Growth factor modulation of melanoma growth stimulatory activity mRNA expression in human malignant melanoma cells correlates with cell growth

MicroRNAs regulate gene expression by repressing translation or directing sequence-specific degradation of their complementary mRNA. We recently reported that miR-203 is down-regulated, and its exogenous expression inhibits cell growth in canine oral malignant melanoma tissue specimens as well as in canine and human malignant melanoma cells. A microRNA target database predicted E2F3 and ZBP-89 as putative targets of microRNA-203 (miR-203). The expression levels of E2F3a, E2F3b, and ZBP-89 were markedly up-regulated in human malignant melanoma Mewo cells compared with those in human epidermal melanocytes. miR-203 significantly suppressed the luciferase activity of reporter plasmids containing the 3′-UTR sequence of either E2F3 or ZBP-89 complementary to miR-203. The ectopic expression of miR-203 in melanoma cells reduced the levels of E2F3a, E2F3b, and ZBP-89 protein expression. At the same time, miR-203 induced cell cycle arrest and senescence phenotypes, such as elevated expression of hypophosphorylated retinoblastoma and other markers for senescence. Silencing of E2F3, but not of ZBP-89, inhibited cell growth and induced cell cycle arrest and senescence. These results demonstrate a novel role for miR-203 as a tumor suppressor acting by inducing senescence in melanoma cells.

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Autoinduction of Platelet Derived Growth Factor (PDGF) A-Chain mRNA Expression in a Human Malignant Melanoma Cell Line and Growth Inhibitory Effects of PDGF-A-Chain mRNA-Specific Antisense Molecules

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1993.1688 ◽

1993 ◽

Vol 193 (2) ◽

pp. 744-751 ◽

Cited By ~ 14

Author(s):

C. Behl ◽

U. Bogdahn ◽

J. Winkler ◽

R. Apfel ◽

W. Brysch ◽

...

Keyword(s):

Growth Factor ◽

Malignant Melanoma ◽

Mrna Expression ◽

Cell Line ◽

Melanoma Cell Line ◽

Platelet Derived Growth Factor ◽

Inhibitory Effects ◽

Human Malignant Melanoma ◽

Growth Inhibitory ◽

A Chain

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E3 ubiquitin ligase PARK2, an inhibitor of melanoma cell growth, is repressed by the oncogenic ERK1/2-ELK1 transcriptional axis

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.014615 ◽

2020 ◽

Vol 295 (47) ◽

pp. 16058-16071

Author(s):

Valentina Montagnani ◽

Luisa Maresca ◽

Alessandro Apollo ◽

Sara Pepe ◽

Ryan M. Carr ◽

...

Keyword(s):

Cell Growth ◽

Malignant Melanoma ◽

Melanoma Cell ◽

Ubiquitin Ligase ◽

E3 Ubiquitin Ligase ◽

Melanoma Cells ◽

Mapk Signaling ◽

Braf V600e ◽

Promising Therapeutic Approach ◽

Melanoma Growth

Malignant melanoma, the most aggressive form of skin cancer, is characterized by high prevalence of BRAF/NRAS mutations and hyperactivation of extracellular signal-regulated kinase 1 and 2 (ERK1/2), mitogen-activated protein kinases (MAPK), leading to uncontrolled melanoma growth. Efficacy of current targeted therapies against mutant BRAF or MEK1/2 have been hindered by existence of innate or development of acquired resistance. Therefore, a better understanding of the mechanisms controlled by MAPK pathway driving melanogenesis will help develop new treatment approaches targeting this oncogenic cascade. Here, we identify E3 ubiquitin ligase PARK2 as a direct target of ELK1, a known transcriptional effector of MAPK signaling in melanoma cells. We show that pharmacological inhibition of BRAF-V600E or ERK1/2 in melanoma cells increases PARK2 expression. PARK2 overexpression reduces melanoma cell growth in vitro and in vivo and induces apoptosis. Conversely, its genetic silencing increases melanoma cell proliferation and reduces cell death. Further, we demonstrate that ELK1 is required by the BRAF-ERK1/2 pathway to repress PARK2 expression and promoter activity in melanoma cells. Clinically, PARK2 is highly expressed in WT BRAF and NRAS melanomas, but it is expressed at low levels in melanomas carrying BRAF/NRAS mutations. Overall, our data provide new insights into the tumor suppressive role of PARK2 in malignant melanoma and uncover a novel mechanism for the negative regulation of PARK2 via the ERK1/2-ELK1 axis. These findings suggest that reactivation of PARK2 may be a promising therapeutic approach to counteract melanoma growth.

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