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: Tao Du, Ying Qu, Jianfang Li, Hao Li, Liping Su, Quan Zhou, Min Yan, Chen Li, Zhenggang Zhu, Bingya Liu
• Journal: Molecular cancer (Mol Cancer) Vol. 13 Pg. 100 (May 04 2014) ISSN: 1476-4598 [Electronic] England
• PMID: 24885567 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Paxillin
• Pxn protein, mouse
• RNA, Small Interfering
• Melk protein, mouse
• Focal Adhesion Kinase 1
• Ptk2 protein, mouse
• Protein Serine-Threonine Kinases
• Fluorouracil

Topics

• Actin Cytoskeleton (drug effects)
• Aged
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Cycle (drug effects, genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Female
• Fluorouracil (pharmacology)
• Focal Adhesion Kinase 1 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Nude
• Middle Aged
• Neoplasm Invasiveness
• Paxillin (genetics, metabolism)
• Phosphorylation
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
• RNA, Small Interfering (genetics, metabolism)
• Signal Transduction
• Stomach Neoplasms (drug therapy, genetics, metabolism, pathology)
• Xenograft Model Antitumor Assays