Lack of extracellular signal-regulated kinase mitogen-activated protein kinase signaling shows a new type of melanoma.
The majority of human melanomas harbor activating mutations of either N-RAS or its downstream effector B-RAF, which cause activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase and the ERK MAPK cascade. The melanoma-relevant effectors of ERK activation, however, are largely unknown. In this work, we show that increased ERK activation correlates strongly with mutational status of N-RAS or B-RAF in 21 melanoma cell lines. Melanoma lines that were wild-type for RAS/RAF showed low levels of ERK activation comparable with primary human melanocytes. Through supervised analysis of RNA expression profiles, we identified 82 genes, including TWIST1, HIF1alpha, and IL-8, which correlated with ERK activation across the panel of cell lines and which decreased with pharmacologic inhibition of ERK activity, suggesting that they are ERK transcriptional targets in melanoma. Additionally, lines lacking mutations of N-RAS and B-RAF were molecularly distinct and characterized by p53 inactivation, reduced ERK activity, and increased expression of epithelial markers. Analysis of primary human melanomas by tissue microarray confirmed a high correlation among expression of these epithelial markers in a heterogeneous sample of 570 primary human tumors, suggesting that a significant frequency of primary melanomas is of this "epithelial-like" subtype. These results show a molecularly distinct melanoma subtype that does not require ERK activation or epithelial-mesenchymal transformation for progression.
Shields
Janiel M
JM
Department of Biochemistry and Biophysics, The Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
Thomas
Nancy E
NE
Cregger
Melissa
M
Berger
Aaron J
AJ
Leslie
Michael
M
Torrice
Chad
C
Hao
Honglin
H
Penland
Shannon
S
Arbiser
Jack
J
Scott
Glynis
G
Zhou
Tong
T
Bar-Eli
Menashe
M
Bear
James E
JE
Der
Channing J
CJ
Kaufmann
William K
WK
Rimm
David L
DL
Sharpless
Norman E
NE
D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004847:Epithelial Cells / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D020935:MAP Kinase Signaling System; D008544:Melanocytes / Q000201:enzymology; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D048490:raf Kinases / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
D019941:Cyclin-Dependent Kinase Inhibitor p16; D012334:RNA, Neoplasm; D048490:raf Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins