title: The leukemia inhibitory factor (LIF) and p21 mediate the TGFβ tumor suppressive effects in human cutaneous melanoma.
abstract: BACKGROUND
  Cutaneous melanoma is the most lethal skin cancer and its incidence in developed countries has dramatically increased over the past decades. Localized tumors are easily treated by surgery, but advanced melanomas lack efficient treatment and are associated with very poor outcomes. Thus, understanding the processes underlying melanoma development and progression is critical. The Transforming Growth Factor beta (TGFβ) acts as a potent tumor suppressor in human melanoma, by inhibiting cell growth and preventing cellular migration and invasion.
  
  
  METHODS
  In this study, we aimed at elucidating the molecular mechanisms underlying TGFβ-mediated tumor suppression. Human cutaneous melanoma cell lines, derived from different patients, were used to assess for cell cycle analysis, apoptosis/caspase activity and cell migration. Techniques involved immunoblotting, immunohistochemistry, real time PCR and luciferase reporter assays.
  
  
  RESULTS
  We found the leukemia inhibitory factor (LIF) to be strongly up-regulated by TGFβ in melanoma cells, defining LIF as a novel TGFβ downstream target gene in cutaneous melanoma. Interestingly, we also showed that TGFβ-mediated LIF expression is required for TGFβ-induced cell cycle arrest and caspase-mediated apoptosis, as well as for TGFβ-mediated inhibition of cell migration. Moreover, we found that TGFβ-mediated LIF expression leads to activation of transcription of the cell cycle inhibitor p21 in a STAT3-dependent manner, and further showed that p21 is required for TGFβ/LIF-mediated cell cycle arrest and TGFβ-induced gene activation of several pro-apoptotic genes.
  
  
  CONCLUSIONS
  Together, our results define the LIF/p21 signaling cascade as a novel tumor suppressive-like pathway in melanoma, acting downstream of TGFβ to regulate cell cycle arrest and cell death, further highlight new potential therapeutic strategies for the treatment of cutaneous melanoma.
authors.affiliation: Division of Medical Oncology, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada. laure.humbert@mail.mcgill.ca.
authors.forename: Laure
authors.initials: L
authors.lastname: Humbert
authors.affiliation: Division of Medical Oncology, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada. mostafa.ghozlan@mail.mcgill.ca.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Ghozlan
authors.affiliation: Division of Medical Oncology, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada. lucie.canaff@gmail.com.
authors.forename: Lucie
authors.initials: L
authors.lastname: Canaff
authors.affiliation: Division of Medical Oncology, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada. jun.tian3@mail.mcgill.ca.
authors.forename: Jun
authors.initials: J
authors.lastname: Tian
authors.affiliation: Division of Medical Oncology, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada. JJ.Lebrun@mcgill.ca.|Department of Medicine, Royal Victoria Hospital, Suite H7.66, 687 Pine Avenue West, H3A 1A1, Montreal, QC, Canada. JJ.Lebrun@mcgill.ca.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Lebrun
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053605:Leukemia Inhibitory Factor / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D061251:Primary Cell Culture; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D000096142:Cutaneous Malignant Melanoma
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; D050796:STAT3 Transcription Factor; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1