MITF depletion elevates expression levels of ERBB3 receptor and its cognate ligand NRG1-beta in melanoma

Alver, Tine Norman; Lavelle, Timothy J; Longva, Ane Sager; Øy, Geir Frode; Hovig, Eivind; Bøe, Sigurd Leinæs

doi:10.18632/oncotarget.10422

Cited by 11 publications

(22 citation statements)

References 35 publications

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“…NRG1α also stimulates cell proliferation mediated by multiple matrix metalloproteases during tumor cell migration (10). Another study demonstrated that the expression levels of NRG1β were significantly increased in melanoma cell lines (32). These previous studies indicated that both CHL1 and NRG1 are involved in the invasion and reduced apoptosis of glioma cells.…”

Section: Discussionmentioning

confidence: 84%

Neuregulin 1 enhances cell adhesion molecule L1 like expression levels and promotes malignancy in human glioma

Lin

et al. 2020

Oncol Lett

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Neural cell adhesion molecular L1-like protein (CHL1) is a member of the cell adhesion molecule L1 family and serves an important role in the development and progression of tumors. The cytokine neuregulin 1 (NRG1) has been indicated in the tumorigenesis and promotion of metastasis through the modulation of L1. However, the roles of NRG1 in regulating CHL1 in glioma have not been elucidated. The present study investigated the protein expression levels and roles of CHL1 and the possible correlation between NRG1 and CHL1 protein expression levels in human gliomas, both in vivo and in vitro. Using immunohistochemistry coupled with a human glioma tissue microarray, it was demonstrated that the percentage of CHL1-positive areas was the highest in grade II glioma tissues. Using immunofluorescence staining, a positive correlation was identified between the expression levels of CHL1 and proliferating cell nuclear antigen. In addition, CHL1 downregulation also resulted in increased senescence of U-87 MG human glioblastoma cells. In vitro, administration of NRG1α induced a significant increase in CHL1 protein expression levels in human glioma SHG-44 and U251 cells and in human glioblastoma U-87 MG cells, whereas NRG1β failed to increase CHL1 expression levels in U251 cells. These findings were further confirmed by the downregulation of NRG1 expression levels using small interfering RNA treatment, which resulted in the reduction of CHL1 protein expression levels in U-87 MG cells. These data indicate that NRG1 can regulate CHL1 protein expression levels in gliomas, that it is correlated with malignancy, and that NRG1 may contribute to malignancy by upregulating CHL1 protein expression levels in glioma/glioblastoma cells.

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Section: Discussionmentioning

confidence: 84%

Neuregulin 1 enhances cell adhesion molecule L1 like expression levels and promotes malignancy in human glioma

Lin

et al. 2020

Oncol Lett

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“…To evaluate the quality of the MITFBSs observed in the Hermes cell lines, we compared our MITF-M ChIP-seq data with data from previously published data [ 40 ] ( Figure 3 A). Consensus MITFBSs overlapped 40–60% with these datasets.…”

Section: Resultsmentioning

confidence: 99%

“…CT stimulates cyclic adenosine 3′,5′-monophosphate (cAMP) production within the cells. All Hermes lines and their derivatives were cultured as previously described [ 40 ], with the following modifications: RPMI was replaced by M254 medium (Cascade Biologics, Portland, OR, USA) and cells were incubated in 5% CO 2 . SKMEL28 was purchased from ATCC and grown in RPMI (Sigma Aldrich, Saint Louis, MO, USA) with 8% FBS (PAA), 5% CO 2 , at 37 °C.…”

Section: Methodsmentioning

confidence: 99%

“…Western Blot analysis was performed as previously described [ 40 ]. The following antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA); MITF (1:1000; #12590), SOX10 (1:1000; #14374, Phospho-Akt-Serine-473 XP (1:2000; #4060), Phospho-ERK–Thr202/Tyr204) XP (1:3000; #4370), PTEN XP (1:1000; #9188) and Histone H3 (1:3000; #4499) was used as loading control.…”

Section: Methodsmentioning

confidence: 99%

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Dysregulation of MITF Leads to Transformation in MC1R-Defective Melanocytes

Lavelle

Alver

Heintz

et al. 2020

Cancers

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The MC1R/cAMP/MITF pathway is a key determinant for growth, differentiation, and survival of melanocytes and melanoma. MITF-M is the melanocyte-specific isoform of Microphthalmia-associated Transcription Factor (MITF) in human melanoma. Here we use two melanocyte cell lines to show that forced expression of hemagglutinin (HA) -tagged MITF-M through lentiviral transduction represents an oncogenic insult leading to consistent cell transformation of the immortalized melanocyte cell line Hermes 4C, being a melanocortin-1 receptor (MC1R) compound heterozygote, while not causing transformation of the MC1R wild type cell line Hermes 3C. The transformed HA-tagged MITF-M transduced Hermes 4C cells form colonies in soft agar and tumors in mice. Further, Hermes 4C cells display increased MITF chromatin binding, and transcriptional reprogramming consistent with an invasive melanoma phenotype. Mechanistically, forced expression of MITF-M drives the upregulation of the AXL tyrosine receptor kinase (AXL), with concomitant downregulation of phosphatase and tensin homolog (PTEN), leading to increased activation of the PI3K/AKT pathway. Treatment with AXL inhibitors reduces growth of the transformed cells by reverting AKT activation. In conclusion, we present a model system of melanoma development, driven by MITF-M in the context of MC1R loss of function, and independent of UV exposure. This model provides a basis for further studies of critical changes in the melanocyte transformation process.

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“…Expression patterns of transcription factors like microphthalmia-associated transcription factor (MITF) and inversely correlated receptor tyrosine kinases like AXL have been implicated in staging of melanoma with respect to progression and resistance 19 . However, the expression levels of MITF in various melanoma cell lines are highly variable and correlation to other receptor tyrosine kinases may be also implicated in acquired drug resistance 20 . WM793b cells were selected from primary melanoma which lack metastatic potential in a SCID murine xenograft model 21 .…”

Section: Resultsmentioning

confidence: 99%

Amino Acid Signature in Human Melanoma Cell Lines from Different Disease Stages

Wasinger

Hofer

Spadiut

et al. 2018

Sci Rep

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Cancer cells rewire metabolism to sustain high proliferation rates. Beside glycolysis and glutaminolysis, amino acids substitute as energy source, feed fatty acid biosynthesis and represent part of the secretome of transformed cells, including melanoma. We have therefore investigated acetate, pyruvate and the amino acid composition of the secretome of human melanoma cells representing the early slow (WM35, WM278, WM793b and VM21) and metastatic fast (A375, 518a2, 6F and WM8) growth phase in order to identify possible signalling components within these profiles. Proliferation assays and a principle component analysis revealed a stringent difference between the fast and slow growing melanoma cells. Moreover, upon inhibition of the mevalonate pathway, glutamic acid and alanine were identified as the central difference in the conditional media. A supplementation of the media with glutamic acid and the combination with alanine significantly accelerated the proliferation, migration and invasion of early stage melanoma cells, but not metastatic cells. Finally, the inhibition of the mevalonate pathway abolished the growth advantage of the melanoma cells in a time dependent manner. Taken together, these data corroborate a stage specific response in growth and aggressiveness to extracellular glutamic acid and alanine, indicative for microenvironmental signalling of individual amino acids.

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MITF depletion elevates expression levels of ERBB3 receptor and its cognate ligand NRG1-beta in melanoma

Cited by 11 publications

References 35 publications

Neuregulin 1 enhances cell adhesion molecule L1 like expression levels and promotes malignancy in human glioma

Neuregulin 1 enhances cell adhesion molecule L1 like expression levels and promotes malignancy in human glioma

Dysregulation of MITF Leads to Transformation in MC1R-Defective Melanocytes

Amino Acid Signature in Human Melanoma Cell Lines from Different Disease Stages

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