Sun Xianting, Fang Jianchen, Ye Fen, Zhang Shuxian, Huang Honghui, Hou Jian, Wang Ting
Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
Front Oncol. 2022 Apr 12;12:871788. doi: 10.3389/fonc.2022.871788. eCollection 2022.
Diffuse large B-cell lymphoma (DLBCL) is one type of highly heterogeneous lymphoid malignancy with 30%~40% of patients experiencing treatment failure. Novel risk stratification and therapeutic approaches for DLBCL are urgently needed. Endothelial-to-mesenchymal transition (EndMT), which contributes to tumor angiogenesis, metastasis, drug resistance, and cancer-associated fibroblast generation, has been detected in the microenvironment of many types of cancers. However, the existence of EndMT in the hematological malignancies microenvironment remains unknown. Here, we identified the existence of EndMT in DLBCL-associated endothelial cells and the clinical relevance of EndMT markers in DLBCL, which was associated with advanced clinical stage and poor prognosis. experiments confirmed that DLBCL cells stimulated angiogenesis and EndMT of human umbilical vein endothelial cells (HUVECs). We further unveiled the molecular mechanisms underlying this process. We demonstrated that WNT10A, a WNT family member overexpressed in DLBCL tissues and correlated with clinical features in DLBCL, promoted EndMT through glycogen synthase kinase 3β (GSK3β)/β-catenin/snail signaling. WNT10A inhibited the binding of GSK3β to β-catenin/snail, resulting in β-catenin and snail nuclear accumulation and target gene transcription. Silencing β-catenin and snail respectively attenuated WNT10A-induced angiogenesis and EndMT. The interplay between β-catenin-dependent and snail-dependent signaling was also confirmed in this study. Collectively, these findings identified that WNT10A/GSK3β/β-catenin/snail pathway performed vital roles in DLBCL-induced EndMT and indicated that EndMT markers and WNT10A may serve as novel predictors of clinical outcome.
弥漫性大B细胞淋巴瘤（DLBCL）是一种高度异质性的淋巴系统恶性肿瘤，30%~40%的患者会出现治疗失败。DLBCL迫切需要新的风险分层和治疗方法。内皮-间充质转化（EndMT）参与肿瘤血管生成、转移、耐药以及癌症相关成纤维细胞的生成，已在多种癌症的微环境中被检测到。然而，血液系统恶性肿瘤微环境中是否存在EndMT尚不清楚。在此，我们证实了EndMT在DLBCL相关内皮细胞中的存在以及EndMT标志物在DLBCL中的临床相关性，其与晚期临床分期和不良预后相关。实验证实DLBCL细胞可刺激人脐静脉内皮细胞（HUVECs）的血管生成和EndMT。我们进一步揭示了这一过程的分子机制。我们发现WNT10A，一种在DLBCL组织中过表达且与DLBCL临床特征相关的WNT家族成员，通过糖原合酶激酶3β（GSK3β）/β-连环蛋白/蜗牛信号通路促进EndMT。WNT10A抑制GSK3β与β-连环蛋白/蜗牛的结合，导致β-连环蛋白和蜗牛在细胞核内积累并启动靶基因转录。分别沉默β-连环蛋白和蜗牛可减弱WNT10A诱导的血管生成和EndMT。本研究还证实了β-连环蛋白依赖性和蜗牛依赖性信号之间的相互作用。总之，这些发现表明WNT10A/GSK3β/β-连环蛋白/蜗牛通路在DLBCL诱导的EndMT中起关键作用，并提示EndMT标志物和WNT10A可能作为临床结局的新预测指标。
