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

Research output: Contribution to journalArticlepeer-review

Abstract

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. Wang et al. define the role of receptor tyrosine kinase EphA2 in the development of hepatocellular carcinoma and elucidate its mechanisms of action. Inhibition of EphA2 is a promising strategy for the treatment of advanced hepatocellular carcinoma.

Original languageEnglish (US)
Article number108765
JournalCell reports
Volume34
Issue number8
DOIs
StatePublished - Feb 23 2021

Keywords

  • AKT
  • EphA2
  • HCC
  • JAK1
  • STAT3

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Targeting EphA2 suppresses hepatocellular carcinoma initiation and progression by dual inhibition of JAK1/STAT3 and AKT signaling'. Together they form a unique fingerprint.

Cite this