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TROP2 is epigenetically inactivated and modulates IGF-1R signalling in lung adenocarcinoma

Jau-Chen Lin1, Yi-Ying Wu, Jing-Yi Wu

  • 1Department of Respiratory Therapy, Fu-Jen Catholic University, New Taipei, Taiwan.

EMBO Molecular Medicine
|March 16, 2012
PubMed

Insights

Trop-2 (trophoblast cell surface antigen 2) inactivation, via loss of heterozygosity or DNA methylation, promotes lung cancer growth. Restoring Trop-2 expression suppresses tumor cell proliferation and signaling pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Trop-2 (trophoblast cell surface antigen 2) is a cell surface glycoprotein with specific extracellular domains.
  • Reduced Trop-2 expression is observed in lung adenocarcinoma compared to normal tissues.

Purpose of the Study:

  • To investigate the mechanisms of Trop-2 downregulation in lung cancer.
  • To elucidate the role of Trop-2 in regulating lung cancer cell proliferation and signaling pathways.

Main Methods:

  • Bisulphite sequencing and methylation-specific PCR to assess DNA methylation.
  • 5-Aza-2'-deoxycytidine treatment to reverse hypermethylation.
  • RNA interference (shRNA) to silence Trop-2 expression.
  • Western blotting and cell proliferation assays to evaluate protein expression and tumor growth.

Main Results:

  • Loss of heterozygosity (LOH) or promoter hypermethylation causes Trop-2 inactivation.
  • Demethylation treatment restored Trop-2 mRNA and protein levels.
  • Enforced Trop-2 expression suppressed AKT and ERK activation, reducing cell proliferation and colony formation.
  • Trop-2 silencing enhanced AKT activation and tumor growth.
  • Trop-2 attenuates IGF-1R signaling-mediated AKT/β-catenin and ERK activation.

Conclusions:

  • Trop-2 inactivation, through LOH or DNA methylation, contributes to lung cancer progression.
  • Trop-2 acts as a tumor suppressor by inhibiting IGF-1R signaling and tumor growth.

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