MiRNAs as Potential Prognostic Biomarkers for Metastasis in Thin and Thick Primary Cutaneous Melanomas

Abstract

Background/Aim: The identification of novel prognostic biomarkers for melanoma metastasis is essential to improve patient outcomes. To this aim, we characterized miRNA expression profiles in relation to metastasis in melanoma and correlated miRNAs expression with clinicalpathological factors. Materials and Methods: MiR-145-5p, miR-150-5p, miR-182-5p, miR-203-3p, miR-205-5p and miR-211-5p expression levels were analyzed in primary cutaneous melanomas, including thin and thick melanomas, and in melanoma metastases by quantitative Real-Time PCR. Results: A significantly lower miR-205-5p expression was found in metastases compared to primary melanomas. Furthermore, a progressive down-regulation of miR-205-5p expression was observed from loco-regional to distant metastasis. Significantly lower miR-145-5p and miR-203-3p expression levels were found in cases with Breslow thickness >1 mm, high Clark level, ulceration and mitotic rate ≥1/mm 2. Conclusion: Our findings point to miR-205-5p as potential biomarker of distant metastases and to miR-145-5p and miR-203-3p as markers of aggressiveness in melanoma. Cutaneous melanoma is increasing in incidence worldwide (1). In Italy, the incidence of cutaneous melanoma is about 5-7 cases/100,000 per year (2). From a clinical and biological standpoint, melanoma is a heterogeneous and unpredictable disease. In early detected melanoma, surgical excision remains the best choice of treatment and is curative in the vast majority of cases (3). However, when diagnosed at an advanced stage melanoma is metastatic (4) and, despite the scientific and technological advancements in the oncology field, there are currently no treatments capable of permanently treating patients with metastatic melanoma. For this reason, the most important strategy to reduce mortality is the early detection of the primary tumor and the identification of patients at highrisk of metastatic dissemination (5). Main prognostic factors in primary melanomas include Breslow thickness, presence of ulceration, lymph node involvement and distant metastases (6). Breslow thickness provides the most useful histological information for prognosis in cutaneous melanoma. Thin melanomas, which are lesions ≤1.00 mm in Breslow thickness, have an excellent prognosis (7). However, about 5-10% of patients with thin melanoma develop metastases, fatal in 5% of the cases (7-9). Therefore, there is still controversy over the best way to use the clinical-pathological features to predict melanoma progression and metastasis development, and further molecular biomarkers are needed to identify cases with a high-risk of metastasis (10). An increasing number of studies have shown that microRNAs (miRNAs), small (22 nucleotides) single-stranded non-coding RNAs that negatively regulate the expression of more than 60% of human genes (11), play an important role in different biological processes, including cell survival, apoptosis, cell cycle regulation and differentiation (12). MiRNA misregulation and the subsequent alteration of target gene expression ...

Learning from Embryogenesis—A Comparative Expression Analysis in Melanoblast Differentiation and Tumorigenesis Reveals miRNAs Driving Melanoma Development

“…Many of the miRNAs, which we detected as significantly regulated in melanoma, are already described in the literature as relevant for the development of other cancers [69,70] or are known to be dysregulated in melanoma, but without a distinctly described molecular function [17,71]. The analysis of their potential target genes and involved pathways in our study allows interesting conclusions to be drawn about their role in melanoma tumorigenesis.…”

Distinguishing Tumor and Stromal Sources of MicroRNAs Linked to Metastasis in Cutaneous Melanoma

“…For this reason, candidate "metastasis-suppressor" miRNA with large apparent negative fold changes between primary and metastatic sites should be investigated for cell-type enriched expression patterns. [15], functions [10,11,32,34,36,39,52]. These studies have relied on both conventional differential expression, as well as supervised machine learning algorithms to identify miRNA of interest from tumor tissue expression profiles [11,32,34,36,39,52].…”

“…(miR-205, miR-203, miR-200a-c, and miR-141) [10][11][12][32][33][34][35][36][37][38][39]. Although many differences were highly statistically significant, the effect sizes were relatively small (Table 3).…”

“…Due to the relative abundance and often restricted expression patterns, many miRNAs can serve as biomarkers of cell-type and disease [7,8]. Identifying miRNA that are downregulated in metastasis, termed metastasis-suppressor miRNA, has been an area of considerable interest [9][10][11][12]. Defining miRNA associated with metastasis in melanoma could provide insights into the genes and pathways that drive metastatic progression, and potentially lead to the discovery of new therapeutic targets or biomarkers.…”

Circulating MicroRNAs as Prognostic and Therapeutic Biomarkers in Breast Cancer Molecular Subtypes

“…MicroRNAs (miRNAs) are short, single-stranded non-coding RNAs that regulate gene expression at the post-transcriptional level, the dysregulated expression of which is involved in some high-impact diseases, such as cancer [4,5]. In the last few years, great attention was addressed to the role of miRNAs as potential biomarkers in cancer: in particular, circulating miRNAs can be released from the tumor microenvironment and poured into the bloodstream, where they are stable and resistant to endogenous RNase activity [6], thus reflecting the homeostatic response of the organism to disease development and progression.…”