Circulating microRNA biomarkers in melanoma and non-melanoma skin cancer

ABSTRACT

Introduction

Skin cancer is the most common type of cancer and is classified in melanoma and non-melanoma cancers, which include basal cell, squamous cell, and Merkel cell carcinoma. Specific microRNAs are dysregulated in each skin cancer type. MicroRNAs act as oncogene or tumor suppressor gene regulators and are actively released from tumor cells in the circulation. Cell-free microRNAs serve many, and possibly yet unexplored, functional roles, but their presence and abundance in the blood has been investigated as disease biomarker. Indeed, specific microRNAs can be isolated and quantified in the blood, usually in serum or plasma fractions, where they are uncommonly stable. MicroRNA levels reflect underlying conditions and have been associated with skin cancer presence, stage, evolution, or therapy efficacy.

Areas covered

In this review, we summarize the state of the art on circulating microRNAs detectable in skin cancer patients including all the studies that performed microRNA identification and quantification in the circulation using appropriate sample size and statistics and providing detailed methodology, with a specific focus on diagnostic and prognostic biomarkers.

Expert Opinion

Circulating microRNAs display a relevant biomarker potential. We expect the development of methodological guidelines and standardized protocols for circulating miRNA quantification in clinical settings.

KEYWORDS:

• Basal cell carcinoma
• biomarkers
• cutaneous squamous cell carcinoma
• liquid biopsy
• melanoma
• Merkel cell carcinoma
• microRNA
• plasma
• serum
• skin cancer

Abbreviations

Serine/threonine-protein kinase B-raf (BRAF)

Mitogen-activated protein kinase kinase (MEK)

Immune checkpoint inhibitors (ICI)

microRNAs (miRNAs)

3’ untranslated regions (3ʹUTR)

Microprocessor Complex Subunit DGCR8 (DGCR8)

Transactivation response element RNA-binding protein (TRBP) protein

Argonaute (AGO)

miRNA-Induced Silencing Complex (miRISC)

Extracellular vesicles (EVs)

Microvesicles (MV)

Apoptotic body (AB)

International Society for Extracellular Vesicles (ISEV)

Minimal Information for studies of EVs 2018 (MISEV2018)

Nucleophosmin1 (NPM1)

High-density lipoprotein (HDL)

Low-density lipoprotein (LDL)

Scavenger Receptor Class B Member 1 (SRB1)

Human umbilical vein endothelial cells (HUVECs)

Extracellular-signal Regulated Kinase (ERK)

Signal Transducer and Activator of Transcription 1 (STAT1)

Signal Transducer and Activator of Transcription 3 (STAT3)

Toll Like Receptor 8 (TLR8)

Tumor microenvironment (TME)

Real-time quantitative reverse transcription polymerase-chain reaction (qRT-PCR)

Droplet digital polymerase-chain reaction (ddPCR)

Ethylenediaminetetraacetic acid (EDTA)

Cutaneous melanoma (CM)

Ultraviolet light (UV)

Confocal microscopy (RCM)

Optical coherence tomography (OCT)

Breslow thickness (BT)

American Joint Committee on Cancer (AJCC)

Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4)

Programmed cell death protein 1 (PD-1)

Overall survival (OS)

Relapse-free survival (RFS)

Lactate dehydrogenase (LDH)

RT-qPCR directly-in-plasma assay (RT-qPCR-DP)

Cutaneous squamous cell carcinoma (cSCC)

5-aminolaevulinic acid photodynamic therapy (ALA-PDT)

Actinic keratosis (AK)

Basal cell carcinoma (BCC)

Merkel cell carcinoma (MCC)

Mammalian target of rapamycin (mTOR)

Magnetic resonance imaging (MRI)

Positron Emission Tomography/Computed Tomography (PET/CT)

Article highlights

• Skin cancers release circulating microRNAs in the circulation, which can be detected both in serum and plasma tissue.

• Circulating microRNA levels can be associated with skin cancer presence, stage, evolution, or therapy efficacy.

• Circulating microRNAs reflect the contribution of many cells and mirror the systemic effects of cancer or its evolution over time.

• Circulating microRNA quantifications protocols still need standardization, and is necessary to develop reliable procedures and methodologies.

Acknowledgments

Figures were created with Biorender.com

Declaration of interest

M Milani is an employee of Cantabria Labs Difa Cooper. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by FLAG-ERA JTC 2019 LEGOCHIP project (PCI2019-111890-2) to M. Ferracin and Fondazione Cassa di Risparmio in Bologna (CARISBO) funds to E.D. (Call 2019).