Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of General Practice and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Oncogene. 2022 Jul;41(28):3655-3663. doi: 10.1038/s41388-022-02372-0. Epub 2022 Jun 14.
Bcl-2 (B-cell lymphoma 2), the first identified anti-apoptosis factor, encodes two transcripts, the long isoform α and the short isoform β. The current understanding of the Bcl-2 function mainly focuses on Bcl-2α, while little is known about the function of Bcl-2β, which lacks the transmembrane domain and contains 10 unique amino acids at the C-terminus instead. Here, we analyzed the expressions of BCL-2 two isoforms in diffused large B-cell lymphoma (DLBCL) and found a significant positive correlation between them. Then, with the CRISPR/Cas9-based transcriptional activator (CRISPRa), we generated mouse B-cell lymphomas with Bcl-2 upregulation from the endogenous locus, in which both Bcl-2α and Bcl-2β levels were increased. Bcl-2β itself promoted angiogenesis both in vitro and in vivo through increased vascular endothelial growth factor A (VEGF-A). Inhibiting VEGF receptors with Axitinib reduced angiogenesis induced by Bcl-2β overexpression. Co-immunoprecipitation and mass spectrometry analysis revealed that Bcl-2β interacted with the T-complex protein ring complex (TRiC). Disruption of TRiC significantly impaired the angiogenesis-promoting activity of Bcl-2β, indicated by reduced VEGF-A protein level and HUVEC tube formation. Thus, our study suggests that Bcl-2 isoform β plays a role in promoting tumor angiogenesis through the Bcl-2β-TRiC-VEGF-A axis.
Bcl-2（B 细胞淋巴瘤 2）是第一个被鉴定的抗细胞凋亡因子，它编码两种转录本，长型 α 和短型 β。目前对 Bcl-2 功能的理解主要集中在 Bcl-2α 上，而对缺乏跨膜结构域且 C 末端含有 10 个独特氨基酸的 Bcl-2β 的功能知之甚少。在这里，我们分析了弥漫性大 B 细胞淋巴瘤（DLBCL）中 BCL-2 两种异构体的表达情况，发现它们之间存在显著的正相关。然后，我们使用基于 CRISPR/Cas9 的转录激活剂（CRISPRa），从内源性基因座中产生了 Bcl-2 上调的小鼠 B 细胞淋巴瘤，其中 Bcl-2α 和 Bcl-2β 的水平都增加了。Bcl-2β 本身通过增加血管内皮生长因子 A（VEGF-A）在体外和体内都促进了血管生成。用 Axitinib 抑制血管内皮生长因子受体可减少 Bcl-2β 过表达诱导的血管生成。共免疫沉淀和质谱分析显示，Bcl-2β 与 T 复合物蛋白环复合物（TRiC）相互作用。破坏 TRiC 显著削弱了 Bcl-2β 促进血管生成的活性，表现为 VEGF-A 蛋白水平降低和 HUVEC 管形成减少。因此，我们的研究表明，Bcl-2 异构体 β 通过 Bcl-2β-TRiC-VEGF-A 轴在促进肿瘤血管生成中发挥作用。
