Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China.
Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, 211166, China.
Mol Cancer. 2022 Feb 14;21(1):49. doi: 10.1186/s12943-021-01471-y.
Exosomes have emerged as vital biomarkers of multiple cancers and contain abundant circular RNAs (circRNAs). However, the potential for exosomal circRNAs to be used in diagnostics and their molecular mechanism of action in colorectal cancer (CRC) remain unclear.
CRC-specific exosomal circRNAs were identified by RNA sequencing, exoRBase database and a tissue microarray. The diagnostic performance of plasma exosomal circRNAs was evaluated among cancer-free controls, precancer individuals, CRC patients, and patients with other types of cancer. The corresponding biological functions were mainly assessed using circRNA pull-down, proteomic analysis, and RNA immunoprecipitation assay underlying cellular and mouse models.
CircLPAR1 was encapsulated in exosomes with high stability and detectability, and its expression in plasma exosomes was remarkably decreased during CRC development but recovered after surgery. Exosomal circLPAR1 showed cancer specificity in CRC diagnosis and increased the diagnostic performance to an area under the receiver operating characteristic curve of 0.875, as determined by analysing its performance in combination with common clinical biomarkers CEA and CA19-9. Additionally, circLPAR1 was downregulated in CRC tissues and was associated with overall survival. Mechanistically, exosomal circLPAR1 was internalized by CRC cells, and it suppressed tumor growth, likely because exosomal circLPAR1 directly bound with eIF3h specifically suppressed the METTL3-eIF3h interaction, decreasing the translation of oncogene BRD4.
This comprehensive study highlights plasma exosomal circLPAR1 as a promising predictor in CRC diagnosis and describes its biological regulation of colorectal tumorigenesis. This study provides a new perspective on early diagnosis in the clinic and pathogenesis in disease development.
外泌体已成为多种癌症的重要生物标志物，其中包含丰富的环状 RNA（circRNA）。然而，外泌体 circRNA 用于诊断的潜力及其在结直肠癌（CRC）中的作用机制尚不清楚。
通过 RNA 测序、exoRBase 数据库和组织微阵列鉴定 CRC 特异性外泌体 circRNA。在无癌对照、癌前个体、CRC 患者和其他类型癌症患者中评估血浆外泌体 circRNA 的诊断性能。主要通过细胞和小鼠模型中的 circRNA 下拉、蛋白质组分析和 RNA 免疫沉淀分析来评估相应的生物学功能。
CircLPAR1 被包裹在具有高稳定性和可检测性的外泌体中，其在 CRC 发展过程中外泌体中的表达显著降低，但在手术后恢复。外泌体 circLPAR1 在 CRC 诊断中具有癌症特异性，并通过分析其与常见临床生物标志物 CEA 和 CA19-9 的联合性能，将诊断性能提高到 0.875 的受试者工作特征曲线下面积。此外，CRC 组织中 circLPAR1 下调，与总生存期相关。从机制上讲，外泌体 circLPAR1 被 CRC 细胞内化，它抑制肿瘤生长，可能是因为外泌体 circLPAR1 直接与 eIF3h 结合，特异性抑制 METTL3-eIF3h 相互作用，从而降低致癌基因 BRD4 的翻译。
这项全面的研究强调了血浆外泌体 circLPAR1 作为 CRC 诊断的有前途的预测因子，并描述了其对结直肠肿瘤发生的生物学调节。该研究为临床早期诊断和疾病发展中的发病机制提供了新的视角。
