Novel CARD11 Mutations in Human Cutaneous Squamous Cell Carcinoma Lead to Aberrant NF-κB Regulation

Area of Science:

• Dermatology
• Molecular Biology
• Oncology

Background:

• NF-κB signaling is vital for skin cell growth and differentiation.
• Dysregulation of NF-κB is implicated in skin diseases like psoriasis and cutaneous squamous cell carcinoma (cSCC).
• Caspase recruitment domain (CARD)-containing scaffold proteins regulate NF-κB signaling.

Purpose of the Study:

• To investigate the role of CARD11, a CARD scaffold protein, in the development of cSCC.
• To identify mutations in CARD11 in cSCC patients and assess their functional impact on NF-κB signaling.

Main Methods:

• Analysis of CARD11 gene mutations in 111 cSCC samples.
• Assessment of CARD11 protein and mRNA expression in normal skin and cSCC.
• Evaluation of NF-κB signaling activation by novel CARD11 variants.

Main Results:

• Mutations in CARD11 were identified in over 38% of cSCCs.
• Novel CARD11 variants outside the coiled-coil domain resulted in constitutively active NF-κB signaling.
• CARD11 expression was elevated in cSCC compared to normal skin, with mutations also found in surrounding skin.

Conclusions:

• CARD11 mutations are frequent in cSCC and drive aberrant NF-κB signaling.
• CARD11 alterations may represent an early event in cSCC pathogenesis.
• Targeting CARD11-mediated pathways could offer new therapeutic strategies for cSCC.