Met amplification and tumor progression in Cdkn2a-deficient melanocytes.
While many genetic alterations have been identified in melanoma, the relevant molecular events that contribute to disease progression are poorly understood. Most primary human melanomas exhibit loss of expression of the CDKN2A locus in addition to activation of the canonical mitogen-activated protein kinase signaling pathway. In this study, we used a Cdkn2a-deficient mouse melanocyte cell line to screen for secondary genetic events in melanoma tumor progression. Upon investigation, intrachromosomal gene amplification of Met, a receptor tyrosine kinase implicated in melanoma progression, was identified in Cdkn2a-deficient tumors. RNA interference targeting Met in these tumor cells resulted in a significant delay in tumor growth in vivo compared with the control cells. MET expression is rarely detected in primary human melanoma but is frequently observed in metastatic disease. This study validates a role for Met activation in melanoma tumor progression in the context of Cdkn2a deficiency.
Nevada Cancer Institute, One Breakthrough Way, Las Vegas, NV, USA.
Matthew W
MW
Vanbrocklin
James P
JP
Robinson
Todd
T
Whitwam
Adam R
AR
Guilbeault
Julie
J
Koeman
Pamela J
PJ
Swiatek
George F
GF
Vande Woude
Joseph D
JD
Khoury
Sheri L
SL
Holmen
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008544:Melanocytes / Q000378:metabolism* / Q000473:pathology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019859:Proto-Oncogene Proteins c-met / Q000502:physiology*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019859:Proto-Oncogene Proteins c-met