the cellular heterogeneity and molecular mechanisms of hepatocellular carcinoma (HCC). Single cell RNA sequencing (scRNA-seq), transcriptomic data, histone lactylation-related genes were collected from public databases. Cell-cell interaction, trajectory, pathway, and spatial transcriptome analyses were executed. Differential expression and survival analyses were conducted. Western blot, Real-time reverse transcription PCR (qRT-PCR), and Cell Counting Kit 8 (CCK8) assay were used to detect the expression of αSMA, AKR1B10 and its target genes, and verify the roles of AKR1B10 in HCC cells. Hepatic stellate cell (HSC) subgroups strongly interacted with tumor cell subgroups, and their spatial distribution was heterogeneous. Two candidate prognostic genes (AKR1B10 and RMRP) were obtained. LONP1, NPIPB3, and ZSWIM6 were determined as AKR1B10 targets. Besides, the expression levels of AKR1B10 and αSMA were significantly increased in LX-2 + HepG2 and LX-2 + HuH7 groups compared to those in LX-2 group, respectively. sh-AKR1B10 significantly inhibited the HCC cell proliferation and change the expression of AKR1B10 target genes, Bcl-2, Bax, Pan Kla, and H3K18la at protein levels. Our findings unveil the pivotal role of HSCs in HCC pathogenesis through regulating histone lactylation.

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肝星状细胞通过调节组蛋白乳酰化促进肝细胞癌的发展单细胞 RNA 测序和空间转录组学分析的新发现
本研究评估了肝细胞癌(HCC)的细胞异质性和分子机制。研究人员从公共数据库中收集了单细胞 RNA 测序(scRNA-seq)、转录组数据和组蛋白乳化相关基因。进行了细胞-细胞相互作用、轨迹、通路和空间转录组分析。进行了差异表达和存活分析。利用 Western 印迹、实时逆转录 PCR(qRT-PCR)和细胞计数试剂盒 8(CCK8)检测αSMA、AKR1B10 及其靶基因的表达,并验证 AKR1B10 在 HCC 细胞中的作用。肝星状细胞(HSC)亚群与肿瘤细胞亚群之间存在着强烈的相互作用,而且它们的空间分布具有异质性。结果发现了两个候选预后基因(AKR1B10 和 RMRP)。LONP1、NPIPB3和ZSWIM6被确定为AKR1B10的靶点。此外,与LX-2组相比,AKR1B10和αSMA在LX-2 + HepG2组和LX-2 + HuH7组的表达水平均显著升高。 sh-AKR1B10能显著抑制HCC细胞的增殖,并在蛋白水平上改变AKR1B10靶基因Bcl-2、Bax、Pan Kla和H3K18la的表达。我们的研究结果揭示了造血干细胞通过调控组蛋白乳酰化在HCC发病机制中的关键作用。
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来源期刊
Cancer letters
Cancer letters 医学-肿瘤学
CiteScore
17.70
自引率
2.10%
发文量
427
审稿时长
15 days
期刊介绍: Cancer Letters is a reputable international journal that serves as a platform for significant and original contributions in cancer research. The journal welcomes both full-length articles and Mini Reviews in the wide-ranging field of basic and translational oncology. Furthermore, it frequently presents Special Issues that shed light on current and topical areas in cancer research. Cancer Letters is highly interested in various fundamental aspects that can cater to a diverse readership. These areas include the molecular genetics and cell biology of cancer, radiation biology, molecular pathology, hormones and cancer, viral oncology, metastasis, and chemoprevention. The journal actively focuses on experimental therapeutics, particularly the advancement of targeted therapies for personalized cancer medicine, such as metronomic chemotherapy. By publishing groundbreaking research and promoting advancements in cancer treatments, Cancer Letters aims to actively contribute to the fight against cancer and the improvement of patient outcomes.
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