Maternal embryonic leucine zipper kinase enhances gastric cancer progression via the FAK/Paxillin pathway

详细信息    查看全文

• 作者：Tao Du (13)
  Ying Qu (13)
  Jianfang Li (13)
  Hao Li (13)
  Liping Su (13)
  Quan Zhou (13)
  Min Yan (13)
  Chen Li (13)
  Zhenggang Zhu (13)
  Bingya Liu (13)
  
  13. Shanghai Key laboratory of Gastric Neoplasms ; Shanghai Institute of Digestive Surgery ; Department of Surgery ; Ruijin Hospital ; Shanghai Jiao Tong University School of Medicine ; No 197 Ruijin er Road ; Shanghai ; 200025 ; China
  
• 关键词：MELK ; Gastric cancer ; Tumor migration ; Tumor invasion ; FAK ; Paxillin
• 刊名：Molecular Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：13
• 期：1
• 全文大小：2,382 KB
• 参考文献：1. Moore, MA, Manan, AA, Chow, KY, Cornain, SF, Devi, CR, Triningsih, FX, Laudico, A, Mapua, CA, Mirasol-Lumague, MR, Noorwati, S, Nyunt, K, Othman, NH, Shah, SA, Sinuraya, ES, Yip, CH, Sobue, T (2010) Cancer epidemiology and control in peninsular and island South-East Asia - past, present and future. Asian Pac J Cancer Prev 11: pp. 81-98
  2. Jemal, A, Bray, F, Center, MM, Ferlay, J, Ward, E, Forman, D (2011) Global cancer statistics. CA Cancer J Clin 61: pp. 69-90 CrossRef
  3. Kato, M, Asaka, M (2012) Recent development of gastric cancer prevention. Jpn J Clin Oncol 42: pp. 987-994 CrossRef
  4. Kanat, O, O鈥橬eil, BH (2013) Metastatic gastric cancer treatment: a little slow but worthy progress. Med Oncol 30: pp. 464 CrossRef
  5. Steeg, PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12: pp. 895-904 CrossRef
  6. Felding-Habermann, B (2003) Integrin adhesion receptors in tumor metastasis. Clin Exp Metastasis 20: pp. 203-213 CrossRef
  7. Heyer, BS, Warsowe, J, Solter, D, Knowles, BB, Ackerman, SL (1997) New member of the Snf1/AMPK kinase family, Melk, is expressed in the mouse egg and preimplantation embryo. Mol Reprod Dev 47: pp. 148-156 CrossRef
  8. Davezac, N, Baldin, V, Blot, J, Ducommun, B, Tassan, JP (2002) Human pEg3 kinase associates with and phosphorylates CDC25B phosphatase: a potential role for pEg3 in cell cycle regulation. Oncogene 21: pp. 7630-7641 CrossRef
  9. Blot, J, Chartrain, I, Roghi, C, Philippe, M, Tassan, JP (2002) Cell cycle regulation of pEg3, a new Xenopus protein kinase of the KIN1/PAR-1/MARK family. Dev Biol 241: pp. 327-338 CrossRef
  10. Nagase, T, Seki, N, Ishikawa, K, Tanaka, A, Nomura, N (1996) Prediction of the coding sequences of unidentified human genes. V. The coding sequences of 40 new genes (KIAA0161-KIAA0200) deduced by analysis of cDNA clones from human cell line KG-1. DNA Res 3: pp. 17-24 CrossRef
  11. Nakano, I, Paucar, AA, Bajpai, R, Dougherty, JD, Zewail, A, Kelly, TK, Kim, KJ, Ou, J, Groszer, M, Imura, T, Freije, WA, Nelson, SF, Sofroniew, MV, Wu, H, Liu, X, Terskikh, AV, Geschwind, DH, Kornblum, HI (2005) Maternal embryonic leucine zipper kinase (MELK) regulates multipotent neural progenitor proliferation. J Cell Biol 170: pp. 413-427 CrossRef
  12. Badouel, C, Chartrain, I, Blot, J, Tassan, JP (2010) Maternal embryonic leucine zipper kinase is stabilized in mitosis by phosphorylation and is partially degraded upon mitotic exit. Exp Cell Res 316: pp. 2166-2173 CrossRef
  13. Vulsteke, V, Beullens, M, Boudrez, A, Keppens, S, Van Eynde, A, Rider, MH, Stalmans, W, Bollen, M (2004) Inhibition of spliceosome assembly by the cell cycle-regulated protein kinase MELK and involvement of splicing factor NIPP1. J Biol Chem 279: pp. 8642-8647 CrossRef
  14. Beullens, M, Vancauwenbergh, S, Morrice, N, Derua, R, Ceulemans, H, Waelkens, E, Bollen, M (2005) Substrate specificity and activity regulation of protein kinase MELK. J Biol Chem 280: pp. 40003-40011 CrossRef
  15. Kig, C, Beullens, M, Beke, L, Van Eynde, A, Linders, JT, Brehmer, D, Bollen, M (2013) Maternal embryonic leucine zipper kinase (MELK) reduces replication stress in glioblastoma cells. J Biol Chem 288: pp. 24200-24212 CrossRef
  16. Seong, HA, Gil, M, Kim, KT, Kim, SJ, Ha, H (2002) Phosphorylation of a novel zinc-finger-like protein, ZPR9, by murine protein serine/threonine kinase 38 (MPK38). Biochem J 361: pp. 597-604 CrossRef
  17. Kuner, R, Falth, M, Pressinotti, NC, Brase, JC, Puig, SB, Metzger, J, Gade, S, Schafer, G, Bartsch, G, Steiner, E, Klocker, H, Sultmann, H (2013) The maternal embryonic leucine zipper kinase (MELK) is upregulated in high-grade prostate cancer. J Mol Med (Berl) 91: pp. 237-248 CrossRef
  18. Lin, ML, Park, JH, Nishidate, T, Nakamura, Y, Katagiri, T (2007) Involvement of maternal embryonic leucine zipper kinase (MELK) in mammary carcinogenesis through interaction with Bcl-G, a pro-apoptotic member of the Bcl-2 family. Breast Cancer Res 9: pp. R17 CrossRef
  19. Marie, SK, Okamoto, OK, Uno, M, Hasegawa, AP, Oba-Shinjo, SM, Cohen, T, Camargo, AA, Kosoy, A, Carlotti, CG, Toledo, S, Moreira-Filho, CA, Zago, MA, Simpson, AJ, Caballero, OL (2008) Maternal embryonic leucine zipper kinase transcript abundance correlates with malignancy grade in human astrocytomas. Int J Cancer 122: pp. 807-815 CrossRef
  20. Nakano, I, Masterman-Smith, M, Saigusa, K, Paucar, AA, Horvath, S, Shoemaker, L, Watanabe, M, Negro, A, Bajpai, R, Howes, A, Lelievre, V, Waschek, JA, Lazareff, JA, Freije, WA, Liau, LM, Gilbertson, RJ, Cloughesy, TF, Geschwind, DH, Nelson, SF, Mischel, PS, Terskikh, AV, Kornblum, HI (2008) Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells. J Neurosci Res 86: pp. 48-60 CrossRef
  21. Pickard, MR, Green, AR, Ellis, IO, Caldas, C, Hedge, VL, Mourtada-Maarabouni, M, Williams, GT (2009) Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer. Breast Cancer Res 11: pp. R60 CrossRef
  22. Yoshimoto, K, Ma, X, Guan, Y, Mizoguchi, M, Nakamizo, A, Amano, T, Hata, N, Kuga, D, Sasaki, T (2011) Expression of stem cell marker and receptor kinase genes in glioblastoma tissue quantified by real-time RT-PCR. Brain Tumor Pathol 28: pp. 291-296 CrossRef
  23. Hebbard, LW, Maurer, J, Miller, A, Lesperance, J, Hassell, J, Oshima, RG, Terskikh, AV (2010) Maternal embryonic leucine zipper kinase is upregulated and required in mammary tumor-initiating cells in vivo. Cancer Res 70: pp. 8863-8873 CrossRef
  24. Gray, D, Jubb, AM, Hogue, D, Dowd, P, Kljavin, N, Yi, S, Bai, W, Frantz, G, Zhang, Z, Koeppen, H, de Sauvage, FJ, Davis, DP (2005) Maternal embryonic leucine zipper kinase/murine protein serine-threonine kinase 38 is a promising therapeutic target for multiple cancers. Cancer Res 65: pp. 9751-9761 CrossRef
  25. Chung, S, Nakamura, Y (2013) MELK inhibitor, novel molecular targeted therapeutics for human cancer stem cells. Cell Cycle 12: pp. 1655-1656 CrossRef
  26. Nakano, I, Joshi, K, Visnyei, K, Hu, B, Watanabe, M, Lam, D, Wexler, E, Saigusa, K, Nakamura, Y, Laks, DR, Mischel, PS, Viapiano, M, Kornblum, HI (2011) Siomycin A targets brain tumor stem cells partially through a MELK-mediated pathway. Neuro Oncol 13: pp. 622-634 CrossRef
  27. Choi, S, Ku, JL (2011) Resistance of colorectal cancer cells to radiation and 5-FU is associated with MELK expression. Biochem Biophys Res Commun 412: pp. 207-213 CrossRef
  28. Deakin, NO, Turner, CE (2008) Paxillin comes of age. J Cell Sci 121: pp. 2435-2444 CrossRef
  29. Lietha, D, Cai, X, Ceccarelli, DF, Li, Y, Schaller, MD, Eck, MJ (2007) Structural basis for the autoinhibition of focal adhesion kinase. Cell 129: pp. 1177-1187 CrossRef
  30. Mitra, SK, Schlaepfer, DD (2006) Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol 18: pp. 516-523 CrossRef
  31. Schaller, MD, Parsons, JT (1995) pp125FAK-dependent tyrosine phosphorylation of paxillin creates a high-affinity binding site for Crk. Mol Cell Biol 15: pp. 2635-2645
  32. Grimsley, CM, Kinchen, JM, Tosello-Trampont, AC, Brugnera, E, Haney, LB, Lu, M, Chen, Q, Klingele, D, Hengartner, MO, Ravichandran, KS (2004) Dock180 and ELMO1 proteins cooperate to promote evolutionarily conserved Rac-dependent cell migration. J Biol Chem 279: pp. 6087-6097 CrossRef
  33. Siesser, PM, Hanks, SK (2006) The signaling and biological implications of FAK overexpression in cancer. Clin Cancer Res 12: pp. 3233-3237 CrossRef
  34. Raftopoulou, M, Hall, A (2004) Cell migration: Rho GTPases lead the way. Dev Biol 265: pp. 23-32 CrossRef
  35. Valles, AM, Beuvin, M, Boyer, B (2004) Activation of Rac1 by paxillin-Crk-DOCK180 signaling complex is antagonized by Rap1 in migrating NBT-II cells. J Biol Chem 279: pp. 44490-44496 CrossRef
  36. Tsubouchi, A, Sakakura, J, Yagi, R, Mazaki, Y, Schaefer, E, Yano, H, Sabe, H (2002) Localized suppression of RhoA activity by Tyr31/118-phosphorylated paxillin in cell adhesion and migration. J Cell Biol 159: pp. 673-683 CrossRef
  37. Hsia, DA, Mitra, SK, Hauck, CR, Streblow, DN, Nelson, JA, Ilic, D, Huang, S, Li, E, Nemerow, GR, Leng, J, Spencer, KS, Cheresh, DA, Schlaepfer, DD (2003) Differential regulation of cell motility and invasion by FAK. J Cell Biol 160: pp. 753-767 CrossRef
  38. Yu, HG, Nam, JO, Miller, NL, Tanjoni, I, Walsh, C, Shi, L, Kim, L, Chen, XL, Tomar, A, Lim, ST, Schlaepfer, DD (2011) p190RhoGEF (Rgnef) promotes colon carcinoma tumor progression via interaction with focal adhesion kinase. Cancer Res 71: pp. 360-370 CrossRef
  39. Joshi, K, Banasavadi-Siddegowda, Y, Mo, X, Kim, SH, Mao, P, Kig, C, Nardini, D, Sobol, RW, Chow, LM, Kornblum, HI, Waclaw, R, Beullens, M, Nakano, I (2013) MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells. Stem Cells 31: pp. 1051-1063 CrossRef
  40. Saito, R, Nakauchi, H, Watanabe, S (2012) Serine/threonine kinase, Melk, regulates proliferation and glial differentiation of retinal progenitor cells. Cancer Sci 103: pp. 42-49 CrossRef
  41. Badouel, C, Korner, R, Frank-Vaillant, M, Couturier, A, Nigg, EA, Tassan, JP (2006) M-phase MELK activity is regulated by MPF and MAPK. Cell Cycle 5: pp. 883-889 CrossRef
  42. Yilmaz, M, Christofori, G, Lehembre, F (2007) Distinct mechanisms of tumor invasion and metastasis. Trends Mol Med 13: pp. 535-541 CrossRef
  43. Chodniewicz, D, Klemke, RL (2004) Regulation of integrin-mediated cellular responses through assembly of a CAS/Crk scaffold. Biochim Biophys Acta 1692: pp. 63-76 CrossRef
  44. Zhai, J, Lin, H, Nie, Z, Wu, J, Canete-Soler, R, Schlaepfer, WW, Schlaepfer, DD (2003) Direct interaction of focal adhesion kinase with p190RhoGEF. J Biol Chem 278: pp. 24865-24873 CrossRef
  45. Qu, Y, Li, J, Cai, Q, Liu, B (2014) Hec1/Ndc80 is overexpressed in human gastric cancer and regulates cell growth. J Gastroenterol 49: pp. 408-418 CrossRef
  46. Bandyopadhyay, S, Zhan, R, Chaudhuri, A, Watabe, M, Pai, SK, Hirota, S, Hosobe, S, Tsukada, T, Miura, K, Takano, Y, Saito, K, Pauza, ME, Hayashi, S, Wang, Y, Mohinta, S, Mashimo, T, Iiizumi, M, Furuta, E, Watabe, K (2006) Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nat Med 12: pp. 933-938 CrossRef
  
• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

Background Elevated MELK expression is featured in multiple tumors and correlated with tumorigenesis and tumor development. This study is aimed to investigate the mechanisms of MELK-mediated development of gastric cancer. Methods MELK expression levels in human gastric cancer were determined by quantitative-PCR and immunohistochemistry. The effect of MELK on cell activity was explored by knockdown and overexpression experiments. Cell growth was measured using the CCK-8 assay. Apoptosis and cell cycle distributions were analyzed by flow cytometry. Migration and invasion were tested using a transwell migration assay. Cytoskeletal changes were analyzed by immunofluorescence. To explore the molecular mechanism and effect of MELK on migration and invasion, Western blotting was used to analyze the FAK/Paxillin pathway and pull down assays for the activity of small Rho GTPases. In vivo tumorigenicity and peritoneal metastasis experiments were performed by tumor cell engraftment into nude mice. Results MELK mRNA and protein expression were both elevated in human gastric cancer, and this was associated with chemoresistance to 5-fluorouracil (5-FU). Knockdown of MELK significantly suppressed cell proliferation, migration and invasion of gastric cancer both in vitro and in vivo, decreased the percentages of cells in the G1/G0 phase and increased those in the G2/M and S phases. Moreover, knockdown of MELK decreased the amount of actin stress fibers and inhibited RhoA activity. Finally, knockdown of MELK decreased the phosphorylation of the FAK and paxillin, and prevented gastrin-stimulated FAK/paxillin phosphorylation. By contrast, MELK overexpression had the opposite effect. Conclusions MELK promotes cell migration and invasion via the FAK/Paxillin pathway, and plays an important role in the occurrence and development of gastric cancer. MELK may be a potential target for treatment against gastric cancer.