title: Maternal embryonic leucine zipper kinase enhances gastric cancer progression via the FAK/Paxillin pathway.
abstract: 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.
authors.forename: Tao
authors.initials: T
authors.lastname: Du
authors.forename: Ying
authors.initials: Y
authors.lastname: Qu
authors.forename: Jianfang
authors.initials: J
authors.lastname: Li
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.forename: Liping
authors.initials: L
authors.lastname: Su
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhou
authors.forename: Min
authors.initials: M
authors.lastname: Yan
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: 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. byliu@sjtu.edu.cn.
authors.forename: Bingya
authors.initials: B
authors.lastname: Liu
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D051417:Focal Adhesion Kinase 1 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D051419:Paxillin / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051419:Paxillin; C496062:Pxn protein, mouse; D034741:RNA, Small Interfering; C108524:Melk protein, mouse; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D005472:Fluorouracil