期刊
CANCER LETTERS
卷 442, 期 -, 页码 383-395出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2018.11.014
关键词
PEAK1; PPP1R12B; Colorectal cancer; PI3K/Akt; Cell proliferation and invasion
类别
资金
- National Science and Technology Major Project of China [2018ZX09301026-005]
- National Natural Science Foundation of China [81773624]
- Project of Social Development of Jiangsu Province [BE2017746]
- Postgraduate Research and Practice Innovation Program of Jiangsu Province [KYCX17_0179]
- Scientific Research Foundation of Graduate School of Southeast University [YBJJ1798]
Pseudopodium enriched atypical kinase 1 (PEAK1), a novel non-receptor tyrosine kinase, was recently implicated in cancer pathogenesis. However, its functional role in colorectal cancer (CRC) is not well known. Herein, we demonstrated that PEAK1 was frequently downregulated in CRC and significantly associated with tumor size, differentiation status, metastasis, and clinical stage. PEAK1 overexpression suppressed CRC cell growth, invasion, and metastasis in vitro and in vivo, whereas knockout had the opposite effects. Further evaluation revealed that PEAK1 expression was positively correlated with protein phosphatase 1 regulatory subunit 12B (PPP1R12B) in CRC cell lines and clinical tissues, and this protein was found to suppress activation of the Grb2/PI3K/Akt pathway. Moreover, PPP1R12B knockdown markedly abrogated PEAK1-mediated tumor suppressive effects, whereas its upregulation recapitulated the effects of PEAK1 knockout on cell behaviours and the activation of signalling. Mechanistically, P13K and Akt inhibitors reversed impaired the effect of PEAK1 function on cell proliferation, migration, and invasion. Our results provide compelling evidence that the PEAK1 PPP1R12B axis inhibits colorectal tumorigenesis and metastasis through deactivation of the Grb2/PI3K/Akt pathway, which might provide a novel therapeutic strategy for CRC treatment.
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