背景:钙调磷酸酶1(RCAN1)的调节剂在多个器官中表达,包括心脏,肝脏,大脑,和肾脏,并且与心血管疾病的发病机理密切相关,唐氏综合症,和老年痴呆症。它也与各种器官肿瘤的发展有关;然而,其在肝细胞癌(HCC)中的潜在作用仍然知之甚少。因此,本研究的目的是通过生物信息学分析探讨RCAN1在HCC中的潜在机制。
方法:我们基于NCBI和TCGA数据库进行了联合分析,整合批量转录组和单细胞分析,以检查RCAN1在HCC中的主要生物学功能,以及它与表型相关的作用,新陈代谢,和细胞通讯。随后,建立了RCAN1过表达细胞系,并通过体外实验验证了RCAN1对肿瘤细胞的作用。此外,我们努力使用分子对接和分子动力学模拟来识别潜在的相关药物。
结果:发现RCAN1在19种癌组织中表达下调,在11种癌组织中表达上调。更高水平的RCAN1表达与改善患者生存率相关。RCAN1主要在肝细胞中表达,巨噬细胞,内皮细胞,和单核细胞,它的高表达不仅与HCC表型相关细胞的分布密切相关,而且与HCC细胞本身的分布密切相关。此外,Rcan1可能直接或间接参与代谢途径,如丙氨酸,天冬氨酸,和谷氨酸代谢,以及丁酸代谢,从而影响肿瘤细胞的增殖和迁移。体外实验证实RCAN1过表达在抑制肝癌细胞增殖和侵袭的同时促进细胞凋亡。通过1615种药物的分子对接,我们筛选了溴苯那敏作为潜在的靶药物,并通过分子动力学验证了我们的结果。
结论:在这项研究中,我们通过生物信息学方法揭示了RCAN1与HCC之间的关系,通过实验验证RCAN1能影响疾病的进展,最后通过药物分子对接和分子动力学确定了潜在的治疗药物。
BACKGROUND: The regulator of calcineurin 1 (
RCAN1) is expressed in multiple organs, including the heart, liver, brain, and kidney, and is closely linked to the pathogenesis of cardiovascular diseases, Down syndrome, and Alzheimer\'s disease. It is also implicated in the development of various organ tumors; however, its potential role in hepatocellular carcinoma (HCC) remains poorly understood. Therefore, the objective of this study was to investigate the potential mechanisms of
RCAN1 in HCC through bioinformatics analysis.
METHODS: We conducted a joint analysis based on the NCBI and TCGA databases, integrating both bulk transcriptome and single-cell analyses to examine the principal biological functions of RCAN1 in HCC, as well as its roles related to phenotype, metabolism, and cell communication. Subsequently, an
RCAN1-overexpressing cell line was established, and the effects of
RCAN1 on tumor cells were validated through in vitro experiments. Moreover, we endeavored to identify potential related drugs using molecular docking and molecular dynamics simulations.
RESULTS: The expression of RCAN1 was found to be downregulated in 19 types of cancer tissues and upregulated in 11 types of cancer tissues. Higher levels of
RCAN1 expression were associated with improved patient survival.
RCAN1 was predominantly expressed in hepatocytes, macrophages, endothelial cells, and monocytes, and its high expression not only closely correlated with the distribution of cells related to the HCC phenotype but also with the distribution of HCC cells themselves. Additionally, Rcan1 may directly or indirectly participate in metabolic pathways such as alanine, aspartate, and glutamate metabolism, as well as butanoate metabolism, thereby influencing tumor cell proliferation and migration. In vitro experiments confirmed that RCAN1 overexpression promoted apoptosis while inhibiting proliferation and invasion of HCC cells. Through molecular docking of 1615 drugs, we screened brompheniramine as a potential target drug and verified our results by molecular dynamics.
CONCLUSIONS: In this study, we revealed the relationship between RCAN1 and HCC through bioinformatics methods, verified that RCAN1 can affect the progress of the disease through experiments, and finally identified potential therapeutic drugs through drug molecular docking and molecular dynamics.