Regulation of Hippo-YAP signaling by insulin-like growth factor-1 receptor in the tumorigenesis of diffuse large B-cell lymphoma

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Small extracellular vesicles with LncRNA H19 “overload”: YAP Regulation as a Tendon Repair Therapeutic Tactic

“…The Hippo-YAP signaling pathway is known as a pivotal regulator of organ growth and tissue regeneration ( Moya and Halder, 2019 ). In recent years, there have been an increasing number of regenerative medicine strategies in different organs targeting this pathway ( Aharonov et al., 2020 ; Aloia et al., 2019 ; Alsamman et al., 2020 ; Brusatin et al., 2018 ; Cheung et al., 2020 ; Gilbert-Honick et al., 2020 ; Hageman et al., 2020 ; Li et al., 2020 ; Sprangers et al., 2020 ; Zhou et al., 2020 ). Thus, the Hippo-YAP signaling pathway has great potential and is worthy of further study to better promote the development of regenerative medicine.…”

Cell type-specific Pathways Associated with Diffuse Large B-cell Lymphoma Metastasis Related to Neuro-Diseases

“…Though it is evidenced that, DLBCL samples with high expression rate of YAP shows poor prognosis. A recent study demonstrated that insulin-like growth factor-1 receptor (IGF-1R) acted as an upstream negative regulator of Hippo-YAP signaling [37]. It is extremely interesting to note that IGF-1R inhibition resulted in decreased activation of Hippo-YAP signalling in DLBCL.…”

New Insights into YES-Associated Protein Signaling Pathways in Hematological Malignancies: Diagnostic and Therapeutic Challenges

“…An amplified expression of YAP was remarkably associated with lymphoma progression and a bad outcome. A knockdown of YAP expression reduced cell growth and caused cell-cycle arrest in DLBCL cells [ 128 ].…”