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EphA2-to-YAP pathway drives gastric cancer growth and therapy resistance

Changhao Huang1,2,3, Weijie Yuan1,2, Chen Lai2,3

  • 1Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China.

International Journal of Cancer
|August 4, 2019
PubMed

Insights

Erythropoietin-producing hepatocellular receptor A2 (EphA2) activates Yes-associated protein (YAP) in gastric cancer, driving tumor growth and chemotherapy resistance. Targeting this EphA2-YAP pathway offers a new therapeutic strategy for gastric cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Yes-associated protein (YAP) is a key transcriptional coactivator regulating cell proliferation and tissue homeostasis.
  • YAP activity is typically inhibited by the Hippo pathway kinases through phosphorylation.
  • Gastric cancer (GC) progression and therapy resistance remain significant clinical challenges.

Purpose of the Study:

  • To investigate the role of receptor tyrosine kinase (RTK) EphA2 in regulating YAP activity in gastric cancer.
  • To elucidate the molecular mechanisms underlying EphA2-mediated YAP activation and its impact on GC.
  • To evaluate the therapeutic potential of targeting the EphA2-YAP axis in gastric cancer.

Main Methods:

  • Co-immunoprecipitation assays to confirm EphA2-YAP interaction.
  • Western blotting to assess YAP phosphorylation, stability, and nuclear translocation.
  • Cell proliferation assays and xenograft mouse models to evaluate tumor growth.
  • Analysis of clinical GC samples for EphA2 and YAP co-expression.

Main Results:

  • EphA2 directly interacts with and phosphorylates YAP in GC cells, leading to YAP stabilization and nuclear translocation.
  • EphA2-induced YAP activation promotes GC cell proliferation and confers resistance to chemotherapy.
  • Knockdown of YAP inhibits EphA2-driven tumor growth in vivo.
  • Coactivation of EphA2 and YAP is observed in human GC and correlates with disease recurrence.

Conclusions:

  • A novel EphA2-to-YAP signaling pathway drives gastric cancer growth, progression, and therapy resistance.
  • This pathway represents a promising therapeutic target for gastric cancer, especially for chemotherapy-resistant cases.
  • Targeting the EphA2-YAP axis could offer a new strategy for improving GC treatment outcomes.
Keywords:
EphA2YAPchemoresistancegastric cancerphosphorylation

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