MicroRNA expression profiling of cutaneous squamous cell carcinomas and precursor lesions

Area of Science:

• Dermatology and Oncology
• Molecular Biology
• Gene Expression Profiling

Background:

• Actinic keratoses (AKs) are pre-malignant skin lesions with variable progression rates to invasive squamous cell carcinoma (SCC).
• Current clinical management relies on ad hoc treatment decisions due to the lack of definitive biomarkers for AK progression.
• Understanding the molecular mechanisms underlying AK to SCC transformation is crucial for improved patient care.

Purpose of the Study:

• To characterize the microRNA (miRNA) expression profile across the spectrum of normal skin, photodamaged skin, AK, intraepidermal carcinoma (IEC), and invasive SCC.
• To identify specific miRNAs that are differentially expressed during the progression from AK to SCC.
• To explore the functional role of identified miRNAs in keratinocyte transformation and SCC development.

Main Methods:

• MicroRNA microarray expression profiling of 67 specimens from 27 patients, covering normal skin, photodamaged skin, AK, IEC, and SCC.
• Comprehensive profiling of all miRbase (v.21) miRNAs to identify those associated with SCC progression.
• Validation of miRNA expression using quantitative reverse transcription PCR (qRT-PCR) and in vitro phenotypic assays.

Main Results:

• 234 robustly expressed miRNAs were identified, with 20 showing significant differential expression (p ≤ 0.05, ≥ 10 fold) between normal skin and SCC.
• Hierarchical clustering indicated that AKs, IECs, and SCCs were largely indistinguishable, supporting the continuum of these lesions.
• miR-34a-5p and miR-31-5p exhibited significant differential expression between AKs and IECs, and IECs and SCCs, respectively. miR-31 duplex showed opposing effects in SCC cell lines, suggesting a role in regulating keratinocyte transformation.

Conclusions:

• This study confirms the continuum of AK, IEC, and SCC, highlighting the role of miRNA expression in keratinocyte transformation.
• Dysregulation of specific miRNAs, such as miR-34a-5p and miR-31-5p, is implicated in the progression of skin lesions.
• Development of miRNA-based biomarkers is warranted to aid in the clinical management of patients with high AK burden, optimizing treatment strategies.