Abstract
BackgroundToward identifying new strategies to target gastric cancer stem-like cells (CSCs), we evaluated the function of the tumour suppressor CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) in gastric CSC maintenance.MethodsWe examined the expression of CDK5RAP3 and CD44 in gastric cancer patients. The function and mechanisms of CDK5RAP3 were checked in human and mouse gastric cancer cell lines and in mouse xenograft.ResultsWe show that CDK5RAP3 is weakly expressed in gastric CSCs and is negatively correlated with the gastric CSC marker CD44. CDK5RAP3 overexpression decreased expression of CSC markers, spheroid formation, invasion and migration, and reversed chemoresistance in gastric CSCs in vitro and vivo. CDK5RAP3 expression was found to be regulated by extracellular-related kinase (ERK) signalling. ERK inhibitors decreased spheroid formation, migration and invasion, and the expression of epithelial-to-mesenchymal transition (EMT)-related proteins in both GA cells and organoids derived from a genetically engineered mouse model of GA. Finally, CDK5RAP3 expression was associated with reduced lymph-node metastasis and better prognosis, even in the presence of high expression of the EMT transcription factor Snail, among patients with CD44-positive GA.ConclusionsOur results demonstrate that CDK5RAP3 is suppressed by ERK signalling and negatively regulates the self-renewal and EMT of gastric CSCs.
Highlights
Toward identifying new strategies to target gastric cancer stem-like cells (CSCs), we evaluated the function of the tumour suppressor cyclin dependent kinase 5 (CDK5) regulatory subunit-associated protein 3 (CDK5RAP3) in gastric CSC maintenance
CDK5RAP3 and CD44 expression are negatively correlated in tumours of gastric adenocarcinoma (GA) patients and gastric cell lines Toward evaluating the potential function of CDK5RAP3 in gastric CSCs, we first examined the relationship between CDK5RAP3 and CD44 expression in tumour tissue and adjacent nontumour tissue by IHC in paraffin-embedded specimens from 125 patients undergoing radical gastrectomy at FMUUH (Supplementary Fig. S1A)
Our results demonstrate CDK5RAP3 negatively regulates epithelial-tomesenchymal transition (EMT) in GA and normal gastric epithelial cells, which inhibits the acquisition of CSC phenotypes and metastatic potential
Summary
Toward identifying new strategies to target gastric cancer stem-like cells (CSCs), we evaluated the function of the tumour suppressor CDK5 regulatory subunit-associated protein 3 (CDK5RAP3) in gastric CSC maintenance. CDK5RAP3 overexpression decreased expression of CSC markers, spheroid formation, invasion and migration, and reversed chemoresistance in gastric CSCs in vitro and vivo. ERK inhibitors decreased spheroid formation, migration and invasion, and the expression of epithelial-tomesenchymal transition (EMT)-related proteins in both GA cells and organoids derived from a genetically engineered mouse model of GA. CONCLUSIONS: Our results demonstrate that CDK5RAP3 is suppressed by ERK signalling and negatively regulates the self-renewal and EMT of gastric CSCs. Gastric cancer is one of the most common cancers globally and remains the third leading cause of cancer-related death.[1] In the U. Gastric CSCs have been identified and distinguished by several cell-surface markers including CD133, CD24 and CD44.6–8 Takaishi et al test in six gastric cancer cell lines for seven CSC markers and their association with CSC properties, and found that CD44 was the only gastric CSC marker associated with tumour formation in immunodeficient mice and spheroid colony formation in vitro.[9]
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