Abstract
BackgroundMelanoma is an extremely aggressive type of skin cancer and experiencing a expeditiously rising mortality in a current year. Exploring new potential prognostic biomarkers and therapeutic targets of melanoma are urgently needed. The ambition of this research was to identify genetic markers and assess prognostic performance of N6-methyladenosine (m6A) regulators in melanoma.MethodsGene expression data and corresponding clinical informations of melanoma patients as well as sequence data of normal controls are collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases. Quantitative real-time PCR (qRT-PCR) analysis was carried out to detect the RNA expression of IGF2BP3 in A375 cell line, melanoma tissues, and normal tissues. Western blot, cell proliferation, and migration assays were performed to assess the ability of IGF2BP3 in A375 cell line.ResultsDifferently expressed m6A regulators between tumor samples and normal samples were analyzed. A three-gene prognostic signature including IGF2BP3, RBM15B, and METTL16 was constructed, and the risk score of this signature was identified to be an independent prognostic indicator for melanoma. In addition, IGF2BP3 was verified to promote melanoma cell proliferation and migration in vitro and associate with lymph node metastasis in clinical samples. Moreover, risk score and the expression of IGF2BP3 were positively associated with the infiltrating immune cells and these hub genes made excellent potential drug targets in melanoma.ConclusionWe identified the genetic changes in m6A regulatory genes and constructed a three-gene risk signature with distinct prognostic value in melanoma. This research provided new insights into the epigenetic understanding of m6A regulators and novel therapeutic strategies in melanoma.
Highlights
Melanoma is a highly aggressive form of skin cancer, forming by malignant transformation of melanocytes [1], frequently leading to metastasis with a mortality rate exceeds 80% [2,3,4,5]
Selection and differential expression analysis of m6A WERs regulators In a summing up of the latest published review considering m6A regulators in human cancers [11], we collected twenty m6A WERs regulators (WTAP, RNA binding motif protein 15B (RBM15B), Binding motif protein 15 (RBM15), KIAA1429, METTL3, METTL14, METTL16, IGF2BP1, IGF2BP2, IGF2BP3, Zinc finger CCCH domain-containing protein 13 (ZC3H13), Cbl protooncogene-like 1 (CBLL1), Heterogeneous nuclear ribonucleoprotein C (HNRNPC), YTHDC1, YTHDC2, YTHDF1, YTHDF2, YTHDF3, Fat mass and obesity-associated protein (FTO), and AlkB homolog 5 (ALKBH5)) with available expression and clinical data in The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets
The results showed that three (RBM15B, METTL16, and IGF2BP3) out of twenty regulators were notably associated with overall survival (OS) (Fig. 3A, p < 0.05)
Summary
Melanoma is a highly aggressive form of skin cancer, forming by malignant transformation of melanocytes [1], frequently leading to metastasis with a mortality rate exceeds 80% [2,3,4,5]. The accumulation of genetic and epigenetic alterations results in a multistep process which includes the activation of oncogenes and the inactivation of tumor suppressor genes, eventually leading to the development of melanoma. M6A regulating proteins which include "writers", "erasers" and "readers" (WERs) were reported with important effects in tumor initiation and progression [11]. The ambition of this research was to identify genetic markers and assess prognostic performance of N6-methyladenosine (m6A) regulators in melanoma
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