TNF-α promotes invasive growth through the MET signaling pathway

Viola Bigatto, Francesca De Bacco, Elena Casanova, Gigliola Reato, Letizia Lanzetti, Claudio Isella, Ivana Sarotto, Paolo M. Comoglio, Carla Boccaccio

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The inflammatory cytokine Tumor Necrosis Factor Alpha (TNF-α) is known to trigger invasive growth, a physiological property for tissue healing, turning into a hallmark of progression in cancer. However, the invasive response to TNF-α relies on poorly understood molecular mechanisms. We thus investigated whether it involves the MET oncogene, which regulates the invasive growth program by encoding the tyrosine kinase receptor for Hepatocyte Growth Factor (HGF). Here we show that the TNF-α pro-invasive activity requires MET function, as it is fully inhibited by MET-specific inhibitors (small-molecules, antibodies, and siRNAs). Mechanistically, we show that TNF-α induces MET transcription via NF-κB, and exploits MET to sustain MEK/ERK activation and Snail accumulation, leading to E-cadherin downregulation. We then show that TNF-α not only induces MET expression in cancer cells, but also HGF secretion by fibroblasts. Consistently, we found that, in human colorectal cancer tissues, high levels of TNF-α correlates with increased expression of both MET and HGF. These findings suggest that TNF-α fosters a HGF/MET pro-invasive paracrine loop in tumors. Targeting this ligand/receptor pair would contribute to prevent cancer progression associated with inflammation.

Original languageEnglish
Pages (from-to)377-388
Number of pages12
JournalMolecular Oncology
Volume9
Issue number2
DOIs
Publication statusPublished - Feb 1 2015

Fingerprint

Tumor Necrosis Factor-alpha
Growth
Hepatocyte Growth Factor
Neoplasms
Mitogen-Activated Protein Kinase Kinases
Snails
Receptor Protein-Tyrosine Kinases
Cadherins
Oncogenes
Colorectal Neoplasms
Down-Regulation
Fibroblasts
Cytokines
Ligands
Inflammation
Antibodies

Keywords

  • HGF
  • Inflammation
  • Invasion
  • MET
  • MET inhibitor
  • TNF-α

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Medicine
  • Medicine(all)

Cite this

TNF-α promotes invasive growth through the MET signaling pathway. / Bigatto, Viola; De Bacco, Francesca; Casanova, Elena; Reato, Gigliola; Lanzetti, Letizia; Isella, Claudio; Sarotto, Ivana; Comoglio, Paolo M.; Boccaccio, Carla.

In: Molecular Oncology, Vol. 9, No. 2, 01.02.2015, p. 377-388.

Research output: Contribution to journalArticle

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