Adenoid cystic carcinoma (ACC) is a rare malignant epithelial neoplasm that arises in secretory glands and commonly metastasizes to the lungs. MYBL1 is frequently overexpressed in ACC and has been suggested to be a driver of the disease. Here, we identified a circRNA derived from MYBL1 pre-mRNA that accompanied overexpression of MYBL1 in ACC. Overexpression of circMYBL1 was correlated with increased lung metastasis and poor overall survival in ACC patients. Ectopic circMYBL1 overexpression promoted malignant phenotypes and lung metastasis of ACC cells. Mechanistically, circMYBL1 formed a circRNA-protein complex with CCAAT enhancer binding protein beta (CEBPB), which inhibited ubiquitin-mediated degradation and promoted nuclear translocation of CEBPB. In the nucleus, circMYBL1 increased the binding of CEBPB to the CD44 promoter region and enhanced its transcription. In addition, circMYBL1 was enriched in small extracellular vesicles (sEVs) isolated from the plasma of ACC patients. Treatment with sEVs containing circMYBL1 in sEVs enhanced pro-metastatic phenotypes of ACC cells, elevated the expression of CD44 in human pulmonary microvascular endothelial cells (HPMECs), and enhanced the adhesion between HPMECs and ACC cells. Moreover, circMYBL1 encapsulated in sEVs increased the arrest of circulating ACC cells in the lung and enhanced the lung metastatic burden. This data suggests that circMYBL1 is a tumor-promoting circRNA that could serve as a potential biomarker and therapeutic target in ACC.

中文翻译：

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含有circMYBL1的细胞外囊泡诱导腺样囊性癌细胞和肺内皮细胞中CD44促进肺转移

腺样囊性癌（ACC）是一种罕见的恶性上皮肿瘤，发生于分泌腺，通常转移至肺部。 MYBL1 在 ACC 中经常过度表达，并被认为是该疾病的驱动因素。在这里，我们鉴定了一种源自 MYBL1 前 mRNA 的 circRNA，它伴随着 ACC 中 MYBL1 的过度表达。 circMYBL1 的过度表达与 ACC 患者肺转移增加和总生存率较差相关。异位circMYBL1过表达促进ACC细胞的恶性表型和肺转移。从机制上讲，circMYBL1与CCAAT增强子结合蛋白β（CEBPB）形成circRNA-蛋白复合物，抑制泛素介导的降解并促进CEBPB的核转位。在细胞核中，circMYBL1 增加了 CEBPB 与 CD44 启动子区域的结合并增强了其转录。此外，circMYBL1 在从 ACC 患者血浆中分离的小细胞外囊泡 (sEV) 中富集。 sEVs中含有circMYBL1的sEVs治疗增强了ACC细胞的促转移表型，提高了人肺微血管内皮细胞（HPMECs）中CD44的表达，并增强了HPMECs和ACC细胞之间的粘附。此外，封装在 sEV 中的 circMYBL1 增加了肺中循环 ACC 细胞的停滞，并增加了肺转移负担。该数据表明 circMYBL1 是一种促进肿瘤的 circRNA，可以作为 ACC 的潜在生物标志物和治疗靶点。