Tumour necrosis factor-alpha mediates tumour promotion via a PKC alpha- and AP-1-dependent pathway

Oncogene. 2002 Jul 18;21(31):4728-38. doi: 10.1038/sj.onc.1205588.


Tumour necrosis factor-alpha (TNF-alpha) deficient mice (TNF-alpha(-/-) mice) are resistant to skin carcinogenesis. Cellular signalling via the transcription factor complex AP-1 is thought to play a key role in tumour promotion. The induction of a specific subset of AP-1 responsive genes thought to be important for tumour development, namely GM-CSF, MMP-9 and MMP-3, was suppressed in TNF-alpha(-/-) compared to wild-type mouse skin in response to the tumour promotor TPA. The differential induction of these genes correlated with a temporal shift in AP-1 activation and c-Jun expression in TNF-alpha(-/-) compared to wild-type epidermis. The major receptor for TPA-induced signalling in basal keratinocytes, PKC alpha, was also differentially regulated in wild-type compared with TNF-alpha(-/-) epidermis. A marked delay in TPA-induced intracellular translocation and downregulation of PKC alpha was observed in TNF-alpha(-/-) epidermis, which correlated with the deregulated TPA-induced AP-1 activation and c-Jun expression. The frequency of DNA adduct formation and c-Ha-ras mutations was the same in wild-type and TNF-alpha(-/-) epidermis after DMBA treatment, suggesting that TNF-alpha was not involved in tumour initiation. These data suggest that the pro-inflammatory cytokine TNF-alpha is a critical mediator of tumour promotion, acting via a PKC alpha- and AP-1-dependent pathway. This may be one mechanism by which chronic inflammation increases susceptibility to cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / pharmacology
  • Animals
  • Carcinogens* / pharmacology
  • Epidermal Cells
  • Epidermis / drug effects
  • Epidermis / metabolism
  • Isoenzymes / physiology*
  • Keratinocytes / drug effects
  • Kinetics
  • Matrix Metalloproteinases / biosynthesis
  • Matrix Metalloproteinases / genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Protein Kinase C / physiology*
  • Protein Kinase C-alpha
  • RNA, Messenger / biosynthesis
  • Signal Transduction
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / metabolism*
  • Tetradecanoylphorbol Acetate
  • Transcription Factor AP-1 / physiology*
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / physiology*


  • Carcinogens
  • Isoenzymes
  • RNA, Messenger
  • Transcription Factor AP-1
  • Tumor Necrosis Factor-alpha
  • 9,10-Dimethyl-1,2-benzanthracene
  • Prkca protein, mouse
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Matrix Metalloproteinases
  • Tetradecanoylphorbol Acetate