Melanoma is the most serious type of skin cancer.1 Over the past few years, great efforts have been made to explore the molecular mechanisms of it.6 Previous studies have been focused on the protein-coding genes and miRNAs, however, it rarely involves lncRNAs. In our study, three lncRNAs, MALAT1, LINC00943 and LINC00261 were identified through ceRNA network, as key lncRNA with higher degrees and the number of lncRNA-miRNA and miRNA-mRNA pairs compared to others, indicating that these lncRNAs might closely related to tumorigenesis and development of melanoma.
With the increasing attention to the role of lncRNA, lncRNA have shown superior potential over protein-coding genes as a biomarker for diagnosis and prognosis.39−42 Among these key lncRNAs found in this study, MALAT1 has been demonstrated to be related to multiple tumors.43−47 Studies have confirmed that MALAT1 is a valuable prognostic marker and a promising therapeutic target in lung cancer metastasis.43,44 Lai M. C. et al. suggested that MALAT1 play an important role in tumor progression and could be served as a promising therapeutic target.45 Through the study of whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer, Fujimoto A. and colleges discovered MALAT1 closely related to liver carcinogenesis.46 In addition, a study revealed a novel mechanism of MALAT1-regulated autophagy-related chemoresistance in gastric cancer.47 At present, it is believed that in the process of tumorigenesis and development of malignancies, MALAT1 is mainly responsible for regulating the proliferation, migration and invasion of tumor cells. According to our findings, which indicated that MALAT1 might also be a crucial factor in the tumorigenesis and development of melanoma. In this sub-network, we found that there are nine lncRNA-miRNA pairs, including miRNA-378a-3p, miRNA-23b-3p, miRNA-224-5p, miRNA-204-5p, miRNA-205-5p, miRNA-200c-3p, miRNA-200b-3p, miRNA-149-5p, miRNA-211-5p. Among them, study have demonstrated that MALAT1 can regulate chemoresistance via miRNA-23b-3p sequestration in gastric cancer. 47 In ovarian cancer, a study suggested that MALAT1-miRNA-211-5p may act as a key mediator in prevention of this disease.48 MALAT1 also involved in promoting renal cell carcinoma through interaction with miRNA-205-5p. 49 Studies have confirmed that MALAT1 functions in liver and lung cancer through miRNA-204-5p. 50,51 In addition, targeting MALAT1/miRNA-200c-3p axis in xenograft endometrial carcinoma model can greatly inhibit tumor growth.52
Moreover, studies had been illustrated that these miRNAs were closely related to melanoma in serval ways. miRNA-378a-3p can regulate oncogene PARVA expression in melanoma, preventing its progression.53 miRNA-23b-3p was shown as a tumor suppressor gene in melanoma.54 miRNA-224-5p can be regulated by E2F1 to drive EMT through TXNIP downregulation in melanoma, and it can inhibit uveal melanoma cell proliferation, migration, invasion by targeting PIK3R3/AKT3.55,56 miRNA-204-5p, known as tumor suppressor gene in melanoma, was associated with CDKN2A pathway and NRAS gene, and was contributed to BRAF inhibitor resistance.54.57,58 miRNA-205-5p suppresses proliferation and induces senescence via regulation of E2F1 in melanoma.54.59−61 miRNA-200b/c-3p act as potential diagnostic and prognostic markers for melanoma.62−64. Upregulation of miRNA-149-5p, directedly regulated by p53, results in increased expression of Mcl-1 and resistance to apoptosis in melanoma cells.65 Most importantly, studies have confirmed that miRNA-211-5p play a major role as tumor suppressor via various targets in melanoma.54,58,62,66,67 As these miRNAs we predicted were closely associated with melanoma, we believed that MALAT1 may play a crucial role in tumorigenesis and development of melanoma through competitive interactions with these miRNAs, and subsequently alter expression of downstream mRNAs.
Nothing was known about LINC00943. According to LINC00943-miRNA-mRNA sub-network, miRNA-99a-5p, miRNA-100-5p, miRNA-23b-3p, miRNA-204-5p, miRNA-224-5p, miRNA-149-5p and miRNA-125b-5p, were closely interacted with LINC00943. No connection between LINC00943 and these miRNAs have been discovered yet, however, these miRNAs were also demonstrated to be associated with melanoma, except miRNA-99a-5p. The link between miRNA-204-5p, miRNA-224-5p, miRNA-149-5p and melanoma were discussed above. miRNA-23b was suggested as tumor suppressor gene.54 miRNA-100-5p and miRNA-125b-5p are associated with resistance to treatment with immune checkpoint inhibitors in melanoma patients.68 Therefore, understanding the relationship among LINC00943, miRNA and malignancies may provide a feasible way for the future research of melanoma and other malignancies.
LINC00261 is also significant based on ceRNA network, but its function remains controversial until now. We found that 43 GO-BP terms and 7 KEGG pathways were enriched, based on the sub-network. One of these pathways, PI3K/Akt signaling pathway, is proved to play a critical role in tumorigenesis,69 especially in melanoma.70 Also, study have demonstrated that LINC00261 promotes cancer cell proliferation and metastasis in human choriocarcinoma.71 However, LINC00261 have shown a great capacity in improving the chemotherapeutic response and survival of patients with esophageal cancer.72 And, in gastric cancer, LINC00261 can suppress the tumor metastasis by regulating epithelial-mesenchymal transition (EMT).73 Moreover, LINC00261 can block cellular proliferation by activating the DNA damage response.74 LINC00261 may affect the biological behavior of different tumors in different ways. Therefore, it is very essential to further explore the role of LINC00261 in different tumors. On the other hand, five miRNAs, including miRNA-23b-3p, miRNA-211-5p, miRNA-205-5p, miRNA-140-3p and miRNA-125b-5p were interacted with LINC00261 according to LINC00261-miRNA-mRNA sub-network. Similarly, no connection between LINC00261 and these miRNAs have been discovered yet, but these miRNAs were also demonstrated to be associated with melanoma. The role of miRNA-23b-3p, miRNA-211-5p, miRNA-205-5p, and miRNA-125b-5p in melanoma were discussed above. miRNA-140-3p was reported to be regulated by MALAT1 in uveal melanoma cell,75 while its role in cutaneous melanoma is still unknown.
Three of the 16 predicted miRNAs were not associated with MALAT1, LINC00943 and LINC00261, including miRNA-21-5p, miRNA-20b-5p and miRNA-424-5p. They closely related to SGMS1.AS1, EPB41L4A.AS1 and SNHG1, on the other hand. Little was known about miRNA-424-5p in melanoma, while studies have suggested that miRNA-20b-5p may inhibit tumor metastasis via regulation of PAR-1 receptor in melanoma cells,76and miRNA-21 may regulate melanoma cell proliferation, migration, apoptosis through ERK/NF-κB signaling pathway by targeting SPRY1, PDCD4 and PTEN.77,78
All in all, we reconstructed a ceRNA network, which for the first time enables an overall view and analysis of the lncRNA-associated ceRNA mediated genes in the tumorigenesis and development of melanoma at a system-wide level based on ceRNA theory. Our study discovered that serval lncRNAs, including MALAT1, LINC00943 and LINC00261, might play an essential role in skin cutaneous melanoma. Finally, we verified our findings through q(RT)-PCR assay. This study will advance our understanding of the tumorigenesis and development of melanoma from the perspective of lncRNAs and provide some novel lncRNAs as candidate diagnostic biomarkers or potential therapeutic targets for melanoma. Further studies are required to explore the biological functions and molecular mechanisms of MALAT1, LINC00943 and LINC00261 in melanoma.