Osteosarcoma (OS) is the most common primary malignant tumor of the bone, and pulmonary metastasis is the most frequent cause of OS mortality. The aim of this study was to discover and characterize genetic networks differentially expressed in metastatic OS. Expression profiling of OS tumors, and subsequent supervised network analysis, was performed to discover genetic networks differentially activated or organized in metastatic OS compared to localized OS. Broad trends among the profiles of metastatic tumors include aberrant activity of intracellular organization and translation networks, as well as disorganization of metabolic networks. The differentially activated PRKCε-RASGRP3-GNB2 network, which interacts with the disorganized DLG2 hub, was also found to be differentially expressed among OS cell lines with differing metastatic capacity in xenograft models. PRKCε transcript was more abundant in some metastatic OS tumors; however the difference was not significant overall. In functional studies, PRKCε was not found to be involved in migration of M132 OS cells, but its protein expression was induced in M112 OS cells following IGF-1 stimulation.
References
[1]
Kansara, M.; Thomas, D.M. Molecular pathogenesis of osteosarcoma. DNA Cell Biol. 2007, 26, 1–18, doi:10.1089/dna.2006.0505.
[2]
Murphey, M.D.; Robbin, M.R.; McRae, G.A.; Flemming, D.J.; Temple, H.T.; Kransdorf, M.J. The many faces of osteosarcoma. Radiographics 1997, 17, 1205–1231.
[3]
PosthumaDeBoer, J.; Witlox, M.A.; Kaspers, G.J.; van Royen, B.J. Molecular alterations as target for therapy in metastatic osteosarcoma: A review of literature. Clin. Exp. Metastasis 2011, 28, 493–503, doi:10.1007/s10585-011-9384-x.
[4]
Clark, J.C.; Dass, C.R.; Choong, P.F. A review of clinical and molecular prognostic factors in osteosarcoma. J. Cancer Res. Clin. Oncol. 2008, 134, 281–297, doi:10.1007/s00432-007-0330-x.
[5]
Kong, C.; Hansen, M.F. Biomarkers in Osteosarcoma. Expert Opin. Med. Diagn. 2009, 3, 13–23, doi:10.1517/17530050802608496.
[6]
Schulze, A.; Downward, J. Navigating gene expression using microarrays—A technology review. Nat. Cell Biol. 2001, 3, E190–E195, doi:10.1038/35087138.
[7]
Dupuy, A.; Simon, R.M. Critical review of published microarray studies for cancer outcome and guidelines on statistical analysis and reporting. J. Natl. Cancer Inst. 2007, 99, 147–157, doi:10.1093/jnci/djk018.
[8]
Goeman, J.J.; Buhlmann, P. Analyzing gene expression data in terms of gene sets: Methodological issues. Bioinformatics 2007, 23, 980–987.
[9]
Song, S.; Black, M.A. Microarray-based gene set analysis: A comparison of current methods. BMC Bioinformatics 2008, 9, 502.
[10]
Subramanian, A.; Kuehn, H.; Gould, J.; Tamayo, P.; Mesirov, J.P. GSEA-P: A desktop application for Gene Set Enrichment Analysis. Bioinformatics 2007, 23, 3251–3253.
[11]
Chuang, H.Y.; Lee, E.; Liu, Y.T.; Lee, D.; Ideker, T. Network-based classification of breast cancer metastasis. Mol. Syst. Biol. 2007, 3, 140.
[12]
Taylor, I.W.; Linding, R.; Warde-Farley, D.; Liu, Y.; Pesquita, C.; Faria, D.; Bull, S.; Pawson, T.; Morris, Q.; Wrana, J.L. Dynamic modularity in protein interaction networks predicts breast cancer outcome. Nat. Biotechnol. 2009, 27, 199–204.
[13]
Perou, C.M.; Sorlie, T.; Eisen, M.B.; van de Rijn, M.; Jeffrey, S.S.; Rees, C.A.; Pollack, J.R.; Ross, D.T.; Johnsen, H.; Akslen, L.A.; et al. Molecular portraits of human breast tumours. Nature 2000, 406, 747–752.
[14]
Van’t Veer, L.J.; Dai, H.; van de Vijver, M.J.; He, Y.D.; Hart, A.A.; Mao, M.; Peterse, H.L.; van der Kooy, K.; Marton, M.J.; Witteveen, A.T.; et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002, 415, 530–536.
[15]
Cerami, E.G.; Gross, B.E.; Demir, E.; Rodchenkov, I.; Babur, O.; Anwar, N.; Schultz, N.; Bader, G.D.; Sander, C. Pathway Commons, a web resource for biological pathway data. Nucleic Acids Res. 2011, 39, D685–D690, doi:10.1093/nar/gkq1039.
[16]
Osaka, E.; Suzuki, T.; Osaka, S.; Yoshida, Y.; Sugita, H.; Asami, S.; Tabata, K.; Hemmi, A.; Sugitani, M.; Nemoto, N.; et al. Survivin as a prognostic factor for osteosarcoma patients. Acta Histochem. Cytochem. 2006, 39, 95–100, doi:10.1267/ahc.06005.
[17]
Pradelli, E.; Karimdjee-Soilihi, B.; Michiels, J.F.; Ricci, J.E.; Millet, M.A.; Vandenbos, F.; Sullivan, T.J.; Collins, T.L.; Johnson, M.G.; Medina, J.C.; et al. Antagonism of chemokine receptor CXCR3 inhibits osteosarcoma metastasis to lungs. Int. J. Cancer 2009, 125, 2586–2594, doi:10.1002/ijc.24665.
[18]
Cantiani, L.; Manara, M.C.; Zucchini, C.; de Sanctis, P.; Zuntini, M.; Valvassori, L.; Serra, M.; Olivero, M.; di Renzo, M.F.; Colombo, M.P.; et al. Caveolin-1 reduces osteosarcoma metastases by inhibiting c-Src activity and met signaling. Cancer Res. 2007, 67, 7675–7685, doi:10.1158/0008-5472.CAN-06-4697.
[19]
Entz-Werle, N.; Marcellin, L.; Gaub, M.P.; Guerin, E.; Schneider, A.; Berard-Marec, P.; Kalifa, C.; Brugiere, L.; Pacquement, H.; Schmitt, C.; et al. Prognostic significance of allelic imbalance at the c-kit gene locus and c-kit overexpression by immunohistochemistry in pediatric osteosarcomas. J. Clin. Oncol. 2005, 23, 2248–2255, doi:10.1200/JCO.2005.03.119.
[20]
Boulytcheva, I.V.; Soloviev, Y.N.; Kushlinskii, N.E.; Mahson, A.N. Expression of molecular markers in the tumor and survival prognosis in osteosarcoma. Bull. Exp. Biol. Med. 2010, 150, 237–242.
[21]
Oda, Y.; Wehrmann, B.; Radig, K.; Walter, H.; Rose, I.; Neumann, W.; Roessner, A. Expression of growth factors and their receptors in human osteosarcomas. Immunohistochemical detection of epidermal growth factor, platelet-derived growth factor and their receptors: Its correlation with proliferating activities and p53 expression. Gen. Diagn. Pathol. 1995, 141, 97–103.
Hoang, B.H.; Kubo, T.; Healey, J.H.; Sowers, R.; Mazza, B.; Yang, R.; Huvos, A.G.; Meyers, P.A.; Gorlick, R. Expression of LDL receptor-related protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma. Int. J. Cancer 2004, 109, 106–111.
[24]
Boulytcheva, I.V.; Soloviev, Y.N.; Kushlinskii, N.E.; Mahson, A.N. Expression of molecular markers in the tumor and survival prognosis in osteosarcoma. Bull. Exp. Biol. Med. 2010, 150, 237–242.
[25]
Ferrari, S.; Bertoni, F.; Zanella, L.; Setola, E.; Bacchini, P.; Alberghini, M.; Versari, M.; Bacci, G. Evaluation of P-glycoprotein, HER-2/ErbB-2, p53, and Bcl-2 in primary tumor and metachronous lung metastases in patients with high-grade osteosarcoma. Cancer 2004, 100, 1936–1942, doi:10.1002/cncr.20151.
[26]
Gorlick, R.; Huvos, A.G.; Heller, G.; Aledo, A.; Beardsley, G.P.; Healey, J.H.; Meyers, P.A. Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J. Clin. Oncol. 1999, 17, 2781–2788.
[27]
Onda, M.; Matsuda, S.; Higaki, S.; Iijima, T.; Fukushima, J.; Yokokura, A.; Kojima, T.; Horiuchi, H.; Kurokawa, T.; Yamamoto, T. ErbB-2 expression is correlated with poor prognosis for patients with osteosarcoma. Cancer 1996, 77, 71–78, doi:10.1002/(SICI)1097-0142(19960101)77:1<71::AID-CNCR13>3.0.CO;2-5.
[28]
Scotlandi, K.; Manara, M.C.; Hattinger, C.M.; Benini, S.; Perdichizzi, S.; Pasello, M.; Bacci, G.; Zanella, L.; Bertoni, F.; Picci, P.; et al. Prognostic and therapeutic relevance of HER2 expression in osteosarcoma and Ewing's sarcoma. Eur. J. Cancer 2005, 41, 1349–1361, doi:10.1016/j.ejca.2005.03.015.
[29]
Zhou, H.; Randall, R.L.; Brothman, A.R.; Maxwell, T.; Coffin, C.M.; Goldsby, R.E. Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification. J. Pediatr. Hematol. Oncol. 2003, 25, 27–32, doi:10.1097/00043426-200301000-00007.
[30]
Perbal, B.; Zuntini, M.; Zambelli, D.; Serra, M.; Sciandra, M.; Cantiani, L.; Lucarelli, E.; Picci, P.; Scotlandi, K. Prognostic value of CCN3 in osteosarcoma. Clin. Cancer Res. 2008, 14, 701–709, doi:10.1158/1078-0432.CCR-07-0806.
Gordon, N.; Koshkina, N.V.; Jia, S.F.; Khanna, C.; Mendoza, A.; Worth, L.L.; Kleinerman, E.S. Corruption of the Fas pathway delays the pulmonary clearance of murine osteosarcoma cells, enhances their metastatic potential, and reduces the effect of aerosol gemcitabine. Clin. Cancer Res. 2007, 13, 4503–4510, doi:10.1158/1078-0432.CCR-07-0313.
[33]
Weber, G.F.; Bronson, R.T.; Ilagan, J.; Cantor, H.; Schmits, R.; Mak, T.W. Absence of the CD44 gene prevents sarcoma metastasis. Cancer Res. 2002, 62, 2281–2286.
[34]
Kubo, T.; Piperdi, S.; Rosenblum, J.; Antonescu, C.R.; Chen, W.; Kim, H.S.; Huvos, A.G.; Sowers, R.; Meyers, P.A.; Healey, J.H.; et al. Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma. Cancer 2008, 112, 2119–2129, doi:10.1002/cncr.23437.
[35]
Sulzbacher, I.; Birner, P.; Trieb, K.; Traxler, M.; Lang, S.; Chott, A. Expression of platelet-derived growth factor-AA is associated with tumor progression in osteosarcoma. Mod. Pathol. 2003, 16, 66–71, doi:10.1097/01.MP.0000043522.76788.0A.
[36]
Mizobuchi, H.; Garcia-Castellano, J.M.; Philip, S.; Healey, J.H.; Gorlick, R. Hypoxia markers in human osteosarcoma: An exploratory study. Clin. Orthop. Relat. Res. 2008, 466, 2052–2059, doi:10.1007/s11999-008-0328-y.
[37]
Kashima, T.; Nakamura, K.; Kawaguchi, J.; Takanashi, M.; Ishida, T.; Aburatani, H.; Kudo, A.; Fukayama, M.; Grigoriadis, A.E. Overexpression of cadherins suppresses pulmonary metastasis of osteosarcoma in vivo. Int. J. Cancer 2003, 104, 147–154, doi:10.1002/ijc.10931.
[38]
Ek, E.T.; Dass, C.R.; Contreras, K.G.; Choong, P.F. PEDF-derived synthetic peptides exhibit antitumor activity in an orthotopic model of human osteosarcoma. J. Orthop. Res. 2007, 25, 1671–1680, doi:10.1002/jor.20434.
[39]
Duan, X.; Jia, S.F.; Koshkina, N.; Kleinerman, E.S. Intranasal interleukin-12 gene therapy enhanced the activity of ifosfamide against osteosarcoma lung metastases. Cancer 2006, 106, 1382–1388, doi:10.1002/cncr.21744.
[40]
Xu, J.; Wu, S.; Shi, X. Expression of matrix metalloproteinase regulator, RECK, and its clinical significance in osteosarcoma. J. Orthop. Res. 2010, 28, 1621–1625, doi:10.1002/jor.21178.
[41]
Kaya, M.; Wada, T.; Nagoya, S.; Yamashita, T. Prevention of postoperative progression of pulmonary metastases in osteosarcoma by antiangiogenic therapy using endostatin. J. Orthop. Sci. 2007, 12, 562–567, doi:10.1007/s00776-007-1179-1.
[42]
Luu, H.H.; Zhou, L.; Haydon, R.C.; Deyrup, A.T.; Montag, A.G.; Huo, D.; Heck, R.; Heizmann, C.W.; Peabody, T.D.; Simon, M.A.; He, T.C. Increased expression of S100A6 is associated with decreased metastasis and inhibition of cell migration and anchorage independent growth in human osteosarcoma. Cancer Lett. 2005, 229, 135–148, doi:10.1016/j.canlet.2005.02.015.
[43]
Braczkowski, R.; Schally, A.V.; Plonowski, A.; Varga, J.L.; Groot, K.; Krupa, M.; Armatis, P. Inhibition of proliferation in human MNNG/HOS osteosarcoma and SK-ES-1 Ewing sarcoma cell lines in vitro and in vivo by antagonists of growth hormone-releasing hormone: Effects on insulin-like growth factor II. Cancer 2002, 95, 1735–1745.
[44]
Burrow, S.; Andrulis, I.L.; Pollak, M.; Bell, R.S. Expression of insulin-like growth factor receptor, IGF-1, and IGF-2 in primary and metastatic osteosarcoma. J. Surg. Oncol. 1998, 69, 21–27, doi:10.1002/(SICI)1096-9098(199809)69:1<21::AID-JSO5>3.0.CO;2-M.
Kolb, E.A.; Gorlick, R.; Houghton, P.J.; Morton, C.L.; Lock, R.; Carol, H.; Reynolds, C.P.; Maris, J.M.; Keir, S.T.; Billups, C.A.; et al. Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program. Pediatr. Blood Cancer 2008, 50, 1190–1197, doi:10.1002/pbc.21450.
[47]
Kolb, E.A.; Kamara, D.; Zhang, W.; Lin, J.; Hingorani, P.; Baker, L.; Houghton, P.; Gorlick, R. R1507, a fully human monoclonal antibody targeting IGF-1R, is effective alone and in combination with rapamycin in inhibiting growth of osteosarcoma xenografts. Pediatr. Blood Cancer 2010, 55, 67–75.
[48]
Pinski, J.; Schally, A.V.; Groot, K.; Halmos, G.; Szepeshazi, K.; Zarandi, M.; Armatis, P. Inhibition of growth of human osteosarcomas by antagonists of growth hormone-releasing hormone. J. Natl. Cancer Inst. 1995, 87, 1787–1794, doi:10.1093/jnci/87.23.1787.
[49]
Pinski, J.; Schally, A.V.; Halmos, G.; Szepeshazi, K.; Groot, K. Somatostatin analog RC-160 inhibits the growth of human osteosarcomas in nude mice. Int. J. Cancer 1996, 65, 870–874, doi:10.1002/(SICI)1097-0215(19960315)65:6<870::AID-IJC27>3.0.CO;2-6.
[50]
Pollack, R. Suramin Blockade of InsulinLike Growth Factor I-Stimulated Proliferation of Human Osteosarcoma Cells. J. Natl. Cancer Inst. 1990, 82, 1349–1352, doi:10.1093/jnci/82.16.1349.
[51]
Sekyi-Otu, A.; Bell, R.S.; Ohashi, C.; Pollak, M.; Andrulis, I.L. Insulin-like growth factor 1 (IGF-1) receptors, IGF-1, and IGF-2 are expressed in primary human sarcomas. Cancer Res. 1995, 55, 129–134.
[52]
Kim, S.Y.; Lee, C.H.; Midura, B.V.; Yeung, C.; Mendoza, A.; Hong, S.H.; Ren, L.; Wong, D.; Korz, W.; Merzouk, A.; et al. Inhibition of the CXCR4/CXCL12 chemokine pathway reduces the development of murine pulmonary metastases. Clin. Exp. Metastasis 2008, 25, 201–211, doi:10.1007/s10585-007-9133-3.
[53]
Laverdiere, C.; Hoang, B.H.; Yang, R.; Sowers, R.; Qin, J.; Meyers, P.A.; Huvos, A.G.; Healey, J.H.; Gorlick, R. Messenger RNA expression levels of CXCR4 correlate with metastatic behavior and outcome in patients with osteosarcoma. Clin. Cancer Res. 2005, 11, 2561–2567.
[54]
Lin, F.; Zheng, S.E.; Shen, Z.; Tang, L.N.; Chen, P.; Sun, Y.J.; Zhao, H.; Yao, Y. Relationships between levels of CXCR4 and VEGF and blood-borne metastasis and survival in patients with osteosarcoma. Med. Oncol. 2011, 28, 649–653, doi:10.1007/s12032-010-9493-4.
[55]
Oda, Y.; Yamamoto, H.; Tamiya, S.; Matsuda, S.; Tanaka, K.; Yokoyama, R.; Iwamoto, Y.; Tsuneyoshi, M. CXCR4 and VEGF expression in the primary site and the metastatic site of human osteosarcoma: Analysis within a group of patients, all of whom developed lung metastasis. Mod. Pathol. 2006, 19, 738–745, doi:10.1038/modpathol.3800587.
[56]
Dalla-Torre, C.A.; Yoshimoto, M.; Lee, C.H.; Joshua, A.M.; de Toledo, S.R.; Petrilli, A.S.; Andrade, J.A.; Chilton-MacNeill, S.; Zielenska, M.; Squire, J.A. Effects of THBS3, SPARC and SPP1 expression on biological behavior and survival in patients with osteosarcoma. BMC Cancer 2006, 6, 237, doi:10.1186/1471-2407-6-237.
[57]
Engin, F.; Bertin, T.; Ma, O.; Jiang, M.M.; Wang, L.; Sutton, R.E.; Donehower, L.A.; Lee, B. Notch signaling contributes to the pathogenesis of human osteosarcomas. Hum. Mol. Genet. 2009, 18, 1464–1470, doi:10.1093/hmg/ddp057.
[58]
Ferrari, C.; Benassi, S.; Ponticelli, F.; Gamberi, G.; Ragazzini, P.; Pazzaglia, L.; Balladelli, A.; Bertoni, F.; Picci, P. Role of MMP-9 and its tissue inhibitor TIMP-1 in human osteosarcoma: Findings in 42 patients followed for 1–16 years. Acta Orthop. Scand. 2004, 75, 487–491, doi:10.1080/00016470410001295-1.
[59]
Yang, C.; Ji, D.; Weinstein, E.J.; Choy, E.; Hornicek, F.J.; Wood, K.B.; Liu, X.; Mankin, H.; Duan, Z. The kinase Mirk is a potential therapeutic target in osteosarcoma. Carcinogenesis 2010, 31, 552–558, doi:10.1093/carcin/bgp330.
[60]
Kersting, C.; Gebert, C.; Agelopoulos, K.; Schmidt, H.; van Diest, P.J.; Juergens, H.; Winkelmann, W.; Kevric, M.; Gosheger, G.; Brandt, B.; et al. Epidermal growth factor receptor expression in high-grade osteosarcomas is associated with a good clinical outcome. Clin. Cancer Res. 2007, 13, 2998–3005, doi:10.1158/1078-0432.CCR-06-2432.
[61]
Dass, C.R.; Nadesapillai, A.P.; Robin, D.; Howard, M.L.; Fisher, J.L.; Zhou, H.; Choong, P.F. Downregulation of uPAR confirms link in growth and metastasis of osteosarcoma. Clin. Exp. Metastasis 2005, 22, 643–652, doi:10.1007/s10585-006-9004-3.
[62]
Uchibori, M.; Nishida, Y.; Nagasaka, T.; Yamada, Y.; Nakanishi, K.; Ishiguro, N. Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma. Int. J. Oncol. 2006, 28, 33–42.
Feng, Y.; Hu, J.; Ma, J.; Feng, K.; Zhang, X.; Yang, S.; Wang, W.; Zhang, J.; Zhang, Y. RNAi-mediated silencing of VEGF-C inhibits non-small cell lung cancer progression by simultaneously down-regulating the CXCR4, CCR7, VEGFR-2 and VEGFR-3-dependent axes-induced ERK, p38 and AKT signalling pathways. Eur. J. Cancer 2011, 47, 2353–2363.
[68]
Kaya, M.; Wada, T.; Akatsuka, T.; Kawaguchi, S.; Nagoya, S.; Shindoh, M.; Higashino, F.; Mezawa, F.; Okada, F.; Ishii, S. Vascular endothelial growth factor expression in untreated osteosarcoma is predictive of pulmonary metastasis and poor prognosis. Clin. Cancer Res. 2000, 6, 572–577.
[69]
Kaya, M.; Wada, T.; Kawaguchi, S.; Nagoya, S.; Yamashita, T.; Abe, Y.; Hiraga, H.; Isu, K.; Shindoh, M.; Higashino, F.; et al. Increased pre-therapeutic serum vascular endothelial growth factor in patients with early clinical relapse of osteosarcoma. Br. J. Cancer 2002, 86, 864–869, doi:10.1038/sj.bjc.6600201.
[70]
Kaya, M.; Wada, T.; Nagoya, S.; Sasaki, M.; Matsumura, T.; Yamashita, T. The level of vascular endothelial growth factor as a predictor of a poor prognosis in osteosarcoma. J. Bone Joint Surg. Br. 2009, 91, 784–788, doi:10.1302/0301-620X.91B6.21853.
[71]
Lee, Y.H.; Tokunaga, T.; Oshika, Y.; Suto, R.; Yanagisawa, K.; Tomisawa, M.; Fukuda, H.; Nakano, H.; Abe, S.; Tateishi, A.; et al. Cell-retained isoforms of vascular endothelial growth factor (VEGF) are correlated with poor prognosis in osteosarcoma. Eur. J. Cancer 1999, 35, 1089–1093, doi:10.1016/S0959-8049(99)00073-8.
[72]
Sulzbacher, I.; Birner, P.; Trieb, K.; Lang, S.; Chott, A. Expression of osteopontin and vascular endothelial growth factor in benign and malignant bone tumors. Virchows Arch. 2002, 441, 345–349, doi:10.1007/s00428-002-0671-4.
[73]
Foukas, A.F.; Deshmukh, N.S.; Grimer, R.J.; Mangham, D.C.; Mangos, E.G.; Taylor, S. Stage-IIB osteosarcomas around the knee. A study of MMP-9 in surviving tumour cells. J. Bone Joint Surg. Br. 2002, 84, 706–711, doi:10.1302/0301-620X.84B5.12512.
Koshkina, N.V.; Khanna, C.; Mendoza, A.; Guan, H.; DeLauter, L.; Kleinerman, E.S. Fas-negative osteosarcoma tumor cells are selected during metastasis to the lungs: The role of the Fas pathway in the metastatic process of osteosarcoma. Mol. Cancer Res. 2007, 5, 991–999, doi:10.1158/1541-7786.MCR-07-0007.
[77]
Lafleur, E.A.; Koshkina, N.V.; Stewart, J.; Jia, S.F.; Worth, L.L.; Duan, X.; Kleinerman, E.S. Increased Fas expression reduces the metastatic potential of human osteosarcoma cells. Clin Cancer Res. 2004, 10, 8114–8119, doi:10.1158/1078-0432.CCR-04-0353.
[78]
Asai, T.; Tomita, Y.; Nakatsuka, S.; Hoshida, Y.; Myoui, A.; Yoshikawa, H.; Aozasa, K. VCP (p97) regulates NFkappaB signaling pathway, which is important for metastasis of osteosarcoma cell line. Jpn. J. Cancer Res. 2002, 93, 296–304.
[79]
Rubin, E.M.; Guo, Y.; Tu, K.; Xie, J.; Zi, X.; Hoang, B.H. Wnt inhibitory factor 1 decreases tumorigenesis and metastasis in osteosarcoma. Mol. Cancer Ther. 2010, 9, 731–741, doi:10.1158/1535-7163.MCT-09-0147.
[80]
De Nigris, F.; Rossiello, R.; Schiano, C.; Arra, C.; Williams-Ignarro, S.; Barbieri, A.; Lanza, A.; Balestrieri, A.; Giuliano, M.T.; Ignarro, L.J.; et al. Deletion of Yin Yang 1 protein in osteosarcoma cells on cell invasion and CXCR4/angiogenesis and metastasis. Cancer Res. 2008, 68, 1797–1808, doi:10.1158/0008-5472.CAN-07-5582.
[81]
Han, J.D.; Bertin, N.; Hao, T.; Goldberg, D.S.; Berriz, G.F.; Zhang, L.V.; Dupuy, D.; Walhout, A.J.; Cusick, M.E.; Roth, F.P.; et al. Evidence for dynamically organized modularity in the yeast protein-protein interaction network. Nature 2004, 430, 88–93.
[82]
Aziz, M.H.; Manoharan, H.T.; Verma, A.K. Protein kinase C epsilon, which sensitizes skin to sun’s UV radiation-induced cutaneous damage and development of squamous cell carcinomas, associates with Stat3. Cancer Res. 2007, 67, 1385–1394, doi:10.1158/0008-5472.CAN-06-3350.
[83]
Gundimeda, U.; Schiffman, J.E.; Gottlieb, S.N.; Roth, B.I.; Gopalakrishna, R. Negation of the cancer-preventive actions of selenium by over-expression of protein kinase Cepsilon and selenoprotein thioredoxin reductase. Carcinogenesis 2009, 30, 1553–1561.
[84]
Hafeez, B.B.; Zhong, W.; Weichert, J.; Dreckschmidt, N.E.; Jamal, M.S.; Verma, A.K. Genetic ablation of PKC epsilon inhibits prostate cancer development and metastasis in transgenic mouse model of prostate adenocarcinoma. Cancer Res. 2011, 71, 2318–2327, doi:10.1158/0008-5472.CAN-10-4170.
[85]
McJilton, M.A.; van Sikes, C.; Wescott, G.G.; Wu, D.; Foreman, T.L.; Gregory, C.W.; Weidner, D.A.; Harris Ford, O.; Morgan Lasater, A.; Mohler, J.L.; et al. Protein kinase Cepsilon interacts with Bax and promotes survival of human prostate cancer cells. Oncogene 2003, 22, 7958–7968, doi:10.1038/sj.onc.1206795.
[86]
Meshki, J.; Caino, M.C.; von Burstin, V.A.; Griner, E.; Kazanietz, M.G. Regulation of prostate cancer cell survival by protein kinase Cepsilon involves bad phosphorylation and modulation of the TNFalpha/JNK pathway. J. Biol. Chem. 2010, 285, 26033–26040.
[87]
Wu, D.; Foreman, T.L.; Gregory, C.W.; McJilton, M.A.; Wescott, G.G.; Ford, O.H.; Alvey, R.F.; Mohler, J.L.; Terrian, D.M. Protein kinase cepsilon has the potential to advance the recurrence of human prostate cancer. Cancer Res. 2002, 62, 2423–2429.
[88]
Grossoni, V.C.; Todaro, L.B.; Kazanietz, M.G.; de Kier Joffe, E.D.; Urtreger, A.J. Opposite effects of protein kinase C beta1 (PKCbeta1) and PKCepsilon in the metastatic potential of a breast cancer murine model. Breast Cancer Res. Treat. 2009, 118, 469–480.
[89]
Pan, Q.; Bao, L.W.; Kleer, C.G.; Sabel, M.S.; Griffith, K.A.; Teknos, T.N.; Merajver, S.D. Protein kinase C epsilon is a predictive biomarker of aggressive breast cancer and a validated target for RNA interference anticancer therapy. Cancer Res. 2005, 65, 8366–8371.
[90]
Huang, B.; Cao, K.; Li, X.; Guo, S.; Mao, X.; Wang, Z.; Zhuang, J.; Pan, J.; Mo, C.; Chen, J.; et al. The expression and role of protein kinase C (PKC) epsilon in clear cell renal cell carcinoma. J. Exp. Clin. Cancer Res. 2011, 30, 88, doi:10.1186/1756-9966-30-88.
[91]
Jansen, A.P.; Verwiebe, E.G.; Dreckschmidt, N.E.; Wheeler, D.L.; Oberley, T.D.; Verma, A.K. Protein kinase C-epsilon transgenic mice: A unique model for metastatic squamous cell carcinoma. Cancer Res. 2001, 61, 808–812.
[92]
Reddig, P.J.; Dreckschmidt, N.E.; Zou, J.; Bourguignon, S.E.; Oberley, T.D.; Verma, A.K. Transgenic mice overexpressing protein kinase C epsilon in their epidermis exhibit reduced papilloma burden but enhanced carcinoma formation after tumor promotion. Cancer Res. 2000, 60, 595–602.
[93]
Sand, J.M.; Aziz, M.H.; Dreckschmidt, N.E.; Havighurst, T.C.; Kim, K.; Oberley, T.D.; Verma, A.K. PKCepsilon overexpression, irrespective of genetic background, sensitizes skin to UVR-induced development of squamous-cell carcinomas. J. Invest. Dermatol. 2010, 130, 270–277, doi:10.1038/jid.2009.212.
[94]
Sand, J.M.; Hafeez, B.B.; Aziz, M.H.; Siebers, E.M.; Dreckschmidt, N.E.; Verma, A.K. Ultraviolet radiation and 12-O-tetradecanoylphorbol-13-acetate-induced interaction of mouse epidermal protein kinase C epsilon with Stat3 involve integration with Erk1/2. Mol. Carcinog. 2012, 51, 291–302, doi:10.1002/mc.20776.
[95]
Wheeler, D.L.; Ness, K.J.; Oberley, T.D.; Verma, A.K. Inhibition of the development of metastatic squamous cell carcinoma in protein kinase C epsilon transgenic mice by alpha-difluoromethylornithine accompanied by marked hair follicle degeneration and hair loss. Cancer Res. 2003, 63, 3037–3042.
[96]
Bao, L.; Gorin, M.A.; Zhang, M.; Ventura, A.C.; Pomerantz, W.C.; Merajver, S.D.; Teknos, T.N.; Mapp, A.K.; Pan, Q. Preclinical development of a bifunctional cancer cell homing, PKCepsilon inhibitory peptide for the treatment of head and neck cancer. Cancer Res. 2009, 69, 5829–5834, doi:10.1158/0008-5472.CAN-08-3465.
[97]
Martinez-Gimeno, C.; Diaz-Meco, M.T.; Dominguez, I.; Moscat, J. Alterations in levels of different protein kinase C isotypes and their influence on behavior of squamous cell carcinoma of the oral cavity: Epsilon PKC, a novel prognostic factor for relapse and survival. Head Neck 1995, 17, 516–525.
[98]
Pan, Q.; Bao, L.W.; Teknos, T.N.; Merajver, S.D. Targeted disruption of protein kinase C epsilon reduces cell invasion and motility through inactivation of RhoA and RhoC GTPases in head and neck squamous cell carcinoma. Cancer Res. 2006, 66, 9379–9384, doi:10.1158/0008-5472.CAN-06-2646.
[99]
Tosi, L.; Rinaldi, E.; Carinci, F.; Farina, A.; Pastore, A.; Pelucchi, S.; Cassano, L.; Evangelisti, R.; Carinci, P.; Volinia, S. Akt, protein kinase C, and mitogen-activated protein kinase phosphorylation status in head and neck squamous cell carcinoma. Head Neck 2005, 27, 130–137, doi:10.1002/hed.20120.
[100]
Bae, K.M.; Wang, H.; Jiang, G.; Chen, M.G.; Lu, L.; Xiao, L. Protein kinase C epsilon is overexpressed in primary human non-small cell lung cancers and functionally required for proliferation of non-small cell lung cancer cells in a p21/Cip1-dependent manner. Cancer Res. 2007, 67, 6053–6063, doi:10.1158/0008-5472.CAN-06-4037.
[101]
Caino, M.C.; von Burstin, V.A.; Lopez-Haber, C.; Kazanietz, M.G. Differential regulation of gene expression by protein kinase C isozymes as determined by genome-wide expression analysis. J. Biol. Chem. 2011, 286, 11254–11264.
[102]
Ding, L.; Wang, H.; Lang, W.; Xiao, L. Protein kinase C-epsilon promotes survival of lung cancer cells by suppressing apoptosis through dysregulation of the mitochondrial caspase pathway. J. Biol. Chem. 2002, 277, 35305–35313, doi:10.1074/jbc.M201460200.
[103]
Felber, M.; Sonnemann, J.; Beck, J.F. Inhibition of novel protein kinase C-epsilon augments TRAIL-induced cell death in A549 lung cancer cells. Pathol. Oncol. Res. 2007, 13, 295–301.
[104]
Aviel-Ronen, S.; Coe, B.P.; Lau, S.K.; da Cunha Santos, G.; Zhu, C.Q.; Strumpf, D.; Jurisica, I.; Lam, W.L.; Tsao, M.S. Genomic markers for malignant progression in pulmonary adenocarcinoma with bronchioloalveolar features. Proc. Natl. Acad. Sci. USA 2008, 105, 10155–10160, doi:10.1073/pnas.0709618105.
[105]
Yang, D.; Kedei, N.; Li, L.; Tao, J.; Velasquez, J.F.; Michalowski, A.M.; Toth, B.I.; Marincsak, R.; Varga, A.; Biro, T.; et al. RasGRP3 contributes to formation and maintenance of the prostate cancer phenotype. Cancer Res. 2010, 70, 7905–7917, doi:10.1158/0008-5472.CAN-09-4729.
[106]
Kimura, K.; Nakano, T.; Park, Y.B.; Tani, M.; Tsuda, H.; Beppu, Y.; Moriya, H.; Yokota, J. Establishment of human osteosarcoma cell lines with high metastatic potential to lungs and their utilities for therapeutic studies on metastatic osteosarcoma. Clin. Exp. Metastasis 2002, 19, 477–485.
[107]
Nakano, T.; Tani, M.; Ishibashi, Y.; Kimura, K.; Park, Y.B.; Imaizumi, N.; Tsuda, H.; Aoyagi, K.; Sasaki, H.; Ohwada, S.; et al. Biological properties and gene expression associated with metastatic potential of human osteosarcoma. Clin. Exp. Metastasis 2003, 20, 665–674, doi:10.1023/A:1027355610603.
[108]
Jia, S.F.; Worth, L.L.; Kleinerman, E.S. A nude mouse model of human osteosarcoma lung metastases for evaluating new therapeutic strategies. Clin. Exp. Metastasis 1999, 17, 501–506, doi:10.1023/A:1006623001465.
[109]
Zhu, W.; Guo, F.; Xu, T.; Chen, A. Establishment of nude mice model of human osteosarcoma cell line MG63 with different potential of metastasis. Chin. Ger. J. Clin. Oncol. 2007, 6, 484–486, doi:10.1007/s10330-007-0068-6.
[110]
England, K.; Ashford, D.; Kidd, D.; Rumsby, M. PKC epsilon is associated with myosin IIA and actin in fibroblasts. Cell. Signal. 2002, 14, 529–536, doi:10.1016/S0898-6568(01)00277-7.
[111]
Allen, T.R.; Krueger, K.D.; Hunter, K.W.; Agrawal, D.K. Evidence that insulin-like growth factor-1 requires protein kinase C-(epsilon), PI3-kinase and mitogen-activated protein kinase pathways to protect human vascular smooth muscle cells from apoptosis. Immunol. Cell. Biol. 2005, 83, 651–667.
[112]
Thommes, K.B.; Hoppe, J.; Vetter, H.; Sachinidis, A. The synergistic effect of PDGF-AA and IGF-1 on VSMC proliferation might be explained by the differential activation of their intracellular signaling pathways. Exp. Cell Res. 1996, 226, 59–66.
[113]
Yano, K.; Bauchat, J.R.; Liimatta, M.B.; Clemmons, D.R.; Duan, C. Down-regulation of protein kinase C inhibits insulin-like growth factor I-induced vascular smooth muscle cell proliferation, migration, and gene expression. Endocrinology 1999, 140, 4622–4632, doi:10.1210/en.140.10.4622.
[114]
Newton, A.C. Regulation of the ABC kinases by phosphorylation: Protein kinase C as a paradigm. Biochem. J. 2003, 370, 361–371, doi:10.1042/BJ20021626.
[115]
Mamane, Y.; Petroulakis, E.; LeBacquer, O.; Sonenberg, N. mTOR, translation initiation and cancer. Oncogene 2006, 25, 6416–6422.
[116]
Hua, Y.; Qiu, Y.; Zhao, A.; Wang, X.; Chen, T.; Zhang, Z.; Chi, Y.; Li, Q.; Sun, W.; Li, G.; et al. Dynamic metabolic transformation in tumor invasion and metastasis in mice with LM-8 osteosarcoma cell transplantation. J. Proteome Res. 2011, 10, 3513–3521, doi:10.1021/pr200147g.
[117]
Huang, B.; Cao, K.; Li, X.; Guo, S.; Mao, X.; Wang, Z.; Zhuang, J.; Pan, J.; Mo, C.; Chen, J.; et al. The expression and role of protein kinase C (PKC) epsilon in clear cell renal cell carcinoma. J. Exp. Clin. Cancer Res. 2011, 30, 88, doi:10.1186/1756-9966-30-88.
[118]
Leask, A.; Shi-Wen, X.; Khan, K.; Chen, Y.; Holmes, A.; Eastwood, M.; Denton, C.P.; Black, C.M.; Abraham, D.J. Loss of protein kinase Cepsilon results in impaired cutaneous wound closure and myofibroblast function. J. Cell. Sci. 2008, 121, 3459–3467, doi:10.1242/jcs.029215.
[119]
Simon, R.M.; Lam, A.; Li, M.C.; Ngan, M.; Menenzes, S.; Zhao, Y. Analysis of Gene Expression Data Using BRB-Array Tools. Cancer Inform. 2007, 3, 11–17.
[120]
Merico, D.; Isserlin, R.; Stueker, O.; Emili, A.; Bader, G.D. Enrichment map: A network-based method for gene-set enrichment visualization and interpretation. PLoS One 2010, 5, e13984.
[121]
Cline, M.S.; Smoot, M.; Cerami, E.; Kuchinsky, A.; Landys, N.; Workman, C.; Christmas, R.; Avila-Campilo, I.; Creech, M.; Gross, B.; et al. Integration of biological networks and gene expression data using Cytoscape. Nat. Protoc. 2007, 2, 2366–2382, doi:10.1038/nprot.2007.324.
[122]
Harris, M.A.; Clark, J.; Ireland, A.; Lomax, J.; Ashburner, M.; Foulger, R.; Eilbeck, K.; Lewis, S.; Marshall, B.; Mungall, C.; et al. The Gene Ontology (GO) database and informatics resource. Nucleic Acids Res. 2004, 32, D258–D261, doi:10.1093/nar/gkh036.
[123]
Boyle, E.I.; Weng, S.; Gollub, J.; Jin, H.; Botstein, D.; Cherry, J.M.; Sherlock, G. GO::TermFinder—open source software for accessing Gene Ontology information and finding significantly enriched Gene Ontology terms associated with a list of genes. Bioinformatics 2004, 20, 3710–3715.
