Abstract
Maternal embryonic leucine zipper kinase (MELK) is upregulated in a variety of human tumors, and is considered an attractive molecular target for cancer treatment. We characterized the expression of MELK in gastric cancer (GC) and measured the effects of reducing MELK mRNA levels and protein activity on GC growth. MELK was frequently overexpressed in primary GCs, and higher MELK levels correlated with worse clinical outcomes. Reducing MELK expression or inhibiting kinase activity resulted in growth inhibition, G2/M arrest, apoptosis and suppression of invasive capability of GC cells in vitro and in vivo. MELK knockdown led to alteration of epithelial mesenchymal transition (EMT)-associated proteins. Furthermore, targeting treatment with OTSSP167 in GC patient-derived xenograft (PDX) models had anticancer effects. Thus, MELK promotes cell growth and invasiveness by inhibiting apoptosis and promoting G2/M transition and EMT in GC. These results suggest that MELK may be a promising target for GC treatment.
Highlights
Gastric cancer is the fourth most common malignant tumor and the second leading cause of cancer-related deaths [1]
Elevated Maternal embryonic leucine zipper kinase (MELK) expression has been identified in a variety of tumors and is associated with poor prognosis in cancer patients
Our previous Affimetrix HG-133 array data showed that MELK is strongly upregulated in gastric cancer (GC) tumors as compared to normal gastric tissue
Summary
Gastric cancer is the fourth most common malignant tumor and the second leading cause of cancer-related deaths [1]. Because patients in the early stages of GC are either asymptomatic or report only nonspecific symptoms, by the time of diagnosis the tumor has often progressed to an advanced stage or has even metastasized to distant organs. Metastasis is the most common cause of death in patients with GC [3]. Further study of the molecular mechanisms of GC development and progression may help identify new molecular targets for more effective therapies. Molecules that are uniquely overexpressed in cancer cells are ideal targets for the development of anticancer drugs, and treatments focusing on specific molecular targets often have fewer negative side effects. Protein kinases have emerged as the most important targets for drug discovery because of their critical roles in regulating cell growth and survival. Data collected previously using an Affimetrix HG-133 array showed a 3.84-fold increase in MELK expression in 79 GC tissues as compared to 24 non-cancerous tissues, making it one of the most upregulated genes in GC (p < 0.05) (unpublished data)
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