CDK5RAP3 as tumour suppressor negatively regulates self-renewal and invasion and is regulated by ERK1/2 signalling in human gastric cancer Journal Article

   

Authors:	Lin, J. X.; Yoon, C.; Li, P.; Ryeom, S. W.; Cho, S. J.; Zheng, C. H.; Xie, J. W.; Wang, J. B.; Lu, J.; Chen, Q. Y.; Yoon, S. S.; Huang, C. M.
Article Title:	CDK5RAP3 as tumour suppressor negatively regulates self-renewal and invasion and is regulated by ERK1/2 signalling in human gastric cancer
Abstract:	Background: 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. Methods: We 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. Results: We 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. Conclusions: Our results demonstrate that CDK5RAP3 is suppressed by ERK signalling and negatively regulates the self-renewal and EMT of gastric CSCs. © 2020, The Author(s), under exclusive licence to Cancer Research UK.
Keywords:	adult; controlled study; human tissue; middle aged; unclassified drug; human cell; major clinical study; overall survival; cisplatin; fluorouracil; nonhuman; lymph node metastasis; ki 67 antigen; animal cell; mouse; animal tissue; animal experiment; animal model; in vivo study; caspase 3; in vitro study; tumor xenograft; chemosensitivity; uvomorulin; cancer resistance; regulatory mechanism; nerve cell adhesion molecule; cancer stem cell; cell migration; mitogen activated protein kinase 1; mitogen activated protein kinase 3; stomach cancer; down regulation; hermes antigen; tumor suppressor protein; stomach adenocarcinoma; transcription factor snail; cell invasion; transcription factor sox2; vimentin; epithelial mesenchymal transition; cyclin dependent kinase 5; cancer prognosis; mapk signaling; tumor spheroid; human; male; female; priority journal; article; stem cell self-renewal; genetically engineered mouse strain; organoid; cdk5 regulatory subunit associated protein 3
Journal Title:	British Journal of Cancer
Volume:	123
Issue:	7
ISSN:	0007-0920
Publisher:	Nature Publishing Group
Date Published:	2020-09-29
Start Page:	1131
End Page:	1144
Language:	English
DOI:	10.1038/s41416-020-0963-y
PUBMED:	32606358
PROVIDER:	scopus
PMCID:	PMC7525566
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85087117871&doi=10.1038%2fs41416-020-0963-y&partnerID=40&md5=aec1cb8be743fb34f81152294114f162
Notes:	Article -- Export Date: 2 November 2020 -- Source: Scopus

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