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Wistar Institute [K. S., G. L., M. H.]; Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center [M. R. G., M. S. B., P. V., B. L. W.]; and Anatomic Pathology, Hospital of the University of Pennsylvania [P. v. B., D. E. E.], Philadelphia, Pennsylvania 19104
| ABSTRACT |
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| Introduction |
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| Materials and Methods |
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Antibodies and Reagents.
Mouse anti-ß-actin antibody was purchased from Sigma. Anti-p44/42 MAPK, anti-phospho-p44/42 MAPK (Thr202/Tyr204), anti-phospho-MEK, and anti-phospho-c-RAF antibodies were purchased from Cell Signaling Technology, Inc. (Beverly, MA). Anti-pan-Ras kit was obtained from Transduction Laboratories (Lexington, KY). Replication defective adenovirus containing antisense bFGF has been reported (13)
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Mutation Analyses.
Mutations in H-Ras, K-Ras, and N-Ras at codons 12, 13, and 61 were analyzed in both the strands. Genomic DNA was extracted from melanoma cell lines after proteinase K digestion and phenol-chloroform extraction. A total of 10 ng of DNA was subjected to PCR amplification using primers as described (14)
and sequencing. Mutational analysis of BRAF was performed using heteroduplex and sequence analysis. A modified heteroduplex method, CSCE, was used to screen for somatic mutations in BRAF, H-Ras, and K-Ras. The fluorescence-based CSCE technique, adapted from Rozycka et al. (15)
, is both sensitive and high-throughput. PCR primers were designed to amplify the exon plus at least 50 bp of flanking intronic sequence. Template for detection of somatic changes was 12 ng genomic DNA from the cell lines spiked with 3 ng of normal DNA to insure heteroduplex formation in case the mutation is accompanied by loss of the wild-type allele. PCR reactions were performed using standard PCR conditions with fluorescence-labeled primers. Products were denatured followed by incubation at 68°C for 1 h to allow for reannealing and the generation of heteroduplexes. The samples were then analyzed on the ABI PRISM 3100 automated capillary sequencer under semidenaturing conditions using polymer provided by ABI and optimized run conditions. Data were captured using GeneScan to identify samples that produced a shift in peak migration relative to either the matched normal control from the same individual or a standard normal control, indicating the presence of a putative sequence variation. Amplicons, selected by the presence of a heteroduplex shift, were then sequenced directly in both the forward and reverse directions on the automated sequencer to confirm the presence of a mutation. Exons 11 and 15 were screened for BRAF mutations, exon 2 for K-Ras mutations, and exon 3 for N-Ras mutations (10)
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Western Analysis.
Cells were grown in six-well dishes except melanocytes, which were grown in 100-mm dishes. These cells were starved of serum or growth factors for indicated period of time and subsequently lysed in the extraction buffer containing 40 mM Tris (pH 7.6), 100 mM NaCl, 50 mM NaF, 5 mM EDTA, 1 mM NaVO4, 5 µg/ml of aprotinin, leupeptin, and pepstatin, respectively, and 1% Triton X-100. The extracts were spun down at 12,000 rpm for 20 min, supernatant was separated, and protein concentration was estimated using BCA assay (Pierce Chemical Co., Rockford, IL). Protein samples were loaded at 35 µg/lane, and were separated on 10% SDS polyacrylamide gels and transferred to polyvinylidene difluoride membranes. The proteins were detected using appropriate primary antibody, and signal was detected using peroxidase-conjugated secondary antibody followed by development using enhanced electrochemiluminescence system (Amersham, Arlington Heights, IL).
Ras Activation Assay.
Ras activation assay was performed as suggested by the manufacturer (Upstate Biotechnology, Waltham, MA).
| Results and Discussion |
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We also examined the activation status of Ras using an immunoprecipitation assay involving immobilized RAF-1 Ras binding domain. We observed in serum-starved cells the constitutive activation of Ras in all of the melanoma cell lines examined (Fig. 1F)
. However, normal melanocytes did not show activation of Ras in the absence of serum (Fig. 1F)
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We next examined Erk1/2 activation in melanoma tissue samples from patients harboring melanocytic lesions of defined stages (Fig. 2)
. Normal melanocytes and nevus cells did not exhibit phosphorylated Erk1/2 (Fig. 2, A and B)
, whereas VGP (Fig. 2, CF)
and metastatic melanoma (Fig. 2, G and H)
tissue sections stained intensely for phosphorylated Erk.
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Aggressive melanoma cells can survive in the absence of exogenous growth stimulation by serum through several autocrine mechanisms. They express FGF receptor 1 and bFGF, forming an autocrine loop (19) , and inhibition of this loop inhibited Erk1/2 phosphorylation (20) . Melanoma cells also express c-Met and secrete its ligand HGF (5) . We have shown before that HGF induces Erk1/2 phosphorylation through activation of its receptor, c-Met, which can be inhibited by neutralizing antibody against HGF (5) . Therefore, HGF and FGF-2 may act in an additive fashion to stimulate Erk1/2 activation and, hence, proliferation and migration of melanoma cells. However, melanoma in a tissue context may have additional support from paracrine mechanisms such as insulin-like growth factor-1 and platelet-derived growth factor (16) . Because several growth factors may converge at the Ras signaling pathway, the cumulative strength and duration of the activation signal may play an important role in melanoma progression and maintenance.
Ras (H-Ras, K-Ras, and N-Ras) gene mutations are detected frequently in human cancers. These genes are converted to active oncogenes by point mutations occurring in codon 12, 13, or 61 (8) . We analyzed mutations of these codons in a number of melanoma cell lines using CSCE and PCR sequencing method. Sequence analysis of Ras genes did not indicate any activating mutations in the codons associated frequently with tumor. However, most of the cell lines demonstrated activating mutations in the kinase domain of BRAF. A consequence of this mutation is that BRAF gains the ability to interact with MEK and several other signaling molecules without the prerequisite of being phosphorylated (10) . Independent activation of BRAF without the involvement of Ras has also been reported (6) . In this instance, a parallel pathway for activation of BRAF through protein kinase A has been proposed. However, the extent of participation of this pathway in melanoma is not clear.
In conclusion, we have demonstrated that in melanoma cell lines and melanoma tumor tissues the Erk1/2 pathway is constitutively active as a consequence of autocrine growth factor stimulation and activating mutations in the BRAF gene. Identification and understanding of precise cellular events, which precede these two independentmechanisms, may provide clues to critical pathways necessary for melanoma progression.
| FOOTNOTES |
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1 Supported in part by NIH Grants CA-25874, CA-47159, CA-76674, and CA-10815 (to M. H.). ![]()
2 These authors contributed equally to this study. ![]()
3 To whom requests for reprints should be addressed, at The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. Phone: (215) 898-3950; Fax: (215) 898-0980; E-mail: herlynm{at}wistar.upenn.edu ![]()
4 The abbreviations used are: bFGF, basic fibroblast growth factor; CSCE, conformation-sensitive capillary electrophoresis; HGF, hepatocyte growth factor; IL-8, interleukin 8; VGP, vertical growth phase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; FBS, fetal bovine serum; RGP, radial growth phase; FGF, fibroblast growth factor. ![]()
Received 9/30/02. Accepted 1/ 3/03.
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J. Yang, M. A. Price, C. L. Neudauer, C. Wilson, S. Ferrone, H. Xia, J. Iida, M. A. Simpson, and J. B. McCarthy Melanoma chondroitin sulfate proteoglycan enhances FAK and ERK activation by distinct mechanisms J. Cell Biol., June 21, 2004; 165(6): 881 - 891. [Abstract] [Full Text] [PDF] |
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D. C. Lev, A. Onn, V. O. Melinkova, C. Miller, V. Stone, M. Ruiz, E. C. McGary, H. N. Ananthaswamy, J. E. Price, and M. Bar-Eli Exposure of Melanoma Cells to Dacarbazine Results in Enhanced Tumor Growth and Metastasis In Vivo J. Clin. Oncol., June 1, 2004; 22(11): 2092 - 2100. [Abstract] [Full Text] [PDF] |
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C. Wellbrock, L. Ogilvie, D. Hedley, M. Karasarides, J. Martin, D. Niculescu-Duvaz, C. J. Springer, and R. Marais V599EB-RAF is an Oncogene in Melanocytes Cancer Res., April 1, 2004; 64(7): 2338 - 2342. [Abstract] [Full Text] [PDF] |
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B. Bedogni, M. S. O'Neill, S. M. Welford, D. M. Bouley, A. J. Giaccia, N. C. Denko, and M. B. Powell Topical Treatment with Inhibitors of the Phosphatidylinositol 3'-Kinase/Akt and Raf/Mitogen-Activated Protein Kinase Kinase/Extracellular Signal-Regulated Kinase Pathways Reduces Melanoma Development in Severe Combined Immunodeficient Mice Cancer Res., April 1, 2004; 64(7): 2552 - 2560. [Abstract] [Full Text] [PDF] |
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R H Edwards, M R Ward, H Wu, C A Medina, M S Brose, P Volpe, S Nussen-Lee, H M Haupt, A M Martin, M Herlyn, et al. Absence of BRAF mutations in UV-protected mucosal melanomas J. Med. Genet., April 1, 2004; 41(4): 270 - 272. [Abstract] [Full Text] [PDF] |
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C. Perlis and M. Herlyn Recent Advances in Melanoma Biology Oncologist, April 1, 2004; 9(2): 182 - 187. [Abstract] [Full Text] [PDF] |
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M. Shinozaki, A. Fujimoto, D. L. Morton, and D. S. B. Hoon Incidence of BRAF Oncogene Mutation and Clinical Relevance for Primary Cutaneous Melanomas Clin. Cancer Res., March 1, 2004; 10(5): 1753 - 1757. [Abstract] [Full Text] [PDF] |
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A. Bagnato, L. Rosano, F. Spinella, V. Di Castro, R. Tecce, and P. G. Natali Endothelin B Receptor Blockade Inhibits Dynamics of Cell Interactions and Communications in Melanoma Cell Progression Cancer Res., February 15, 2004; 64(4): 1436 - 1443. [Abstract] [Full Text] [PDF] |
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K. M. Eisenmann, M. W. VanBrocklin, N. A. Staffend, S. M. Kitchen, and H.-M. Koo Mitogen-Activated Protein Kinase Pathway-Dependent Tumor-Specific Survival Signaling in Melanoma Cells through Inactivation of the Proapoptotic Protein Bad Cancer Res., December 1, 2003; 63(23): 8330 - 8337. [Abstract] [Full Text] [PDF] |
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K. Jorgensen, R. Holm, G. M. Maelandsmo, and V. A. Florenes Expression of Activated Extracellular Signal-Regulated Kinases 1/2 in Malignant Melanomas: Relationship with Clinical Outcome Clin. Cancer Res., November 1, 2003; 9(14): 5325 - 5331. [Abstract] [Full Text] [PDF] |
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D. Rimoldi, S. Salvi, D. Lienard, F. J. Lejeune, D. Speiser, L. Zografos, and J.-C. Cerottini Lack of BRAF Mutations in Uveal Melanoma Cancer Res., September 15, 2003; 63(18): 5712 - 5715. [Abstract] [Full Text] [PDF] |
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S. R. Conner, G. Scott, and A. E. Aplin Adhesion-dependent Activation of the ERK1/2 Cascade Is By-passed in Melanoma Cells J. Biol. Chem., September 5, 2003; 278(36): 34548 - 34554. [Abstract] [Full Text] [PDF] |
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S. R. Hingorani, M. A. Jacobetz, G. P. Robertson, M. Herlyn, and D. A. Tuveson Suppression of BRAFV599E in Human Melanoma Abrogates Transformation Cancer Res., September 1, 2003; 63(17): 5198 - 5202. [Abstract] [Full Text] [PDF] |
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R. Kumar, S. Angelini, K. Czene, I. Sauroja, M. Hahka-Kemppinen, S. Pyrhonen, and K. Hemminki BRAF Mutations in Metastatic Melanoma: A Possible Association with Clinical Outcome Clin. Cancer Res., August 1, 2003; 9(9): 3362 - 3368. [Abstract] [Full Text] [PDF] |
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A. Gorden, I. Osman, W. Gai, D. He, W. Huang, A. Davidson, A. N. Houghton, K. Busam, and D. Polsky Analysis of BRAF and N-RAS Mutations in Metastatic Melanoma Tissues Cancer Res., July 15, 2003; 63(14): 3955 - 3957. [Abstract] [Full Text] [PDF] |
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