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

Abstract

To discover vulnerabilities associated with dermokine (DMKN) as a new trigger of the epithelial-mesenchymal transition (EMT) -driven melanoma, we undertook a genome-wide genetic screening using transgenic. Here, we showed that DMKN expression could be constitutively increased in human malignant melanoma (MM) and that this correlates with poor overall survival in melanoma patients, especially in BRAF-mutated MM samples. Furthermore, in vitro, knockdown of DMKN inhibited the cell proliferation, migration, invasion, and apoptosis of MM cancer cells by the activation of ERK/MAPK signaling pathways and regulator of STAT3 in downstream molecular. By interrogating the in vitro melanoma dataset and characterization of advanced melanoma samples, we found that DMKN downregulated the EMT-like transcriptional program by disrupting EMT cortical actin, increasing the expression of epithelial markers, and decreasing the expression of mesenchymal markers. In addition, whole exome sequencing was presented with p.E69D and p.V91A DMKN mutations as a novel somatic loss of function mutations in those patients. Moreover, our purposeful proof-of-principle modeled the interaction of ERK with p.E69D and p.V91A DMKN mutations in the ERK-MAPK kinas signaling that may be naturally associated with triggering the EMT during melanomagenesis. Altogether, these findings provide preclinical evidence for the role of DMKN in shaping the EMT-like melanoma phenotype and introduced DMKN as a new exceptional responder for personalized MM therapy.

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

“…Following the publication of this article [ 1 ], concerns were raised regarding results presented in Fig 2 of [ 1 ] that appear similar to results previously published under a CC-BY 4.0 license in [ 2 ] by a different author group. Specifically,…”

“…- The Fig 2D MUM-8B shDMKN panel in [ 1 ] and the Fig 9C SK-HEP-1 SKLB1002/miR-101 mimics panel in [ 2 ].…”

Skin biophysical parameters and serum dermokine levels in airline pilots: a comparative study with office workers

“…Intriguingly, we found that serum DMKN levels in APs was independently associated with the melanin index rather than typical skin barrier parameters such as hydration levels in the stratum corneum or TEWL. Although no previous studies have established a link between DMKN and skin pigmentation, it is noteworthy that mutations in the DMKN gene are implicated in the development of MM via the ERK/MAPK signalling pathways [ 20 ]. Moreover, DMKN microRNAs have emerged as potentially promising biomarkers for diagnosing and treating MM [ 30 ].…”

“…We examined these characteristics in a group of 40 male APs, each matched in terms of age and service tenure (minimum of 5 years) with a control group of 40 male office workers (OWs). Considering the potential role of DMKN in skin barrier dysfunction [ 17 ] and the pathogenesis of MM [ 20 ], and its possible regulation by hypoxic conditions, we further analyzed the serum levels of this molecule and correlated them with the observed skin parameters.…”

“…Hypoxia can occur in aviation even in pressurized environments, whether due to life support systems failure or incorrect equipment usage [ 19 ]. In a recent study, Ma et al [ 20 ] have also shown that DMKN expression might be persistently increased, triggering the epithelial-mesenchymal transition signalling pathway, in human MM – a malignancy whose risk is known to be elevated among APs [ 6 ].…”