Impact of apolipoprotein A1 on tumor immune microenvironment, clinical prognosis and genomic landscape in hepatocellular carcinoma.

IF 5.1 4区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Precision Clinical Medicine Pub Date : 2023-09-02 eCollection Date: 2023-09-01 DOI:10.1093/pcmedi/pbad021
Ying Wang, Shipeng Chen, Xiao Xiao, Fan Yang, Jinhan Wang, Hui Zong, Yuzhen Gao, Chenjun Huang, Xuewen Xu, Meng Fang, Xiaoyan Zhang, Chunfang Gao
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Abstract

Background: Current knowledge on apolipoprotein A1 (APOA1) in hepatocellular carcinoma (HCC) is fragmented and even contradictory. Multi-dimensional analyses are required to comprehensively elucidate its value and underlying mechanism.

Methods: We collected 49 RNA-seq datasets, 40 cell line types data and 70 scRNA pan-cancer datasets public available, including 17 HCC datasets (1754 tumor samples), and enrolled 73 pairs of HCC tissue and 516 blood samples independently from our clinics. APOA1 impacting on the HCC tumor microenvironment (TME) was analyzed using intensive data mining. Methylation sequencing, flow cytometry, quantitative PCR, western blot, immunohistochemistry and clinical chemistry assays were conducted for wet experimental investigation.

Results: The APOA1 ontology fingerprint indicated that it played various crucial biological roles in HCC, primarily involved in cholesterol efflux. Consistent findings at histology, serology, and clinical follow-up revealed that high APOA1 was a good prognosis indicator of HCC. Hypermethylation in the APOA1 promoter region was found in clinical samples which is in accordance with the reduction of APOA1 in HCC. The cell cycle, DNA replication, mismatch repair pathways, and tumor cell proliferation were less observed in the HCC APOA1high subgroup. The favorable immunoregulatory abilities of APOA1 showed interesting findings: a positive correlation between APOA1 and anti-tumor immune cells (NK, CD8+ T cells) and a negative association with immune cells exerting immunosuppressive effects, including M2 macrophages.

Conclusion: This is an integrative multidimensional exploration of APOA1 using bioinformatics and experiments. Both the prognostic value and anti-tumor effects based on APOA1 panoramic exploration in the HCC TME demonstrate a new potential clinical target for HCC assessment and intervention in the future.

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载脂蛋白A1对肝细胞癌肿瘤免疫微环境、临床预后和基因组景观的影响
背景:目前关于载脂蛋白A1 (APOA1)在肝细胞癌(HCC)中的作用的认识是碎片化的,甚至是相互矛盾的。要全面阐明其价值和作用机制,需要多维度分析。方法:我们收集了49个RNA-seq数据集,40个细胞系类型数据集和70个scRNA泛癌症数据集,包括17个HCC数据集(1754个肿瘤样本),并独立从我们的诊所收集了73对HCC组织和516个血液样本。APOA1对HCC肿瘤微环境(TME)的影响采用密集的数据挖掘分析。采用甲基化测序、流式细胞术、定量PCR、western blot、免疫组织化学、临床化学等方法进行湿法实验研究。结果:APOA1本体论指纹图谱显示其在HCC中发挥多种重要的生物学作用,主要参与胆固醇外排。组织学、血清学和临床随访的一致结果表明,高APOA1是HCC的良好预后指标。在临床样本中发现APOA1启动子区域的高甲基化,这与HCC中APOA1的减少一致。细胞周期、DNA复制、错配修复途径和肿瘤细胞增殖在HCC apoa1高亚组中较少观察到。APOA1良好的免疫调节能力显示出有趣的发现:APOA1与抗肿瘤免疫细胞(NK、CD8+ T细胞)呈正相关,与具有免疫抑制作用的免疫细胞(包括M2巨噬细胞)负相关。结论:利用生物信息学和实验手段对APOA1进行了多维度的综合探索。基于APOA1全景探查在HCC TME中的预后价值和抗肿瘤作用,为未来HCC评估和干预提供了新的潜在临床靶点。
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来源期刊
Precision Clinical Medicine
Precision Clinical Medicine MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
10.80
自引率
0.00%
发文量
26
审稿时长
5 weeks
期刊介绍: Precision Clinical Medicine (PCM) is an international, peer-reviewed, open access journal that provides timely publication of original research articles, case reports, reviews, editorials, and perspectives across the spectrum of precision medicine. The journal's mission is to deliver new theories, methods, and evidence that enhance disease diagnosis, treatment, prevention, and prognosis, thereby establishing a vital communication platform for clinicians and researchers that has the potential to transform medical practice. PCM encompasses all facets of precision medicine, which involves personalized approaches to diagnosis, treatment, and prevention, tailored to individual patients or patient subgroups based on their unique genetic, phenotypic, or psychosocial profiles. The clinical conditions addressed by the journal include a wide range of areas such as cancer, infectious diseases, inherited diseases, complex diseases, and rare diseases.
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