Previous
studies have shown that Meis1 plays an important role in the pathogenesis of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Meis1 belongs
to the TALE family, the members of which are used as biomarkers for AML. Meis1 has
been shown to play a functional role in epithelial tissues, such as skin. However,
its functions in skin carcinogenesis remain poorly understood. On the other hand, the c-Met inhibitor SU11274 has been identified
through drug screening with HOXA9/Meis1-induced AML cell lines. SU11274 altered
cell proliferation and the cell cycle status in human AML cell lines. Thus, we hypothesized
that the effects of SU11274 are dependent on Meis1 and that its knockdown may diminish
the effects of SU11274 not only in AML cell lines, but also in skin cancer cell
lines. In order to test our hypothesis, we established Meis1 knockdown cell lines
using two skin squamous cell carcinoma cell lines (B9 and D3) and treated these
cell lines with SU11274. The results obtained showed that SU11274 suppressed cell
proliferation by modulating cell cycle progression in the presence of Meis1, but
not in its absence. Furthermore, an expression
analysis showed that SU11274 activated the transcription of Meis1, which
led to the transcription of Hif1α and
Cdkn2a (p16Ink4a and p19Arf). These results suggest that Meis1 is required for the
c-Met inhibitor SU11274 to suppress the proliferation of the skin squamous cell
carcinoma cell lines.
References
[1]
Moskow, J.J., Bullrich, F., Huebner, K., Daar, I.O. and Buchberg, A.M. (1995) Meis1, a PBX1-Related Homeobox Gene Involved in Myeloid Leukemia in BXH-2 Mice. Molecular and Cellular Biology, 10, 5434-5443. http://dx.doi.org/10.1128/MCB.15.10.5434
[2]
Steelman, S., Moskow, J.J., Muzynski, K., North, C., Druck, T., Montgomery, J.C., Huebner, K., Daar, I.O. and Buchberg, A.M. (1997) Identification of a Conserved Family of Meis1-Related Homeobox Genes. Genome Research, 2, 142-156. http://dx.doi.org/10.1101/gr.7.2.142
[3]
Thorsteinsdottir, U., Kroon, E., Jerome, L., Blasi, F. and Sauvageau, G. (2001) Defining Roles for HOX and MEIS1 Genes in Induction of Acute Myeloid Leukemia. Molecular and Cellular Biology, 1, 224-234. http://dx.doi.org/10.1128/MCB.21.1.224-234.2001
[4]
Mann, R.S. and Affolter, M. (1998) Hox Proteins Meet More Partners. Current Opinion in Genetics & Development, 4, 423-429. http://dx.doi.org/10.1016/S0959-437X(98)80113-5
[5]
Rozovskaia, T., Feinstein, E., Mor, O., Foa, R., Blechman, J., Nakamura, T., Croce, C.M., Cimino, G. and Canaani, E. (2001) Upregulation of Meis1 and HoxA9 in Acute Lymphocytic Leukemias with the t (4: 11) Abnormality. Oncogene, 7, 874-878. http://dx.doi.org/10.1038/sj.onc.1204174
[6]
Bullinger, L., Döhner, K., Bair, E., Fröhling, S., Schlenk, R.F., Tibshirani, R., Döhner, H. and Pollack, J.R. (2004) Use of Gene-Expression Profiling to Identify Prognostic Subclasses in Adult Acute Myeloid Leukemia. New England Journal of Medicine, 16, 1605-1616. http://dx.doi.org/10.1056/NEJMoa031046
[7]
Dickson, G.J., Liberante, F.G., Kettyle, L.M., O’Hagan, K.A., Finnegan, D.P., Bullinger, L., Geerts, D., McMullin, M.F., Lappin, T.R., Mills, K.I. and Thompson, A. (2013) HOXA/PBX3 Knockdown Impairs Growth and Sensitizes Cytogenetically Normal Acute Myeloid Leukemia Cells to Chemotherapy. Haematologica, 8, 1216-1225. http://dx.doi.org/10.3324/haematol.2012.079012
[8]
Grubach, L., Juhl-Christensen, C., Rethmeier, A., Olesen, L.H., Aggerholm, A., Hokland, P. and Ostergaard, M. (2008) Gene Expression Profiling of Polycomb, Hox and Meis Genes in Patients with Acute Myeloid Leukaemia. European Journal of Haematology, 2, 112-122. http://dx.doi.org/10.1111/j.1600-0609.2008.01083.x
[9]
Zangenberg, M., Grubach, L., Aggerholm, A., Silkjaer, T., Juhl-Christensen, C., Nyvold, C.G., Kjeldsen, E., Ommen, H.B. and Hokland, P. (2009) The Combined Expression of HOXA4 and MEIS1 Is an Independent Prognostic Factor in Patients with AML. European Journal of Haematology, 5, 439-448. http://dx.doi.org/10.1111/j.1600-0609.2009.01309.x
[10]
Fernandez, P., Carretero, J., Medina, P.P., Jimenez, A.I., Rodriguez-Perales, S., Paz, M.F., Cigudosa, J.C., Esteller, M., Lombardia, L., Morente, M., Sanchez-Verde, L., Sotelo, T. and Sanchez-Cespedes, M. (2004) Distinctive Gene Expression of Human Lung Adenocarcinomas Carrying LKB1 Mutations. Oncogene, 23, 5084-5091. http://dx.doi.org/10.1038/sj.onc.1207665
[11]
Geerts, D., Revet, I., Jorritsma, G., Schilderink, N. and Versteeg, R. (2005) MEIS Homeobox Genes in Neuroblastoma. Cancer Letters, 228, 43-50. http://dx.doi.org/10.1016/j.canlet.2005.01.047
[12]
Jones, T.A., Flomen, R.H., Senger, G., Nizetic, D. and Sheer, D. (2000) The Homeobox Gene MEIS1 Is Amplified in IMR-32 and Highly Expressed in Other Neuroblastoma Cell Lines. European Journal of Cancer, 36, 2368-2374. http://dx.doi.org/10.1016/S0959-8049(00)00332-4
[13]
Spieker, N., van Sluis, P., Beitsma, M., Boon, K., van Schaik, B.D., van Kampen, A.H., Caron, H. and Versteeg, R. (2001) The MEIS1 Oncogene Is Highly Expressed in Neuroblastoma and Amplified in Cell Line IMR32. Genomics, 71, 214-221. http://dx.doi.org/10.1006/geno.2000.6408
[14]
Crijns, A.P., de Graeff, P., Geerts, D., Ten Hoor, K.A., Hollema, H., van der Sluis, T., Hofstra, R.M., de Bock, G.H., de Jong, S., van der Zee, A.G. and de Vries, E.G. (2007) MEIS and PBX Homeobox Proteins in Ovarian Cancer. European Journal of Cancer, 43, 2495-2505. http://dx.doi.org/10.1016/j.ejca.2007.08.025
[15]
Dekel, B., Metsuyanim, S., Schmidt-Ott, K.M., Fridman, E., Jacob-Hirsch, J., Simon, A., Pinthus, J., Mor, Y., Barasch, J., Amariglio, N., Reisner, Y., Kaminski, N. and Rechavi, G. (2006) Multiple Imprinted and Stemness Genes Provide a Link between Normal and Tumor Progenitor Cells of the Developing Human Kidney. Cancer Research, 66, 6040-6049. http://dx.doi.org/10.1158/0008-5472.CAN-05-4528
[16]
Okumura, K., Saito, M., Isogai, E., Aoto, Y., Hachiya, T., Sakakibara, Y., Katsuragi, Y., Hirose, S., Kominami, R, Goitsuka, R, Nakamura, T. and Wakabayashi, Y. (2014) Meis1 Regulates Epidermal Stem Cells and Is Required for Skin Tumorigenesis. PLoS ONE, 7, e102111. http://dx.doi.org/10.1371/journal.pone.0102111
[17]
Hisa, T., Spence, S.E., Rachel, R.A., Fujita, M., Nakamura, T., Ward, J.M., Devor-Henneman, D.E., Saiki, Y., Kutsuna, H., Tessarollo, L., Jenkins, N.A. and Copeland, N.G. (2004) Hematopoietic, Angiogenic and Eye Defects in Meis1 Mutant Animals. EMBO Journal, 23, 450-459. http://dx.doi.org/10.1038/sj.emboj.7600038
Li, W.H., Kai, H.A., Guo, H.Z. and Cui, G.H. (2014) Meis1 Regulates Proliferation of Non-Small-Cell Lung Cancer Cells. Journal of Thoracic Disease, 6, 850-855.
[20]
Hirayama, T, Asano, Y, Iida, H., Watanabe, T., Nakamura, T. and Goitsuka, R. (2014) Meis1 Is Required for the Maintenance of Postnatal Thymic Epithelial Cells. PLoS ONE, 9, e89885. http://dx.doi.org/10.1371/journal.pone.0089885
[21]
Simsek, T., Kocabas, F., Zheng, J., Deberardinis, R.J., Mahmoud, A.I., Olson, E.N., Schneider, J.W., Zhang, C.C. and Sadek, H.A. (2010) The Distinct Metabolic Profile of Hematopoietic Stem Cells Reflects Their Location in a Hypoxic Niche. Cell Stem Cell, 3, 380-390. http://dx.doi.org/10.1016/j.stem.2010.07.011
[22]
Takubo, K., Goda, N., Yamada, W., Iriuchishima, H., Ikeda, E., Kubota, Y., Shima, H., Johnson, R.S., Hirao, A., Suematsu, M. and Suda, T. (2010) Regulation of the HIF-1Alpha Level Is Essential for Hematopoietic Stem Cells. Cell Stem Cell, 3, 391-402. http://dx.doi.org/10.1016/j.stem.2010.06.020
[23]
Kocabas, F., Zheng, J., Thet, S., Copeland, N.G., Jenkins, N.A., DeBerardinis, R.J., Zhang, C. and Sadek, H.A. (2012) Meis1 Regulates the Metabolic Phenotype and Oxidant Defense of Hematopoietic Stem Cells. Blood, 25, 4963-4972. http://dx.doi.org/10.1182/blood-2012-05-432260
[24]
Ergen, A.V. and Goodell, M.A. (2010) Mechanisms of Hematopoietic Stem Cell Aging. Experimental Gerontology, 4, 286-290. http://dx.doi.org/10.1016/j.exger.2009.12.010
[25]
Sherr, C.J. (2006) Divorcing ARF and p53: An Unsettled Case. Nature Reviews Cancer, 9, 663-673. http://dx.doi.org/10.1038/nrc1954
[26]
Kamijo, T., Weber, J.D., Zambetti, G., Zindy, F., Roussel, M.F. and Sherr, C.J. (1998) Functional and Physical Interactions of the ARF Tumor Suppressor with p53 and Mdm2. Proceedings of the National Academy of Sciences of the United States of America, 14, 8292-8297. http://dx.doi.org/10.1073/pnas.95.14.8292
[27]
Kelly-Spratt, K.S., Gurley, K.E., Yasui, Y. and Kemp, C.J. (2004) p19Arf Suppresses Growth, Progression, and Metastasis of Hras-Driven Carcinomas through p53-Dependent and -Independent Pathways. PLoS Biology, 8, e242. http://dx.doi.org/10.1371/journal.pbio.0020242
[28]
Takeuchi, S., Takahashi, A., Motoi, N., Yoshimoto, S., Tajima, T., Yamakoshi, K., Hirao, A., Yanagi, S., Fukami, K., Ishikawa, Y., Sone, S., Hara, E. and Ohtani, N. (2010) Intrinsic Cooperation between p16INK4a and p21Waf1/Cip1 in the Onset of Cellular Senescence and Tumor Suppression in Vivo. Cancer Research, 22, 9381-9390. http://dx.doi.org/10.1158/0008-5472.CAN-10-0801
[29]
Wang, X., Le, P., Liang, C., Chan, J., Kiewlich, D., Miller, T., Harris, D., Sun, L., Rice, A., Vasile, S., Blake, R.A., Howlett, A.R., Patel, N., McMahon, G. and Lipson, K.E. (2003) Potent and Selective Inhibitors of the Met [Hepatocyte Growth Factor/Scatter Factor (HGF/SF) Receptor] Tyrosine Kinase Block HGF/SF-Induced Tumor Cell Growth and Invasion. Molecular Cancer Therapeutics, 2, 1085-1092.
[30]
Mulgrew, N.M., Kettyle, L.M., Ramsey, J.M., Cull, S., Smyth, L.J., Mervyn, D.M., Bijl, J.J. and Thompson, A. (2014) c-Met Inhibition in a HOXA9/Meis1 Model of CN-AML. Developmental Dynamics, 1, 172-181. http://dx.doi.org/10.1002/dvdy.24070
[31]
Huang, P.H., Mukasa, A., Bonavia, R., Flynn, R.A., Brewer, Z.E., Cavenee, W.K., Furnari, F.B. and White, F.M. (2007) Quantitative Analysis of EGFRvIII Cellular Signaling Networks Reveals a Combinatorial Therapeutic Strategy for Glioblastoma. Proceedings of the National Academy of Sciences of the United States of America, 31, 12867-12872. http://dx.doi.org/10.1073/pnas.0705158104
[32]
Ma, P.C., Tretiakova, M.S., Nallasura, V., Jagadeeswaran, R., Husain, A.N. and Salgia, R. (2007) Downstream Signalling and Specific Inhibition of c-MET/HGF Pathway in Small Cell Lung Cancer: Implications for Tumour Invasion. British Journal of Cancer, 3, 368-377. http://dx.doi.org/10.1038/sj.bjc.6603884
[33]
Kenessey, I., Keszthelyi, M., Krámer, Z., Berta, J., Adám, A., Dobos, J., Mildner, M., Flachner, B., Cseh, S., Barna, G., Szokol, B., Orfi, L., Kéri, G., Döme, B., Klepetko, W., Tímár, J. and Tóvári, J. (2010) Inhibition of c-Met with the Specific Small Molecule Tyrosine Kinase Inhibitor SU11274 Decreases Growth and Metastasis Formation of Experimental Human Melanoma. Current Cancer Drug Targets, 3, 332-342. http://dx.doi.org/10.2174/156800910791190184
[34]
Wong, P., Iwasaki, M., Somervaille, T.C., So, C.W. and Cleary, M.L. (2007) Meis1 Is an Essential and Rate-Limiting Regulator of MLL Leukemia Stem Cell Potential. Genes & Development, 21, 2762-2774. http://dx.doi.org/10.1101/gad.1602107
[35]
Eder, J.P., Vande Woude, G.F., Boerner, S.A. and LoRusso, P.M. (2009) Novel Therapeutic Inhibitors of the c-Met Signaling Pathway in Cancer. Clinical Cancer Research, 15, 2207-2214. http://dx.doi.org/10.1158/1078-0432.CCR-08-1306
[36]
Arechederra, M., Priego, N., Vázquez-Carballo, A., Sequera, C., Gutiérrez-Uzquiza, á., Cerezo-Guisado, M.I., Ortiz-Rivero, S., Roncero, C., Cuenda, A., Guerrero, C. and Porras, A. (2015) p38 MAPK Down-Regulates Fibulin 3 Expression through Methylation of Gene Regulatory Sequences: Role in Migration and Invasion. The Journal of Biological Chemistry, 290, 4383-4397. http://dx.doi.org/10.1074/jbc.M114.582239
