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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
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A targetable HB-EGF-CITED4 axis controls oncogenesis in lung cancer

C-H Hsieh1, Y-T Chou2, M-H Kuo2

  • 1Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, ROC.

Oncogene
|January 17, 2017
PubMed

Insights

Heparin-binding (HB)-EGF drives lung cancer growth by activating CITED4 and MYC. Inhibiting HB-EGF with CRM197 shows promise for treating lung cancer, offering a new therapeutic target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Aberrant epidermal growth factor receptor (EGFR) signaling is crucial in lung cancer development.
  • Targeted therapies exist for mutated EGFR, but not for wild-type EGFR or its ligands.
  • Heparin-binding (HB)-EGF, an EGF family member, is implicated in a subset of lung cancers.

Purpose of the Study:

  • To investigate the role of HB-EGF in lung cancer proliferation.
  • To elucidate the downstream signaling pathway of HB-EGF.
  • To evaluate HB-EGF as a potential therapeutic target in lung cancer.

Main Methods:

  • RNA interference to silence HB-EGF.
  • Analysis of CITED4 induction via signal transducer and activator of transcription 3 (STAT3) pathway.
  • Assessment of CITED4 interaction with MYC and CCND1 promoter activity.
  • Correlation analysis of HB-EGF and CITED4 expression in patient tumors.
  • In vitro and in vivo experiments using CRM197 to inhibit HB-EGF.

Main Results:

  • HB-EGF expression was high in a subset of lung cancers, driving proliferation.
  • Silencing HB-EGF inhibited cell cycle progression.
  • HB-EGF induced CITED4 expression through a STAT3-dependent pathway.
  • CITED4 interacted with MYC, enhancing CCND1 promoter activity and cell cycle progression.
  • HB-EGF and CITED4 expression positively correlated in lung tumors; HB-EGF predicted poor survival.
  • CRM197 treatment significantly reduced tumor cell growth in vitro and in vivo.

Conclusions:

  • CITED4 acts as a molecular switch in HB-EGF-mediated lung cancer growth.
  • HB-EGF signaling represents a novel therapeutic target for lung cancer intervention.

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