Transcriptomic identification of miR-205 target genes potentially involved in metastasis and survival of cutaneous malignant melanoma

Abstract

Cutaneous melanoma is an aggressive neoplasm and is responsible for the majority of skin cancer deaths. Several miRNAs are involved in melanoma tumor progression. One of them is miR-205, the loss of which contributes to the development of melanoma metastasis. We evaluated whole-genome mRNA expression profiling associated with different miR-205 expression levels in melanoma cells. Differential expression analysis identified 243 differentially expressed transcripts including inositol polyphosphate 5′-phosphatase-like protein-1 (INPPL1) and BTB/POZ Domain-Containing Protein 3 (BTBD3). INPPL1 and BTBD3 were downregulated when melanoma cells expressed miR-205, indicating that these genes are potential miR-205 targets. Additionally, the target prediction algorithm TargetScan revealed that INPPL1 and BTBD3 genes had predicted target sites of miR-205 in their 3′UTRs and functional analysis demonstrated that these genes were directly linked to miR-205. Interestingly, our clinical data showed that INPPL1 was significantly associated with lymph node metastasis-free survival (LNMFS), distant metastasis-free survival (DMFS) and melanoma specific survival (MSS). This study supports INPPL1 as a miR-205 target gene and, therefore, that the involvement of miR-205 in the metastatic dissemination of malignant melanoma is, at least in part, via INPPL1. Most skin cancer related deaths are caused by melanoma, a malignant neoplasm with great potential to metastasize that is increasing in incidence and mortality 1. Epigenetic regulation of gene expression has, as in other cancer types, a significant role in melanoma 2. These epigenetic events include microRNAs (miRNAs). miRNAs are short noncoding RNAs with gene regulatory functions. miRNAs modulate gene expression by post-transcriptional repression, as they can direct mRNA cleavage or direct translational repression of their target protein-coding genes 3,4. Specific miRNAs have been implicated in many biological and pathological processes. miRNA impact on cancer depends on the functional nature of the targeted genes. In this way, miRNAs can produce both oncogenic or tumor suppressive effects by suppressing tumor suppressive mRNAs or oncogenic mRNAs, respectively. With regard to miR-205 target genes in melanoma, Dar et al. reported that miR-205 is potentially involved in melanomagenesis through suppression of cell proliferation and induction of senescence via regulation of E2F1 oncoprotein 5. It has also been suggested that miR-205 controls melanoma cell migration and invasion and that it inhibits the ZEB2 transcription factor 6. In particular, some miRNAs are known to be involved in the development and progression of melanoma 7-9. In this regard, we have recently demonstrated that the intratumoral downregulation of tumor suppressive miR-205 in primary melanomas contributes to the development of distant metastasis, and therefore to a shorter survival. Consequently, miR-205 intratumoral expression levels are useful to predict melanoma metastatic dissemination and patient survival 10. Our ...

Protective Mechanisms of Polyphenol-Enriched Blueberry Preparation in Preventing Inflammation in the Skin against UVB-Induced Damage in an Animal Model

“…In this study, results illustrated the preventive effect of PEBP and OMP by significantly increasing the expression of miR-200c and miR-205 while decreasing the expression of miR-210, miR-146a, and miR-155, leading to regulation of target gene expression after UVB stimulation. These miRNAs were predicted to be involved in distant metastasis and inflammatory pathways [24,81] and ( [82] (p. 25)). According to these results, topical application of PEBP and OMP to the skin exposed to UVB led to regulation of miRNA expression.…”

A novel 7‑hypoxia‑related long non‑coding RNA signature associated with prognosis and proliferation in melanoma

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Targeting SHIP1 and SHIP2 in Cancer

“…MiR-155 upregulation is associated with poorer prognosis in B cell lymphoma [ 97 , 98 ], although upregulation of miR-155 in dendritic cells improves their maturation and promotes adaptive immune response by CD8+T cells [ 99 ]. MicroRNA targeting of INPPL1 (SHIP2) by miR-205 has recently been correlated with oncogenic transformation in melanoma [ 100 ]. However, both SHIP paralogs may enhance AKT activation through production of PI(3,4)P 2 as this PtdIns promotes AKT activation more effectively than the SHIP1/2 substrate (PI(3,4,5)P 3 ) ( Figure 1 ) [ 5 ].…”

“…In these epithelial-derived tumors the SH2-containing SHIP1 isoforms are not thought to be expressed; however, an internal promoter is active in cancer stem cell populations present in epithelial tumors suggesting the s-SHIP stem cell-specific isoform of SHIP1 [ 124 ] may be expressed and contribute to tumor stem cell survival [ 125 , 126 , 127 ]. The more aggressive prognosis of these epithelial cancers that overexpress SHIP2 may be due to increased cell migration and invadopodia maturation [ 128 ], leading to increased metastatic capacity [ 100 , 123 ]. Conversely, SHIP2 has been reported to regulate focal adhesion and suppress motility of PTEN-deficient glioblastoma acting on PI(4,5)P 2 , at the plasma membrane [ 129 ] but SHIP2 inhibition showed reduced fibronectin-dependent cell migration in glioblastoma [ 130 , 131 ].…”