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BCL-2 isoform β promotes angiogenesis by TRiC-mediated upregulation of VEGF-A in lymphoma

Oncogene volume 41, pages 3655–3663 (2022)Cite this article

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Abstract

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.

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Fig. 1: Modeling double expressor lymphoma-associated Bcl-2β upregulation with CRISPRa in mice.
Fig. 2: Bcl-2β promotes tumorigenesis and angiogenesis.
Fig. 3: Bcl-2β promotes angiogenesis through increased VEGF-A secretion.
Fig. 4: Bcl-2β interacts with the TRiC, which is essential for angiogenesis.
Fig. 5: The correlation of the expression levels of BCL-2β and TRiC components with angiogenesis in human DLBCL.
Fig. 6: Schematic illustration of Bcl-2β-TRiC-VEGF-A working model.

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Acknowledgements

We thank Dr. Yuquan Wei for his generous support. We thank Dr. Ruizhan Tong and Dr. Yinglan Zhao for their technical assistance. We thank Dr. Jianjun Li for his clinical assistance. We thank all the lab members in the Chen and Liu laboratory for their insightful advice and kindly support. The results published here are in whole or part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. This work was supported by the National Natural Science Foundation of China (grants 82130007, 81670182, and 82073221), the National Key R&D Program of China (grants 2017YFA0505600 and 2018YFC2000305), the Sichuan Science and Technology Program (grants 2018JZ0077), and the 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (grants ZYJC21009 and ZYYC20007).

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  1. These authors contributed equally: Xiaohang Hang, Lei Zhao, Baohong Wu.

Authors and Affiliations

  1. Department of Hematology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Xiaohang Hang, Lei Zhao, Baohong Wu, Shujun Li, Pengpeng Liu, Jing Xu, Pengliang Chi, Chong Chen, Ting Niu & Yu Liu

  2. Department of General Practice and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China

    Xinyuan Wang & Lunzhi Dai

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  1. Xiaohang Hang
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Contributions

YL, XH, and LZ designed this study, XH, BW, SL, XW, PC carried out the experiments, LZ performed bioinformatics analyses, XH and LZ prepared and assembled the figure. PL and JX provide clinical samples and analyzed data. YL, CC, TN, and LD supervised the study and analyzed data. XH, LZ, and YL wrote the manuscript.

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Correspondence to Lunzhi Dai or Yu Liu.

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Hang, X., Zhao, L., Wu, B. et al. BCL-2 isoform β promotes angiogenesis by TRiC-mediated upregulation of VEGF-A in lymphoma. Oncogene 41, 3655–3663 (2022). https://doi.org/10.1038/s41388-022-02372-0

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