Epidermal p65/NF-κB signalling is essential for skin carcinogenesis

Area of Science:

• Oncology
• Dermatology
• Molecular Biology

Background:

• Nuclear factor kappa B (NF-κB) signaling has dual roles in cancer, acting as both tumor-promoting and tumor-suppressing.
• In epidermal keratinocytes, NF-κB was previously thought to primarily inhibit growth and suppress tumors.

Purpose of the Study:

• To investigate the role of p65/RelA, a key component of NF-κB, in keratinocytes during skin carcinogenesis.
• To determine if p65-dependent NF-κB signaling in keratinocytes promotes or suppresses skin tumor development.

Main Methods:

• Utilized a mouse model with keratinocyte-restricted p65/RelA deficiency.
• Induced skin carcinogenesis using 7,12-dimethylbenz(a)anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA).
• Assessed DNA damage-induced cell death in vivo and in vitro, epidermal hyperplasia, and skin inflammation, including cytokine and chemokine expression.

Main Results:

• Mice lacking p65 in keratinocytes were resistant to DMBA/TPA-induced skin carcinogenesis.
• p65 deficiency sensitized keratinocytes to DNA damage-induced death, preventing tumor initiation.
• Lack of p65 significantly inhibited TPA-induced epidermal hyperplasia and inflammation by suppressing proinflammatory mediators.

Conclusions:

• p65-dependent NF-κB signaling in keratinocytes promotes skin carcinogenesis.
• This promotion occurs by protecting keratinocytes from DNA damage-induced death and by fostering a pro-tumorigenic inflammatory microenvironment.
• Targeting keratinocyte NF-κB signaling may offer a therapeutic strategy for preventing skin cancer.