Campelo Marcelo Monteiro, Reis-das-Mercês Laís, Vidal Amanda Ferreira, da Silva Felipe Rodolfo Pereira, de Oliveira Ana Carolina Alves, Monteiro José Rogério de Souza, Cabral Caique Guimarães, Noronha Renata Coelho Rodrigues, Pereira Adenilson Leão
Laboratory of Genetics and Evidence-Based Medicine, Faculty of Medicine, Federal University of Pará, Altamira, Pará, Brazil.
Laboratory of Human and Medical Genetics, Institute of Biological Sciences, Graduate Program of Genetics and Molecular Biology, Federal University of Pará, Belém, Pará, Brazil.
Front Oncol. 2025 Feb 21;15:1547889. doi: 10.3389/fonc.2025.1547889. eCollection 2025.
circHIPK3 role in cancer as oncogene or tumor suppressor is still debated, therefore, this study aimed to understand the dual role of this circRNA in different cancers. Furthermore, all available evidence of circHIPK3 interactions with sponged-miRNA and RBPs in oncological diseases were systematically gathered to better understand the its functional role in cancer.
PubMed, BioMedCentral, Web of Science, Embase and Scopus databases were searched for articles published until October 2024, following the PRISMA guideline. In computational analysis, miRNAs' sponged target genes and RBPs were used for gene enrichment in KEGG, REACTOME and Gene Ontology, and TISSUES expression. miRTargetLink 2.0 was used to search for target genes, and STRING v.12.0 for gene enrichment.
circHIPK3 can regulate 33 miRNAs which regulate 399 target genes, and that were mainly enriched in major biological pathways important for cancer development and promoting. circHIPK3/miR-124-3p/miR-637/miR-338-3p are the most well documented interactions in cancers that may control MAPK, Jak/STAT3, Wnt/β-catenin, and PI3K/Akt signaling pathways. circHIPK3 regulates miRNAs that modulate genes responsible for chemoresistance, such as ATP-binding cassette and solute carrier transporters genes, and DNA repair genes. circHIPK3 has binding sites for RBPs, which participate mainly of RNA processing and control, and gene expression regulation. Finally, we believe that it has an onco-circRNA role in most cancers, except in bladder cancer, where it has a TS-circRNA function likely due to the microenvironment permeated by high amounts of hydrogen peroxide.
circHIPK3 dysregulation is an important mechanism for cancer establishment, progression and chemoresistance making it an interesting molecule with a potential therapeutic target.
环状HIPK3在癌症中作为癌基因或肿瘤抑制因子的作用仍存在争议，因此，本研究旨在了解这种环状RNA在不同癌症中的双重作用。此外，系统收集了环状HIPK3在肿瘤疾病中与海绵化微小RNA（miRNA）和RNA结合蛋白（RBP）相互作用的所有现有证据，以更好地了解其在癌症中的功能作用。
按照PRISMA指南，检索了PubMed、BioMedCentral、Web of Science、Embase和Scopus数据库中截至2024年10月发表的文章。在计算分析中，将miRNA的海绵化靶基因和RBP用于KEGG、REACTOME和基因本体论中的基因富集分析以及组织表达分析。使用miRTargetLink 2.0搜索靶基因，使用STRING v.12.0进行基因富集分析。
环状HIPK3可调控33种miRNA，这些miRNA调控399个靶基因，且这些靶基因主要富集于对癌症发展和促进至关重要的主要生物学途径中。环状HIPK3/miR-124-3p/miR-637/miR-338-3p是癌症中记录最充分的相互作用，可能控制丝裂原活化蛋白激酶（MAPK）、 Jak/信号转导和转录激活因子3（STAT3）、Wnt/β-连环蛋白和磷脂酰肌醇-3-激酶/蛋白激酶B（PI3K/Akt）信号通路。环状HIPK3调控的miRNA可调节负责化疗耐药性的基因，如ATP结合盒和溶质载体转运蛋白基因以及DNA修复基因。环状HIPK3具有RBP的结合位点，这些RBP主要参与RNA加工与调控以及基因表达调控。最后，我们认为它在大多数癌症中具有癌环状RNA的作用，但在膀胱癌中除外，在膀胱癌中它可能由于被大量过氧化氢渗透的微环境而具有肿瘤抑制环状RNA的功能。
环状HIPK3失调是癌症发生、进展和化疗耐药的重要机制，使其成为一个具有潜在治疗靶点的有趣分子。
