环状DHTKD1通过上调CXCL5促进膀胱癌的淋巴转移。

circDHTKD1 promotes lymphatic metastasis of bladder cancer by upregulating CXCL5.

作者信息

Lu Qun, Yin Haoli, Deng Yongming, Chen Wei, Diao Wenli, Ding Meng, Cao Wenmin, Fu Yao, Mo Wenjing, Chen Xiaoqing, Zhang Qing, Zhao Xiaozhi, Guo Hongqian

机构信息

Department of Urology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Institute of Urology, Nanjing University, Nanjing, Jiangsu, China.

Department of Pathology, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China.

出版信息

Cell Death Discov. 2022 May 3;8(1):243. doi: 10.1038/s41420-022-01037-x.

Lymph node (LN) metastasis is associated with unfavorable prognosis of bladder cancer (BCa). Although lymphangiogenesis is functionally important in LN metastasis of tumors, the potential mechanism in BCa remains unclear. Here, we clarified a regulatory mechanism of circRNA-mediated lymphangiogenesis and LN metastasis in BCa based on next-generation sequencing data. We revealed that circDHTKD1 was positively associated with LN metastasis and significantly upregulated in BCa. By analyzing the co-expression patterns of circDHTKD1 and differentially expressed mRNAs, we identified that circDHTKD1 facilitated lymphangiogenesis by upregulating CXCL5. Mechanistically, circDHTKD1 directly interacted with miR-149-5p, and antagonized the repression of miR-149-5p on CXCL5. Furthermore, circDHTKD1-induced CXCL5 expression recruited and activated neutrophils, which participated in lymphangiogenesis by secreting VEGF-C. Our study supports circDHTKD1 as a promising diagnostic and therapeutic target for LN metastasis in BCa.

淋巴结（LN）转移与膀胱癌（BCa）的不良预后相关。尽管淋巴管生成在肿瘤的LN转移中具有重要功能，但BCa中的潜在机制仍不清楚。在此，我们基于下一代测序数据阐明了circRNA介导的BCa淋巴管生成和LN转移的调控机制。我们发现circDHTKD1与LN转移呈正相关，且在BCa中显著上调。通过分析circDHTKD1与差异表达mRNA的共表达模式，我们确定circDHTKD1通过上调CXCL5促进淋巴管生成。机制上，circDHTKD1直接与miR-149-5p相互作用，并拮抗miR-149-5p对CXCL5的抑制作用。此外，circDHTKD1诱导的CXCL5表达招募并激活中性粒细胞，中性粒细胞通过分泌VEGF-C参与淋巴管生成。我们的研究支持circDHTKD1作为BCa中LN转移的一个有前景的诊断和治疗靶点。