Targeting EphA2 suppresses hepatocellular carcinoma initiation and progression by dual inhibition of JAK1/STAT3 and AKT signaling
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
Affiliations
Hao Wang
Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
Wei Hou
Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
Aldeb Perera
Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
Carlee Bettler
Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
Jordan R. Beach
Department of Cell and Molecular Physiology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
Xianzhong Ding
Department of Pathology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
Jun Li
Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN, USA
Mitchell F. Denning
Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
Asha Dhanarajan
Department of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
Scott J. Cotler
Department of Medicine, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
Cara Joyce
Department of Public Health Sciences, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
Jun Yin
Department of Medicine, Mayo Clinic, Rochester, MN, USA
Fowsiyo Ahmed
Department of Medicine, Mayo Clinic, Rochester, MN, USA
Lewis R. Roberts
Department of Medicine, Mayo Clinic, Rochester, MN, USA
Wei Qiu
Department of Surgery, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA; Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA; Corresponding author
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.
