Department of Respiratory and Critical Care Medicine, Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, Med-X Center for Manufacturing, National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
Mol Cancer. 2022 Mar 2;21(1):63. doi: 10.1186/s12943-022-01546-4.
Circular RNAs (circRNAs) are differentially expressed between normal and cancerous tissues, contributing to tumor initiation and progression. However, comprehensive landscape of dysregulated circRNAs across cancer types remains unclear.
In this study, we conducted Ribo-Zero transcriptome sequencing on tumor tissues and their adjacent normal samples including glioblastoma, esophageal squamous cell carcinoma, lung adenocarcinoma, thyroid cancer, colorectal cancer, gastric cancer and hepatocellular carcinoma. CIRCexplorer2 was employed to identify circRNAs and dysregulated circRNAs and genes were determined by DESeq2 package. The expression of hsa_circ_0072309 (circLIFR) was measured by reverse transcription and quantitative real-time PCR, and its effect on cell migration was examined by Transwell and wound healing assays. The role of circLIFR in tumor metastasis was evaluated via mouse models of tail-vein injection and spleen injection for lung and liver metastasis, respectively.
Distinct circRNA expression signatures were identified among seven types of solid tumors, and the dysregulated circRNAs exhibited cancer-specific expression or shared common expression signatures across cancers. Bioinformatics analyses indicated that aberrant expression of host genes and/or RNA-binding proteins contributed to circRNA dysregulation in cancer. Finally, circLIFR was experimentally validated to be downregulated in six solid tumors and to significantly inhibit cell migration in vitro and tumor metastasis in vivo.
Our results provide a comprehensive landscape of differentially expressed circRNAs in solid tumors and highlight that circRNAs are extensively involved in cancer pathogenesis.
环状 RNA（circRNAs）在正常组织和肿瘤组织之间表达差异，有助于肿瘤的发生和发展。然而，不同癌症类型之间失调的 circRNAs 的综合图谱仍不清楚。
本研究对包括胶质母细胞瘤、食管鳞状细胞癌、肺腺癌、甲状腺癌、结直肠癌、胃癌和肝细胞癌在内的肿瘤组织及其相邻正常样本进行了 Ribo-Zero 转录组测序。利用 CIRCexplorer2 识别 circRNAs，DESeq2 包确定失调的 circRNAs 和基因。通过逆转录和实时定量 PCR 测量 hsa_circ_0072309（circLIFR）的表达，通过 Transwell 和划痕愈合实验检测其对细胞迁移的影响。通过尾静脉注射和脾内注射小鼠模型分别评估 circLIFR 在肺和肝转移中的作用。
在七种实体瘤中鉴定出了不同的 circRNA 表达特征，失调的 circRNAs 表现出癌症特异性表达或在癌症之间具有共同的表达特征。生物信息学分析表明，宿主基因和/或 RNA 结合蛋白的异常表达导致了癌症中 circRNA 的失调。最后，实验验证了 circLIFR 在六种实体瘤中下调，并显著抑制体外细胞迁移和体内肿瘤转移。
我们的研究结果提供了实体瘤中差异表达 circRNAs 的全面图谱，并强调 circRNAs 广泛参与癌症发病机制。
