Reduced SMAD2/3 activation independently predicts increased depth of human cutaneous squamous cell carcinoma

Area of Science:

• Oncology
• Dermatology
• Molecular Biology

Background:

• Cutaneous squamous cell carcinoma (cSCC) incidence is increasing, with aggressive forms having poor prognoses.
• Transforming growth factor beta (TGF-β) signaling pathways have complex roles in skin cancer, acting as both a suppressor and promoter.
• Limited research exists on TGF-β/activin signaling in human skin, hyper-proliferative disorders, and cSCC.

Purpose of the Study:

• To investigate the role of canonical TGF-β/activin signaling, via phosphorylated SMAD proteins (phospho-SMADs), in normal human skin, hyper-proliferative skin conditions, and cSCC.
• To determine if TGF-β/activin signaling acts as a tumor suppressor or promoter in human cSCC.
• To correlate TGF-β/activin signaling levels with cSCC progression and thickness.

Main Methods:

• Validated antibodies for immunohistochemistry to detect phospho-SMAD2 and phospho-SMAD3.
• Analyzed a tissue microarray of human primary invasive cSCC (n=238), cSCC in situ (n=2), and keratocanthoma (n=9) tissues.
• Compared lesional and perilesional cSCC tissues with normal human scalp tissues (n=10).

Main Results:

• Phospho-SMAD2 and SMAD3 were detected in normal interfollicular epidermal keratinocytes, inner root sheath, matrix cells, and Keratin 15 positive cells.
• Lesional cSCC tissue showed significantly reduced levels of activated SMAD2/3 compared to perilesional tissue.
• Reduced phospho-SMAD levels in cSCC tissue correlated inversely with tumor thickness, suggesting a link to disease progression.

Conclusions:

• The findings support a tumor suppressor role for canonical TGF-β/activin signaling (via SMAD2/3 activation) in human cSCC.
• Decreased TGF-β/activin signaling is associated with cSCC progression and increased tumor thickness.
• Further research into TGF-β/activin signaling could offer therapeutic targets for aggressive cSCC.