Regulation of Hippo-YAP signaling by insulin-like growth factor-1 receptor in the tumorigenesis of diffuse large B-cell lymphoma
Open Access
- 16 June 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Hematology & Oncology
- Vol. 13 (1), 1-15
- https://doi.org/10.1186/s13045-020-00906-1
Abstract
Hippo-Yes-associated protein (YAP) signaling is a key regulator of organ size and tumorigenesis, yet the underlying molecular mechanism is still poorly understood. At present, the significance of the Hippo-YAP pathway in diffuse large B-cell lymphoma (DLBCL) is ill-defined. The expression of YAP in DLBCL was determined in public database and clinical specimens. The effects of YAP knockdown, CRISPR/Cas9-mediated YAP deletion, and YAP inhibitor treatment on cell proliferation and the cell cycle were evaluated both in vitro and in vivo. RNA sequencing was conducted to detect dysregulated RNAs in YAP-knockout DLBCL cells. The regulatory effects of insulin-like growth factor-1 receptor (IGF-1R) on Hippo-YAP signaling were explored by targeted inhibition and rescue experiments. High expression of YAP was significantly correlated with disease progression and poor prognosis. Knockdown of YAP expression suppressed cell proliferation and induced cell cycle arrest in DLBCL cells. Verteporfin (VP), a benzoporphyrin derivative, exerted an anti-tumor effect by regulating the expression of YAP and the downstream target genes, CTGF and CYR61. In vitro and in vivo studies revealed that deletion of YAP expression with a CRISPR/Cas9 genome editing system significantly restrained tumor growth. Moreover, downregulation of IGF-1R expression led to a remarkable decrease in YAP expression. In contrast, exposure to IGF-1 promoted YAP expression and reversed the inhibition of YAP expression induced by IGF-1R inhibitors. Our study highlights the critical role of YAP in the pathogenesis of DLBCL and uncovers the regulatory effect of IGF-1R on Hippo-YAP signaling, suggesting a novel therapeutic strategy for DLBCL.Keywords
Funding Information
- National Natural Science Foundation of China (No. 81800194, No.81770210, No.81473486)
- Natural Science Foundation of Shandong Province (No.ZR2018BH011)
- Key Technology Research and Development Program of Shandong (No.2018CXGC1213, No.2017GSF18189)
- Taishan Scholar Foundation of Shandong Province
- Technology Development Projects of Jinan City (No. 201805065)
This publication has 56 references indexed in Scilit:
- Regulation of the Hippo-YAP Pathway by G-Protein-Coupled Receptor SignalingCell, 2012
- Relapsed/Refractory Diffuse Large B-Cell LymphomaHematology, 2011
- YAP is a candidate oncogene for esophageal squamous cell carcinomaCarcinogenesis: Integrative Cancer Research, 2010
- Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphomaNature, 2009
- The 2008 WHO classification of lymphomas: implications for clinical practice and translational researchHematology, 2009
- Picropodophyllin induces downregulation of the insulin-like growth factor 1 receptor: potential mechanistic involvement of Mdm2 and β-arrestin1Oncogene, 2007
- The Transcriptional Coactivator Yes-Associated Protein Drives p73 Gene-Target Specificity in Response to DNA DamageMolecular Cell, 2005
- Insulin-like growth factors and neoplasiaNature Reviews Cancer, 2004
- Inhibition of the insulin-like growth factor receptor-1 tyrosine kinase activity as a therapeutic strategy for multiple myeloma, other hematologic malignancies, and solid tumorsCancer Cell, 2004
- Tyrosine Kinase Inhibition: An Approach to Drug DevelopmentScience, 1995