Department of Liver Surgery and Organ Transplantation, Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
Department of Immunology and Medical Immunology State Key Laboratory, Naval Medical University, Shanghai 200433, China.
Int Immunopharmacol. 2024 Jul 30;136:112340. doi: 10.1016/j.intimp.2024.112340. Epub 2024 May 30.
Adenosine deaminase acting on RNA 1 (ADAR1) is an RNA-editing enzyme that significantly impacts cancer progression and various biological processes. The expression of ADAR1 mRNA has been examined in multiple cancer types using The Cancer Genome Atlas (TCGA) dataset, revealing distinct patterns in kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and liver hepatocellular carcinoma (LIHC) compared to normal controls. However, the reasons for these differential expressions remain unclear.
In this study, we performed RT-PCR and western blotting (WB) to validate ADAR1 expression patterns in clinical tissue samples. Survival analysis and immune microenvironment analysis (including immune score and stromal score) were conducted using TCGA data to determine the specific cell types associated with ADAR1, as well as the key genes in those cell types. The relationship between ADAR1 and specific cell types' key genes was verified by immunohistochemistry (IHC), using clinical liver and kidney cancer samples.
Our validation analysis revealed that ADAR1 expression was downregulated in KICH, KIRC, and KIRP, while upregulated in LIHC compared to normal tissues. Notably, a significant correlation was found between ADAR1 mRNA expression and patient prognosis, particularly in KIRC, KIRP, and LIHC. Interestingly, we observed a positive correlation between ADAR1 expression and stromal scores in KIRC, whereas a negative correlation was observed in LIHC. Cell type analysis highlighted distinct relationships between ADAR1 expression and the two stromal cell types, blood endothelial cells (BECs) and lymphatic endothelial cells (LECs), and further determined the signature gene claudin-5 (CLDN5), in KIRC and LIHC. Moreover, ADAR1 was inversely related with CLDN5 in KIRC (n = 26) and LIHC (n = 30) samples, verified via IHC.
ADAR1 plays contrasting roles in LIHC and KIRC, associated with the enrichment of BECs and LECs within tumors. This study sheds light on the significant roles of stromal cells within the complex tumor microenvironment (TME) and provides new insights for future research in tumor immunotherapy and precision medicine.
腺苷脱氨酶作用于 RNA1（ADAR1）是一种 RNA 编辑酶，它显著影响癌症的进展和各种生物过程。使用癌症基因组图谱（TCGA）数据集检查了 ADAR1 mRNA 在多种癌症类型中的表达，与正常对照相比，在肾嫌色细胞（KICH）、肾透明细胞癌（KIRC）、肾乳头状细胞癌（KIRP）和肝肝细胞癌（LIHC）中观察到不同的模式。然而，这些差异表达的原因尚不清楚。
在这项研究中，我们通过 RT-PCR 和蛋白质印迹（WB）验证了 ADAR1 在临床组织样本中的表达模式。使用 TCGA 数据进行生存分析和免疫微环境分析（包括免疫评分和基质评分），以确定与 ADAR1 相关的特定细胞类型，以及这些细胞类型中的关键基因。通过免疫组织化学（IHC）验证 ADAR1 与特定细胞类型关键基因之间的关系，使用临床肝和肾癌细胞样本。
我们的验证分析表明，与正常组织相比，ADAR1 在 KICH、KIRC 和 KIRP 中的表达下调，而在 LIHC 中上调。值得注意的是，ADAR1 mRNA 表达与患者预后之间存在显著相关性，特别是在 KIRC、KIRP 和 LIHC 中。有趣的是，我们观察到 ADAR1 表达与 KIRC 中基质评分呈正相关，而与 LIHC 中呈负相关。细胞类型分析突出了 ADAR1 表达与两种基质细胞类型，即血管内皮细胞（BECs）和淋巴管内皮细胞（LECs）之间的不同关系，并进一步确定了 KIRC 和 LIHC 中的特征基因紧密连接蛋白 5（CLDN5）。此外，通过 IHC 验证，ADAR1 在 KIRC（n=26）和 LIHC（n=30）样本中与 CLDN5 呈负相关。
ADAR1 在 LIHC 和 KIRC 中发挥相反的作用，与肿瘤内 BECs 和 LECs 的富集有关。本研究揭示了基质细胞在复杂肿瘤微环境（TME）中的重要作用，并为肿瘤免疫治疗和精准医学的未来研究提供了新的见解。
