Yazdan Panah Pegah, Sadeghi Amir, Ghafouri-Fard Soudeh
Student Research Committee School of Medicine Shahid Beheshti University of Medical Sciences Tehran Iran.
Gastroenterology and Liver Diseases Research Center Research Institute for Gastroenterology and Liver Diseases Shahid Beheshti University of Medical Sciences Tehran Iran.
J Cell Commun Signal. 2025 Aug 3;19(3):e70038. doi: 10.1002/ccs3.70038. eCollection 2025 Sep.
Circular RNAs (circRNAs) have emerged as pivotal regulators of the Notch signaling pathway, influencing diverse pathological processes ranging from cancer to neurodegenerative disorders. This review synthesizes evidence demonstrating how circRNAs modulate Notch activity through miRNA sponging (e.g., circ-NOTCH 1 promoting gastric cancer metastasis via miR-637/apelin axis), protein interactions, and peptide encoding. Key examples of oncogenic circRNAs are circNFIX (glioma) and circ-ASH2L (pancreatic cancer), which drive tumor progression by sponging miR-34a-5p, elevating NOTCH 1 expression, and activating downstream effectors. We also discuss tissue-specific duality of circRNAs. In fact, Notch signaling exhibits context-dependent roles, with circFBXW7 suppressing NOTCH 1 in T-ALL (tumor suppressor) versus circ-NSD2 activating JAG1/NOTCH 1 in colorectal cancer (oncogene). While circRNAs like hsa_circ_0001741 show prognostic promise, challenges persist in delivery and target specificity due to miRNA pleiotropy. By integrating mechanistic insights with preclinical examples, this review highlights circRNAs as both biomarkers and therapeutic targets, urging further research to address clinical translation barriers.
环状RNA（circRNAs）已成为Notch信号通路的关键调节因子，影响从癌症到神经退行性疾病等多种病理过程。本综述综合了相关证据，证明了circRNAs如何通过微小RNA海绵作用（例如，circ-NOTCH 1通过miR-637/血管生成素轴促进胃癌转移）、蛋白质相互作用和肽编码来调节Notch活性。致癌circRNAs的关键例子是circNFIX（胶质瘤）和circ-ASH2L（胰腺癌），它们通过海绵吸附miR-34a-5p、提高NOTCH 1表达和激活下游效应器来驱动肿瘤进展。我们还讨论了circRNAs的组织特异性双重性。事实上，Notch信号表现出依赖于背景的作用，circFBXW7在T细胞急性淋巴细胞白血病中抑制NOTCH 1（肿瘤抑制因子），而circ-NSD2在结直肠癌中激活JAG1/NOTCH 1（癌基因）。虽然像hsa_circ_0001741这样的circRNAs显示出预后前景，但由于微小RNA的多效性，在递送和靶点特异性方面仍然存在挑战。通过将机制见解与临床前实例相结合，本综述强调了circRNAs作为生物标志物和治疗靶点的作用，敦促进一步开展研究以克服临床转化障碍。
