Messages from the Border: Novel Insights in Signal Transduction Pathways Involved in Tumor Invasion and Metastasis

Read  full  paper  at:

Cancer is a multistep process encompassing the transformation of normal epithelial cells to the stromal invasion and metastasis, with these last considered the final stage of the disease. Tumor invasiveness is based on creation of a specific peri-tumoral environment which on turn depends upon epithelial-stromal interactions, degradation of extracellular matrix and reorganization of fibrillar components. Even though several aspects of the stromal and cellular remodeling have been elucidated and described, such as the epithelial-mesenchymal transition (EMT) and extracellular matrix degradation, all the underlying molecular mechanism are far to be elucidated in their complexity. In this review we focused on new actors such as microRNAs, G protein coupled receptor kinases (GRKs) and Calcium/calmodulin-dependent protein kinase (CaMKs) known to be involved in several important physiological processes like development, cell differentiation and cell signaling, and more recently linked to tumor progression and invasion.

Cite this paper

Ciccarelli, M. , Rusciano, M. , Sorriento, D. , Maione, A. , Soprano, M. , Iaccarino, G. and Illario, M. (2015) Messages from the Border: Novel Insights in Signal Transduction Pathways Involved in Tumor Invasion and Metastasis. Journal of Cancer Therapy, 6, 199-212. doi: 10.4236/jct.2015.62022.


[1] Stein, C.J. and Colditz, G.A. (2004) Modifiable Risk Factors for Cancer. British Journal of Cancer, 90, 299-303.
[2] Hanahan, D. and Weinberg, R.A. (2000) The Hallmarks of Cancer. Cell, 100, 57-70.
[3] Grothey, A. and Schmoll, H.J. (2001) New Chemotherapy Approaches in Colorectal Cancer. Current Opinion in Oncology, 13, 275-286.
[4] Fidler, I.J. (2003) The Pathogenesis of Cancer Metastasis: The “Seed and Soil” Hypothesis Revisited. Nature Reviews Cancer, 3, 453-458.
[5] Kalluri, R. (2009) EMT: When Epithelial Cells Decide to Become Mesenchymal-Like Cells. The Journal of Clinical Investigation, 119, 1417-1419.
[6] Thiery, J.P., Acloque, H., Huang, R.Y. and Nieto, M.A. (2009) Epithelial-Mesenchymal Transitions in Development and Disease. Cell, 139, 871-890.
[7] Thiery, J.P. and Sleeman, J.P. (2006) Complex Networks Orchestrate Epithelial-Mesenchymal Transitions. Nature Reviews Molecular Cell Biology, 7, 131-142.
[8] Yang, J. and Weinberg, R.A. (2008) Epithelial-Mesenchymal Transition: At the Crossroads of Development and Tumor Metastasis. Developmental Cell, 14, 818-829.
[9] Stahel, R., Bogaerts, J., Ciardiello, F., et al. (2014) Optimising Translational Oncology in Clinical Practice: Strategies to Accelerate Progress in Drug Development. Cancer Treatment Reviews, 41, 129-135.
[10] Garzon, R., Fabbri, M., Cimmino, A., et al. (2006) MicroRNA Expression and Function in Cancer. Trends in Molecular Medicine, 12, 580-587.
[11] DeSano, J.T. and Xu, L. (2009) A Regulation of Cancer Stem Cells and Therapeutic Implications. The AAPS Journal, 11, 682-692.
[12] Perera, R.J. and Ray, A. (2007) MicroRNAs in the Search for Understanding Human Diseases. BioDrugs, 21, 97-104.
[13] He, L., He, X., Lim, L.P., et al. (2007) A msicroRNA Component of the p53 Tumour Suppressor Network. Nature, 447, 1130-1134.
[14] Davis, B.N. and Hata, A. (2009) Regulation of MicroRNA Biogenesis: A miRiad of Mechanisms. Cell Communication & Signal, 7, 18.
[15] Davis, B.N., Hilyard, A.C., Nguyen, P.H., et al. (2009) Induction of Microrna-221 by Platelet-Derived Growth Factor Signaling Is Critical for Modulation of Vascular Smooth Muscle Phenotype. The Journal of Biological Chemistry, 284, 3728-3738.
[16] Shao, M., Rossi, S., Chelladurai, B., et al. (2011) PDGF Induced microRNA Alterations in Cancer Cells. Nucleic Acids Research, 39, 4035-4047.
[17] Butz, H., Racz, K., Hunyady, L. and Patocs, A. (2012) Crosstalk between TGF-β Signaling and the MicroRNA Machinery. Trends in Pharmacological Sciences, 33, 382-393.
[18] Bui, T.V. and Mendell, J.T. (2010) Myc: Maestro of MicroRNAs. Genes & Cancer, 1, 568-575.
[19] Chang, T.C., Yu, D., Lee, Y.S., et al. (2008) Widespread microRNA Repression by Myc Contributes to Tumorigenesis. Nature Genetics, 40, 43-50.
[20] He, L., Thomson, J.M., Hemann, M.T., et al. (2005) A microRNA Polycistron as a Potential Human Oncogene. Nature, 435, 828-833.
[21] Yu, G., Tang, J.Q., Tian, M.L., et al. (2012) Prognostic Values of the miR-17-92 Cluster and Its Paralogs in Colon Cancer. Journal of Surgical Oncology, 106, 232-237.
[22] Dews, M., Homayouni, A., Yu, D., et al. (2006) Augmentation of Tumor Angiogenesis by a Myc-Activated MicroRNA Cluster. Nature Genetics, 38, 1060-1065.
[23] Ma, L., Young, J., Prabhala, H., et al. (2010) miR-9, a MYC/MYCN-Activated microRNA, Regulates E-Cadherin and Cancer Metastasis. Nature Cell Biology, 12, 247-256.
[24] Klein, U., Lia, M., Crespo, M., et al. (2010) The DLEU2/miR-15a/16-1 Cluster Controls B Cell Proliferation and Its Deletion Leads to Chronic Lymphocytic Leukemia. Cancer Cell, 17, 28-40.
[25] Linsley, P.S., Schelter, J., Burchard, J., et al. (2007) Transcripts Targeted by The MicroRNA-16 Family Cooperatively Regulate Cell Cycle Progression. Molecular and Cellular Biology, 27, 2240-2252.
[26] Bandres, E., Agirre, X., Bitarte, N., et al. (2009) Epigenetic Regulation of microRNA Expression in Colorectal Cancer. International Journal of Cancer, 125, 2737-2743.
[27] Toyota, M., Suzuki, H., Sasaki, Y., et al. (2008) Epigenetic Silencing of MicroRNA-34b/c and B-Cell Translocation Gene 4 Is Associated With CpG Island Methylation in Colorectal Cancer. Cancer Research, 68, 4123-4132.
[28] Vogt, M., Munding, J., Gruner, M., et al. (2011) Frequent Concomitant Inactivation of miR-34a and miR-34b/c by CpG Methylation in Colorectal, Pancreatic, Mammary, Ovarian, Urothelial, and Renal Cell Carcinomas and Soft Tissue Sarcomas. Virchows Archive, 458, 313-322.
[29] Goel, A. and Boland, C.R. (2012) Epigenetics of Colorectal Cancer. Gastroenterology, 143, 1442-1460.
[30] Chang, S., Wang, R.H., Akagi, K., et al. (2011) Tumor Suppressor BRCA1 Epigenetically Controls Oncogenic MicroRNA-155. Nature Medicine, 17, 1275-1282.
[31] Du Rieu, M.C., Torrisani, J., Selves, J., et al. (2010) MicroRNA-21 Is Induced Early in Pancreatic Ductal Adenocarcinoma Precursor Lesions. Clinical Chemistry, 56, 603-612.
[32] Munding, J.B., Adai, A.T., Maghnouj, A., et al. (2012) Global microRNA Expression Profiling of Microdissected Tissues Identifies miR-135b as a Novel Biomarker for Pancreatic Ductal Adenocarcinoma. International Journal of Cancer, 131, 86-95.
[33] Georgantas, R.W., Streicher, K., Greenberg, S.A., et al. (2014) Inhibition of Myogenic MicroRNAs 1, 133, and 206 by Inflammatory Cytokines Links Inflammation and Muscle Degeneration in Adult Inflammatory Myopathies. Arthritis & Rheumatology, 66, 1022-1033.
[34] Keklikoglou, I., Hosaka, K., Bender, C., et al. (2014) MicroRNA-206 Functions as a Pleiotropic Modulator of Cell Proliferation, Invasion and Lymphangiogenesis in Pancreatic Adenocarcinoma by Targeting ANXA2 and KRAS Genes. Oncogene, in press.
[35] Poliseno, L., Tuccoli, A., Mariani, L., et al. (2006) MicroRNAs Modulate the Angiogenic Properties of HUVECs. Blood, 108, 3068-3071.
[36] Bonauer, A., Carmona, G., Iwasaki, M., et al. (2009) MicroRNA-92a Controls Angiogenesis and Functional Recovery of Ischemic Tissues in Mice. Science, 324, 1710-1713.
[37] Bierie, B. and Moses, H.L. (2006) Tumour Microenvironment: TGFbeta: The Molecular Jekyll and Hyde of Cancer. Nature Reviews Cancer, 6, 506-520.
[38] Bockhorn, M., Jain, R.K. and Munn, L.L. (2007) Active versus Passive Mechanisms in Metastasis: Do Cancer Cells Crawl into Vessels, or Are They Pushed? The Lancet Oncology, 8, 444-448.
[39] Favaro, E., Lord, S., Harris, A.L. and Buffa, F.M. (2011) Gene Expression and Hypoxia in Breast Cancer. Genome Medicine, 3, 55.
[40] Denko, N.C. (2008) Hypoxia, HIF1 and Glucose Metabolism in the Solid Tumour. Nature Reviews Cancer, 8, 705-713.
[41] Kulshreshtha, R., Ferracin, M., Negrini, M., et al. (2007) Regulation of MicroRNA Expression: The Hypoxic Component. Cell Cycle, 6, 1425-1430.
[42] Kulshreshtha, R., Ferracin, M., Wojcik, S.E., et al. (2007) A MicroRNA Signature of Hypoxia. Molecular and Cellular Biology, 27, 1859-1867.
[43] Liu, L.Z., Li, C., Chen, Q., et al. (2011) miR-21 Induced Angiogenesis through AKT and ERK Activation and HIF-1α Expression. PLoS ONE, 6, e19139.
[44] Nie, Y., Han, B.M., Liu, X.B., et al. (2011) Identification of MicroRNAs Involved in Hypoxia- and Serum Deprivation-Induced Apoptosis in Mesenchymal Stem Cells. International Journal of Biological Sciences, 7, 762-768.
[45] Kong, D., Banerjee, S., Ahmad, A., et al. (2010) Epithelial to Mesenchymal Transition Is Mechanistically Linked with Stem Cell Signatures in Prostate Cancer Cells. PLoS ONE, 5, e12445.
[46] Chang, C.J., Hsu, C.C., Chang, C.H., et al. (2011) Let-7d Functions as Novel Regulator of Epithelial-Mesenchymal Transition and Chemoresistant Property in Oral Cancer. Oncology Reports, 26, 1003-1010.
[47] McCarty, M.F. (2012) Metformin May Antagonize Lin28 and/or Lin28B Activity, Thereby Boosting Let-7 Levels and Antagonizing Cancer Progression. Medical Hypotheses, 78, 262-269.
[48] Li, Y., VandenBoom, T.G., Kong, D., et al. (2009) Up-Regulation of miR-200 and Let-7 by Natural Agents Leads to the Reversal of Epithelial-to-Mesenchymal Transition in Gemcitabine-Resistant Pancreatic Cancer Cells. Cancer Research, 69, 6704-6712.
[49] Li, J., Zhang, Y., Zhao, J., et al. (2011) Over Expression of miR-22 Reverses Paclitaxel-Induced Chemoresistance through Activation of PTEN Signaling in p53-Mutated Colon Cancer Cells. Molecular and Cellular Biochemistry, 357, 31-38.
[50] Tsuchiya, N., Izumiya, M., Ogata-Kawata, H., et al. (2011) Tumor Suppressor miR-22 Determines p53-Dependent Cellular Fate through Post-Transcriptional Regulation of p21. Cancer Research, 71, 4628-4639.
[51] Li, J., Liang, S., Yu, H., et al. (2010) An Inhibitory Effect of miR-22 on Cell Migration and Invasion in Ovarian Cancer. Gynecology Oncology, 119, 543-548.
[52] Zhang, J., Yang, Y., Yang, T., et al. (2010) MicroRNA-22, Downregulated in Hepatocellular Carcinoma and Correlated with Prognosis, Suppresses Cell Proliferation and Tumourigenicity. British Journal of Cancer, 103, 1215-1220.
[53] Brabletz, S. and Brabletz, T. (2010) The ZEB/miR-200 Feedback Loop—A Motor of Cellular Plasticity in Development and Cancer? EMBO Reports, 11, 670-677.
[54] Zhang, Z., Liu, X., Feng, B., et al. (2014) STIM1, a Direct Target of MicroRNA-185, Promotes Tumor Metastasis and Is Associated with Poor Prognosis in Colorectal Cancer. Oncogene, in press.
[55] Lutgendorf, S.K., DeGeest, K., Dahmoush, L., et al. (2011) Social Isolation Is Associated with Elevated Tumor Norepinephrine in Ovarian Carcinoma Patients. Brain, Behavior, and Immunity, 25, 250-255.
[56] Thaker, P.H., Han, L.Y., Kamat, A.A., et al. (2006) Chronic Stress Promotes Tumor Growth and Angiogenesis in a Mouse Model of Ovarian Carcinoma. Nature Medicines, 12, 939-944.
[57] Schuller, H.M., Al-Wadei, H.A., Ullah, M.F. and Plummer, H.K. (2012) Regulation of Pancreatic Cancer by Neuropsychological Stress Responses: A Novel Target for Intervention. Carcinogenesis, 33, 191-196.
[58] Sastry, K.S., Karpova, Y., Prokopovich, S., et al. (2007) Epinephrine Protects Cancer Cells from Apoptosis via Activation of cAMP-Dependent Protein Kinase and BAD Phosphorylation. The Journal of Biological Chemistry, 282, 14094-14100.
[59] Hassan, S., Karpova, Y., Baiz, D., et al. (2013) Behavioral Stress Accelerates Prostate Cancer Development in Mice. The Journal of Clinical Investigation, 123, 874-886.
[60] Wu, W.K., Wong, H.P., Luo, S.W., et al. (2005) 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone from Cigarette Smoke Stimulates Colon Cancer Growth via β-Adrenoceptors. Cancer Research, 65, 5272-5277.
[61] Wong, H.P., Ho, J.W., Koo, M.W., et al. (2011) Effects of Adrenaline in Human Colon Adenocarcinoma HT-29 Cells. Life Science, 88, 1108-1112.
[62] Lee, J.W., Shahzad, M.M., Lin, Y.G., et al. (2009) Surgical Stress Promotes Tumor Growth in Ovarian Carcinoma. Clinical Cancer Research, 15, 2695-2702.
[63] Yang, E., Boire, A., Agarwal, A., et al. (2009) Blockade of PAR1 Signaling with Cell-Penetrating Pepducins Inhibits Akt Survival Pathways in Breast Cancer Cells and Suppresses Tumor Survival and Metastasis. Cancer Research, 69, 6223-6231.
[64] Yang, E.V., Kim, S.J., Donovan, E.L., et al. (2009) Norepinephrine Upregulates VEGF, IL-8, and IL-6 Expression in Human Melanoma Tumor Cell Lines: Implications for Stress-Related Enhancement of Tumor Progression. Brain, Behavior, and Immunity, 23, 267-275.
[65] Madden, K.S., Szpunar, M.J., Brown, E.B. (2011) β-Adrenergic Receptors (β-AR) Regulate VEGF and IL-6 Production by Divergent Pathways in High β-AR-Expressing Breast Cancer Cell Lines. Breast Cancer Research and Treatment, 130, 747-758.
[66] Casini, G., Dal Monte, M., Fornaciari, I., et al. (2014) The β-Adrenergic System as a Possible New Target for Pharmacologic Treatment of Neovascular Retinal Diseases. Progress in Retinal and Eye Research, 42, 103-129
[67] Ciccarelli, M., Sorriento, D., Cipolletta, E., et al. (2011) Impaired Neoangiogenesis in β(2)-Adrenoceptor Gene-Deficient Mice: Restoration by Intravascular Human β(2)-Adrenoceptor Gene Transfer and Role of NFkappaB and CREB Transcription Factors. British Journal of Pharmacology, 162, 712-721.
[68] Ciccarelli, M., Santulli, G., Campanile, A., et al. (2008) Endothelial α1-Adrenoceptors Regulate Neo-Angiogenesis. British Journal of Pharmacology, 153, 936-946.
[69] Sorriento, D., Santulli, G., Del Giudice, C., et al. (2012) Endothelial Cells Are Able to Synthesize and Release Catecholamines Both in Vitro and in Vivo. Hypertension, 60, 129-136.
[70] Vroon, A., Heijnen, C.J. and Kavelaars, A. (2006) GRKs and Arrestins: Regulators of Migration and Inflammation. Journal of Leukocyte Biology, 80, 1214-1221.
[71] Reiter, E. and Lefkowitz, R.J. (2006) GRKs and β-Arrestins: Roles in Receptor Silencing, Trafficking and Signaling. Trends in Endocrinology and Metabolism, 17, 159-165.
[72] Pitcher, J.A., Freedman, N.J. and Lefkowitz, R.J. (1998) G Protein-Coupled Receptor Kinases. Annual Review of Biochemistry, 67, 653-692.
[73] Koch, W.J., Ingles, J., Stone, W.C. and Lefkowitz, R.J. (1993) The Binding Site for the Beta Gamma Subunits of Heterotrimeric G Proteins on the Beta-Adrenergic Receptor Kinase. The Journal of Biological Chemistry, 268, 8256-8260.
[74] Luttrell, L.M., van Biesen, T., Hawes, B.E., et al. (1995) Gβγ Subunits Mediate Mitogen-Activated Protein Kinase Activation by the Tyrosine Kinase Insulin-Like Growth Factor 1 Receptor. The Journal of Biological Chemistry, 270, 16495-16498.
[75] Eichmann, T., Lorenz, K., Hoffmann, M., et al. (2003) The Amino-Terminal Domain of G-Protein-Coupled Receptor Kinase 2 Is a Regulatory Gβγ Binding Site. The Journal of Biological Chemistry, 278, 8052-8057.
[76] Premont, R.T., Macrae, A.D., Stoffel, R.H., et al. (1996) Characterization of the G Protein-Coupled Receptor Kinase GRK4. Identification of Four Splice Variants. The Journal of Biological Chemistry, 271, 6403-6410.
[77] Premont, R.T., Koch, W.J., Inglese, J. and Lefkowitz, R.J. (1994) Identification, Purification, and Characterization of GRK5, a Member of the Family of G Protein-Coupled Receptor Kinases. The Journal of Biological Chemistry, 269, 6832-6841.
[78] Stoffel, R.H., Randall, R.R., Premont, R.T., et al. (1994) Palmitoylation of G Protein-Coupled Receptor Kinase, GRK6. Lipid Modification Diversity in the GRK Family. The Journal of Biological Chemistry, 269, 27791-27794.
[79] Penela, P., Murga, C., Ribas, C., et al. (2010) The Complex G Protein-Coupled Receptor Kinase 2 (GRK2) Interactome Unveils New Physiopathological Targets. The Journal of Biological Chemistry, 160, 821-832.
[80] Ciccarelli, M., Chuprun, J.K., Rengo, G., et al. (2011) G protein-Coupled Receptor Kinase 2 Activity Impairs Cardiac Glucose Uptake and Promotes Insulin Resistance after Myocardial Ischemia. Circulation, 123, 1953-1962.
[81] Penela, P., Rivas, V., Salcedo, A. and Mayor Jr., F. (2010) G Protein-Coupled Receptor Kinase 2 (GRK2) Modulation and Cell Cycle Progression. Proceedings of the National Academy of Sciences of the United States of America, 107, 1118-1123.
[82] Iaccarino, G., Ciccarelli, M., Sorriento, D., et al. (2005) Ischemic Neoangiogenesis Enhanced by β2-Adrenergic Receptor over Expression: A Novel Role for the Endothelial Adrenergic System. Circulation Research, 97, 1182-1189.
[83] Penela, P., Nogues, L. and Mayor Jr., F. (2014) Role of G Protein-Coupled Receptor Kinases in Cell Migration. Current Opinion in Cell Biology, 27, 10-17.
[84] Clift, I.C., Bamidele, A.O., Rodriguez-Ramirez, C., et al. (2014) β-Arrestin1 and Distinct CXCR4 Structures Are Required for Stromal Derived Factor-1 to Downregulate CXCR4 Cell-Surface Levels in Neuroblastoma. Molecular Pharmacology, 85, 542-552.
[85] Jiang, X., Yang, P. and Ma, L. (2009) Kinase Activity-Independent Regulation of Cyclin Pathway by GRK2 Is Essential for Zebrafish Early Development. Proceedings of the National Academy of Sciences of the United States of America, 106, 10183-10188.
[86] Ciccarelli, M., Sorriento, D., Franco, A., et al. (2013) Endothelial G Protein-Coupled Receptor Kinase 2 Regulates Vascular Homeostasis through the Control of Free Radical Oxygen Species. Arteriosclerosis, Thrombosis, and Vascular Biology, 33, 2415-2424.
[87] Rivas, V., Carmona, R., Munoz-Chapuli, R., et al. (2013) Developmental and Tumoral Vascularization Is Regulated by G Protein-Coupled Receptor Kinase 2. The Journal of Clinical Investigation, 123, 4714-4730.
[88] Sorriento, D., Santulli, G., Fusco, A., et al. (2010) Intracardiac Injection of AdGRK5-NT Reduces Left Ventricular Hypertrophy by Inhibiting NF-κB-Dependent Hypertrophic Gene Expression. Hypertension, 56, 696-704.
[89] Sorriento, D., Campanile, A., Santulli, G., et al. (2009) A New Synthetic Protein, TAT-RH, Inhibits Tumor Growth through the Regulation of NFkappaB Activity. Molecular Cancer, 8, 97.
[90] Chakraborty, P.K., Zhang, Y., Coomes, A.S., et al. (2014) G Protein-Coupled Receptor Kinase GRK5 Phosphorylates Moesin and Regulates Metastasis in Prostate Cancer. Cancer Research, 74, 3489-3500.
[91] Buss, M.C., Remke, M., Lee, J., et al. (2014) The WIP1 Oncogene Promotes Progression and Invasion of Aggressive Medulloblastoma Variants. Oncogene, in press.
[92] Michal, A.M., So, C.H., Beeharry, N., et al. (2012) G Protein-Coupled Receptor Kinase 5 Is Localized to Centrosomes and Regulates Cell Cycle Progression. The Journal of Biological Chemistry, 287, 6928-6940.
[93] Chen, X., Zhu, H., Yuan, M., et al. (2010) G-Protein-Coupled Receptor Kinase 5 Phosphorylates p53 and Inhibits DNA Damage-Induced Apoptosis. The Journal of Biological Chemistry, 285, 12823-12830.
[94] Li, Y.P. (2013) GRK6 Expression in Patients with Hepatocellular Carcinoma. Asian Pacific Journal of Tropical Medicine, 6, 220-223.
[95] Yuan, L., Zhang, H., Liu, J., et al. (2013) Growth factor receptor-Src-Mediated Suppression of GRK6 Dysregulates CXCR4 Signaling and Promotes Medulloblastoma Migration. Molecular Cancer, 12, 18.
[96] Raghuwanshi, S.K., Smith, N., Rivers, E.J., et al. (2013) G Protein-Coupled Receptor Kinase 6 Deficiency Promotes Angiogenesis, Tumor Progression, and Metastasis. The Journal of Immunology, 190, 5329-5336.
[97] Raghuwanshi, S.K., Su, Y., Singh, V., et al. (2012) The Chemokine Receptors CXCR1 and CXCR2 Couple to Distinct G Protein-Coupled Receptor Kinases to Mediate and Regulate Leukocyte Functions. The Journal of Immunology, 189, 2824-2832.
[98] Hook, S.S. and Means, A.R. (2001) Ca2+/CaM-Dependent Kinases: From Activation to Function. Annual Review of Pharmacology and Toxicology, 41, 471-505.
[99] Cruzalegui, F.H. and Bading, H. (2000) Calcium-Regulated Protein Kinase Cascades and Their Transcription Factor Targets. Cellular and Molecular Life Sciences CMLS, 57, 402-410.
[100] Wang, S.L., Ribar, T.J. and Means, A.R. (2001) Expression of Ca2+/Calmodulin-Dependent Protein Kinase IV (caMKIV) Messenger RNA during Murine Embryogenesis. Cell Growth & Differentiation, 12, 351-361.
[101] Kitsos, C.M., Sankar, U., Illario, M., et al. (2005) Calmodulin-Dependent Protein Kinase IV Regulates Hematopoietic Stem Cell Maintenance. The Journal of Biological Chemistry, 280, 33101-33108.
[102] Kim Do, Y., Park, M.W., Yuan, H.D., et al. (2009) Compound K Induces Apoptosis via CAMK-IV/AMPK Pathways in HT-29 Colon Cancer Cells. Journal of Agricultural and Food Chemistry, 57, 10573-10578.
[103] Tamura, N., Tai, Y., Sugimoto, K., et al. (2000) Enhanced Expression and Activation of Ca2+/Calmodulin-Dependent Protein Kinase IV in Hepatocellular Carcinoma. Cancer, 89, 1910-1916.<1910::AID-CNCR6>3.3.CO;2-M
[104] Shang, S., Takai, N., Nishida, M., et al. (2003) CaMKIV Expression Is Associated with Clinical Stage and PCNA-Labeling Index in Endometrial Carcinoma. International Journal of Molecular Medicine, 11, 181-186.
[105] Takai, N., Miyazaki, T., Nishida, M., et al. (2002) Ca2+/Calmodulin-Dependent Protein Kinase IV Expression in Epithelial Ovarian Cancer. Cancer Letters, 183, 185-193.
[106] Braun, A.P. and Schulman, H. (1995) The Multifunctional Calcium/Calmodulin-Dependent Protein Kinase: From Form to Function. Annual Review of Physiology, 57, 417-445.
[107] Yang, B.F., Xiao, C., Roa, W.H., et al. (2003) Calcium/Calmodulin-Dependent Protein Kinase II Regulation of c-FLIP Expression and Phosphorylation in Modulation of Fas-Mediated Signaling in Malignant Glioma Cells. The Journal of Biological Chemistry, 278, 7043-7050.
[108] Xiao, C., Yang, B.F., Song, J.H., et al. (2005) Inhibition of CaMKII-Mediated c-FLIP Expression Sensitizes Malignant Melanoma Cells to TRAIL-Induced Apoptosis. Experimental Cell Research, 304, 244-255.
[109] Rodriguez-Mora, O.G., Lahair, M.M., Evans, M.J., et al. (2006) Inhibition of the CaM-Kinases Augments Cell Death in Response to Oxygen Radicals and Oxygen Radical Inducing Cancer Therapies in MCF-7 Human Breast Cancer Cells. Cancer Biology & Therapy, 5, 1022-1030.
[110] Tombes, R.M. and Krystal, G.W. (1997) Identification of Novel Human Tumor Cell-Specific CaMK-II Variants. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1355, 281-292.
[111] Song, J.H., Bellail, A., Tse, M.C.L., Yong, V.W. and Hao, C.H. (2006) Human Astrocytes Are Resistant to Fas Ligand and Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis. The Journal of Neuroscience, 26, 3299-3308.
[112] Fladmark, K.E., Brustugun, O.T., Mellgren, G., et al. (2002) Ca2+/Calmodulin-Dependent Protein Kinase II Is Required for Microcystin-Induced Apoptosis. The Journal of Biological Chemistry, 277, 2804-2811.
[113] Daft, P.G., Yuan, K., Warram, J.M., et al. (2013) Alpha-CaMKII Plays a Critical Role in Determining the Aggressive Behavior of Human Osteosarcoma. Molecular Cancer Research, 11, 349-359.
[114] Wang, Q., Symes, A.J., Kane, C.A., et al. (2010) A Novel Role for Wnt/Ca2+ Signaling in Actin Cytoskeleton Remodeling and Cell Motility in Prostate Cancer. PLoS ONE, 5, e10456.
[115] Rokhlin, O.W., Taghiyev, A.F., Bayer, K.U., et al. (200) Calcium/Calmodulin-Dependent Kinase II Plays an Important Role in Prostate Cancer Cell Survival. Cancer Biology & Therapy, 6, 732-742.
[116] Liu, Z., Han, G., Cao, Y., et al. (2014) Calcium/Calmodulin-Dependent Protein Kinase II Enhances Metastasis of Human Gastric Cancer by Upregulating Nuclear Factor-κB and Akt-Mediated Matrix Metalloproteinase-9 Production. Molecular Medicine Reports, 10, 2459-2464.
[117] Rusciano, M.R., Salzano, M., Monaco, S., et al. (2010) The Ca2+-Calmodulin-Dependent Kinase II Is Activated in Papillary Thyroid Carcinoma (PTC) and Mediates Cell Proliferation Stimulated by RET/PTC. Endocrine-Related Cancer, 17, 113-123.
[118] Si, J., Mueller, L. and Collins, S.J. (2007) CaMKII Regulates Retinoic Acid Receptor Transcriptional Activity and the Differentiation of Myeloid Leukemia Cells. The Journal of Clinical Investigation, 117, 1412-1421.
[119] Gu, Y., Chen, T., Meng, Z., et al. (2012) CaMKII gamma, a Critical Regulator of CML stem/Progenitor Cells, Is a Target of the Natural Product Berbamine. Blood Journal, 120, 4829-4839.
[120] Monaco, S., Rusciano, M.R., Maione, A.S., et al. (2015) A Novel Crosstalk between Calcium/Calmodulin Kinases II and IV Regulates Cell Proliferation in Myeloid Leukemia Cells. Cell Signalling, 27, 204-214.
[121] Ciccarelli, M., Rusciano, M.R., Sorriento, D., et al. (2014) CaMKII Protects MKP-1 from Proteasome Degradation in Endothelial Cells. Cellular Signalling, 26, 2167-2174.                                      eww150213lx


Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out / 更改 )

Twitter picture

You are commenting using your Twitter account. Log Out / 更改 )

Facebook photo

You are commenting using your Facebook account. Log Out / 更改 )

Google+ photo

You are commenting using your Google+ account. Log Out / 更改 )

Connecting to %s