Abstract
While only 15–25 percent of melanoma patients develop distant metastasis and die, this disease is still responsible for the majority of skin cancer-related deaths. The availability of adjuvant therapies makes the selection of high-risk patients essential. We evaluated the intratumoral expression of ten miRNAs in primary melanomas in relation to its ability to predict melanoma survival. To this end, we correlated miRNA expression in 132 cryopreserved primary and metastatic tumors with clinicopathological factors and clinical outcome. We found sequential downregulation of intratumoral expression of miR-125b, miR-182, miR-200c and miR-205 over the full spectrum of melanoma progression. Moreover, downregulation of these miRNAs occurred in primary melanomas that further disseminated to distant sites. Furthermore, miR-125b, miR-200c and miR-205 correlated as independent factors with shorter survival. Our in vitro findings demonstrate that loss of miR-205 potentiates the invasive ability of melanoma cells. We conclude that the downregulation of miR-205 in primary melanomas is an intrinsic property that might contribute to distant metastasis. In particular, the interaction of melanoma cells with the extracellular matrix is one of the key mechanisms by which miR-205 influences melanoma metastasis. In conclusion, miR-125b, miR-200c and miR-205 are useful prognostic biomarkers at the time of diagnosis to select high-risk patients.
Highlights
Malignant melanoma already accounts for around 80% of all skin cancer-related deaths and its incidence is increasing worldwide[1]
We found a significant inverse correlation between miR-125b, miR-182, miR-200c and miR-205 expression and both Breslow thickness and mitotic index in primary melanomas (Spearman correlation) (Table 2)
It is well known that patients with clinicopathologically analogous primary tumors can have different clinical outcomes
Summary
Malignant melanoma already accounts for around 80% of all skin cancer-related deaths and its incidence is increasing worldwide[1]. Metastatic dissemination of cutaneous malignant melanoma is the main cause of the high mortality observed in melanoma. We investigated the ability of a miRNA panel to select patients at high-risk of distant metastasis at the time of primary tumor diagnosis. The current American Joint Committee on Cancer (AJCC) staging system for cutaneous melanoma is based on primary tumor thickness and the presence of ulceration, lymph node spread and distant metastases as determinants of prognosis[2]. While most melanoma patients never develop recurrent disease after excision of the primary tumor, a subset of patients (15–25%) will develop metastases and die from melanoma. MicroRNAs (miRNAs) are endogenous small noncoding RNAs that regulate the stability or translational efficiency of target mRNAs and are involved in various biological www.nature.com/scientificreports/ Deregulation of some microRNAs and their targeted genes have been associated with the well-known hallmark biological characteristics of human cancer3–6. microRNAs (miRNAs) are endogenous small noncoding RNAs that regulate the stability or translational efficiency of target mRNAs and are involved in various biological www.nature.com/scientificreports/
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