The neurotrophin Neuritin1 (NRN1; cpg15) belongs to the candidate plasticity gene (CPG) family and is expressed in postmitotic-differentiating neurons of the developmental nervous system and neuronal structures associated with plasticity in the brain of human adult.,Our newest findings document that NRN1 deregulation could contribute also to disease development and have impact on malignant melanoma.,Our analyses displayed the over-expression of NRN1 in melanoma in vitro and in vivo, shown by immunohistochemistry and qRT-PCR on microdissected melanoma tissue; furthermore, soluble NRN1 was detectable in tissue culture supernatant and serum of melanoma patients.,To investigate the role of NRN1 in melanoma we performed knockdown, over-expression and recombinant-NRN1-treatment experiments affiliated by functional assays.,Our results show that migration, attachment independent growth and vasculogenesis were affected after manipulation of NRN1 on endogenous and extrinsic level.,Interestingly, high NRN1 serum levels correlate with low MIA serum levels (< 10ng/ml).,Therefore, we speculate that NRN1 could be a marker for early melanoma stages, in particular.,In summary, we detected an overexpression of NRN1 in melanoma patient.,In functional cell culture experiments we found a correlation between NRN1 expression and the cancerous behavior of melanoma cells.
Melanoma cells can switch their phenotypes in response to microenvironmental insults.,Heterogeneous melanoma populations characterized by long-term growth and a high self-renewal capacity can be obtained in vitro in EGF(+)bFGF(+) medium whilst invasive potential of melanoma cells is increased in serum-containing cultures.,In the present study, we have shown that originally these patient-derived melanoma populations exhibit variable expression of pro-survival genes from the BCL-2 family and inhibitors of apoptosis (IAPs), and differ in the baseline MCL-1 transcript stability as well.,While being transferred to serum-containing medium, melanoma cells are well protected from death.,Immediate adaptive response of melanoma cells selectively involves a temporary MCL-1 increase, both at mRNA and protein levels, and BCL-XL can complement MCL-1, especially in MITFlow populations.,Thus, the extent of MCL-1 and BCL-XL contributions seems to be cell context-dependent.,An increase in MCL-1 level results from a transiently enhanced stability of its transcript, but not from altered protein turnover.,Inhibition of MCL-1 preceding transfer to serum-containing medium caused the induction of cell death in a subset of melanoma cells, which confirms the involvement of MCL-1 in melanoma cell survival during the rapid alteration of growth conditions.,Additionally, immediate response to serum involves the transient increase in MITF expression and inhibition of ERK-1/2 activity.,Uncovering the mechanisms of adaptive response to rapid changes in microenvironment may extend our knowledge on melanoma biology, especially at the stage of dissemination.