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Targeting EphA2 suppresses hepatocellular carcinoma initiation and progression by dual inhibition of JAK1/STAT3 and AKT signaling

Authors :
Hao Wang
Wei Hou
Aldeb Perera
Carlee Bettler
Jordan R. Beach
Xianzhong Ding
Jun Li
Mitchell F. Denning
Asha Dhanarajan
Scott J. Cotler
Cara Joyce
Jun Yin
Fowsiyo Ahmed
Lewis R. Roberts
Wei Qiu
Source :
Cell Reports, Vol 34, Iss 8, Pp 108765- (2021)
Publication Year :
2021
Publisher :
Elsevier, 2021.

Abstract

Summary: Hepatocellular carcinoma (HCC) remains one of the deadliest malignancies worldwide. One major obstacle to treatment is a lack of effective molecular-targeted therapies. In this study, we find that EphA2 expression and signaling are enriched in human HCC and associated with poor prognosis. Loss of EphA2 suppresses the initiation and growth of HCC both in vitro and in vivo. Furthermore, CRISPR/CAS9-mediated EphA2 inhibition significantly delays tumor development in a genetically engineered murine model of HCC. Mechanistically, we discover that targeting EphA2 suppresses both AKT and JAK1/STAT3 signaling, two separate oncogenic pathways in HCC. We also identify a small molecule kinase inhibitor of EphA2 that suppresses tumor progression in a murine HCC model. Together, our results suggest EphA2 as a promising therapeutic target for HCC.

Details

Language :
English
ISSN :
22111247
Volume :
34
Issue :
8
Database :
Directory of Open Access Journals
Journal :
Cell Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.5490c094d7e84abdba870ac14d82cd3c
Document Type :
article
Full Text :
https://doi.org/10.1016/j.celrep.2021.108765