title: TNF-α promotes invasive growth through the MET signaling pathway.
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.
authors.affiliation: Candiolo Cancer Institute - FPO (IRCCS), Str. Prov. 142, 10060 Candiolo, Torino, Italy.
authors.forename: Viola
authors.initials: V
authors.lastname: Bigatto
authors.affiliation: Candiolo Cancer Institute - FPO (IRCCS), Str. Prov. 142, 10060 Candiolo, Torino, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: De Bacco
authors.affiliation: Candiolo Cancer Institute - FPO (IRCCS), Str. Prov. 142, 10060 Candiolo, Torino, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Casanova
authors.affiliation: Candiolo Cancer Institute - FPO (IRCCS), Str. Prov. 142, 10060 Candiolo, Torino, Italy; Department of Oncology, University of Torino, Italy.
authors.forename: Gigliola
authors.initials: G
authors.lastname: Reato
authors.affiliation: Candiolo Cancer Institute - FPO (IRCCS), Str. Prov. 142, 10060 Candiolo, Torino, Italy; Department of Oncology, University of Torino, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Lanzetti
authors.affiliation: Candiolo Cancer Institute - FPO (IRCCS), Str. Prov. 142, 10060 Candiolo, Torino, Italy; Department of Oncology, University of Torino, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Isella
authors.affiliation: Candiolo Cancer Institute - FPO (IRCCS), Str. Prov. 142, 10060 Candiolo, Torino, Italy.
authors.forename: Ivana
authors.initials: I
authors.lastname: Sarotto
authors.affiliation: Candiolo Cancer Institute - FPO (IRCCS), Str. Prov. 142, 10060 Candiolo, Torino, Italy; Department of Oncology, University of Torino, Italy. Electronic address: antonella.cignetto@ircc.it.
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.affiliation: Candiolo Cancer Institute - FPO (IRCCS), Str. Prov. 142, 10060 Candiolo, Torino, Italy; Department of Oncology, University of Torino, Italy. Electronic address: carla.boccaccio@ircc.it.
authors.forename: Carla
authors.initials: C
authors.lastname: Boccaccio
mesh_terms: D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D009361:Neoplasm Invasiveness / Q000235:genetics; D019899:Paracrine Communication / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: C066855:HGF protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: HGF; Inflammation; Invasion; MET; MET inhibitor; TNF-α