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长链非编码 RNA MIAT 与肝癌中的免疫浸润和药物反应相关。

LncRNA MIAT correlates with immune infiltrates and drug reactions in hepatocellular carcinoma.

机构信息

Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China.

Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, China; Fujian Medical University Cancer Center, Fujian Medical University, Fuzhou, China.

出版信息

Int Immunopharmacol. 2020 Dec;89(Pt A):107071. doi: 10.1016/j.intimp.2020.107071. Epub 2020 Nov 19.

Abstract

Long non-coding RNA (lncRNA) is a kind of important molecules involved in the formation of immune landscape in tumor microenvironment. However, there are few studies on the relationship between lncRNA and immunomodulatory regulation of hepatocellular carcinoma (HCC). In this study, we combined with single cell transcriptome sequencing and TCGA data to analyze the relationship between lncRNA MIAT and immune cells in HCC. TIMER database analysis indicated that the expression of MIAT in HCC was negatively correlated with tumor purity, positively correlated with the number of immune cells such as B cells, T lymphocytes and macrophages, and positively correlated with the expression of immune checkpoint molecules such as PD-1, PD-L1 and CTLA4. Analysis of single cell sequencing data of immune cells in HCC showed that MIAT was mainly distributed in tumor, and enriched in FOXP3CD4T cells and PDCD1CD8, GZMKCD8T cells, indicating that MIAT may be involved in the immune escape process of HCC. Besides, through the construction of transcription factor (TF) regulatory network, MIAT-TF-mRNA, we found that the interaction of MIAT and TFs may affect the immune microenvironment of LIHC by regulating the expression of target genes JAK2, SLC6A6, KCND1, MEIS3 or RIN1; LncMAP and CARE analysis showed that MIAT was highly related to the sensitivity of many anticancer drugs, especially sorafenib. In addition, the effect of MIAT on PD-L1 and its relationship with sorafinib were verified in clinical specimens and cells. This study made a meaningful attempt to reveal the immune escape mechanism and to find the effectiveness of targeted drugs in patients with HCC.

摘要

长链非编码 RNA(lncRNA)是参与肿瘤微环境免疫景观形成的重要分子之一。然而,关于 lncRNA 与肝细胞癌(HCC)免疫调节的关系的研究较少。在这项研究中,我们结合单细胞转录组测序和 TCGA 数据,分析了 lncRNA MIAT 与 HCC 中免疫细胞的关系。TIMER 数据库分析表明,HCC 中 MIAT 的表达与肿瘤纯度呈负相关,与 B 细胞、T 淋巴细胞和巨噬细胞等免疫细胞的数量呈正相关,与免疫检查点分子如 PD-1、PD-L1 和 CTLA4 的表达呈正相关。对 HCC 免疫细胞的单细胞测序数据分析表明,MIAT 主要分布在肿瘤中,在 FOXP3+CD4+T 细胞和 PDCD1+CD8+、GZMK+CD8+T 细胞中富集,表明 MIAT 可能参与 HCC 的免疫逃逸过程。此外,通过构建转录因子(TF)调控网络,我们发现 MIAT-TF-mRNA,MIAT 与 TFs 的相互作用可能通过调节 JAK2、SLC6A6、KCND1、MEIS3 或 RIN1 等靶基因的表达来影响 LIHC 的免疫微环境;LncMAP 和 CARE 分析表明,MIAT 与许多抗癌药物的敏感性高度相关,特别是索拉非尼。此外,在临床标本和细胞中验证了 MIAT 对 PD-L1 的影响及其与索拉非尼的关系。这项研究对揭示 HCC 的免疫逃逸机制和寻找患者靶向药物的疗效做出了有意义的尝试。

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