PLA1A expression as a diagnostic marker of BRAF-mutant metastasis in melanoma cancer

Abstract

BRAF and NRAS are the most reported mutations associated to melanomagenesis. The lack of accurate diagnostic markers in response to therapeutic treatment in BRAF/NRAS-driven melanomagenesis is one of the main challenges in melanoma personalized therapy. In order to assess the diagnostic value of phosphatidylserine-specific phospholipase A1-alpha (PLA1A), a potent lysophospholipid mediating the production of lysophosphatidylserine, PLA1A mRNA and serum levels were compared in subjects with malignant melanoma (n = 18), primary melanoma (n = 13), and healthy subjects (n = 10). Additionally, the correlation between histopathological subtypes of BRAF/NRAS-mutated melanoma and PLA1A was analyzed. PLA1A expression was significantly increased during melanogenesis and positively correlated to disease severity and histopathological markers of metastatic melanoma. PLA1A mRNA and serum levels were significantly higher in patients with BRAF-mutated melanoma compared to the patients with NRAS-mutated melanoma. Notably, PLA1A can be used as a diagnostic marker for an efficient discrimination between naïve melanoma samples and advanced melanoma samples (sensitivity 91%, specificity 57%, and AUC 0.99), as well as BRAF-mutated melanoma samples (sensitivity 62%, specificity 61%, and AUC 0.75). Our findings suggest that PLA1A can be considered as a potential diagnostic marker for advanced and BRAF-mutated melanoma.

Comparative mRNA/micro-RNA co-expression network drives melanomagenesis by promoting epithelial–mesenchymal transition and vasculogenic mimicry signaling

“…For the further confirmation of these results, in our recently published study, we detailed the use of PLA1A as a marker for thre effective prediction of advanced melanoma with subcutaneous metastases following BRAF or NRAS mutation [37] . We confirmed that the upregulation of PLA1A in the serum of patients with advanced MM could represent an excellent distinguishing and diagnostic marker in BRAF/NRAS-driven melanomagenesis.…”

“…In addition, it plays an important role in promoting or inhibiting cancer cell proliferation/migration depending on the origin and type of cancer cell, and the outcome may be associated with expression levels of PLA1A and DMKN in the tumor [ 59 , 60 ]. A literature review revealed that the field is filled with inconsistent findings that make it difficult to ascertain the roles of PLA1A and DMKN in neoplasia and immunity associated with melanoma [ 37 , 57 , 59 , 61 ]. Nonetheless, this pilot study warrants a larger analytical study in transcriptomic and post-transcriptomic levels to confirm the findings.…”

“…In a 10 μl reaction system, 5 μl of 2 × PCR-probe mix, 0.02 μl of probe, 1 μl of primers, 2 μl of H 2 O, and 2 μl of cDNA were mixed, and the reaction was completed in StepOne plus Thermocycler (Applied Biosystem) with 40 amplification cycles, according to the manufacturer's protocol. According our previous setting, we used the most reliable reference genes, 18S RNA and RNU6B snRNA from ABI (Cat# 4,427,975), to normalize targeted mRNA and miRNA expression data, respectively [ 27 , 34 , 35 , 37 , 38 ]. After normalization, relative contents of targeted mRNA and miRNA were calculated and expressed according the 2 −ΔΔCT method.…”

Dermokine mutations contribute to epithelial-mesenchymal transition and advanced melanoma through ERK/MAPK pathways

“…The results of the present study represented that DMKN levels gradually elevated during the progression of melanomagenesis, while negative DMKN expression predicted an optimistic pancreatic cancer clinical stage [7]. Additionally, the upregulation of DMKN in the advanced metastatic melanoma tissues could be an excellent diagnostic marker in BRAF/NRAS-driven melanomagenesis [11]. Interestingly, DMKN genes served as the novel oncogenes triggering VM and EMT processes during melanomagenesis [7,11].…”

“…Therefore, the transcriptome pro ling of the EMT/VM-mediated treatment-resistant samples could be a valuable strategy for nding exceptional responders to the personalized melanoma therapy [9,10].Recently, researchers tried to nd novel VM/EMT-targeted therapeutic genes that are differentially regulated during melanomagenesis. One of the identi ed genes was a recently-reported skin-speci c gene, phosphatidylserine-speci c phospholipase A1-alpha (PLA1A) and dermokine (DMKN) that contribute to melanomagenesis by triggering the EMT signaling pathway and VM formation [11,12]. These genes can be transcriptionally used as promising biomarkers for exceptional responders in the targeted melanoma therapy [12].…”