PPM1D exerts its oncogenic properties in human pancreatic cancer through multiple mechanisms

Protein phosphatase, Mg 2+ /Mn 2+ dependent, 1D (PPM1D) is emerging as an oncogene by virtue of its negative control on several tumor suppressor pathways. However, the clinical significance of PPM1D in pancreatic cancer (PC) has not been defined. In this study, we determined PPM1D expression in huma...

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Published in:Apoptosis (London) 2016-03, Vol.21 (3), p.365-378
Main Authors: Wu, Bo, Guo, Bo-Min, Kang, Jie, Deng, Xian-Zhao, Fan, You-Ben, Zhang, Xiao-Ping, Ai, Kai-Xing
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis Regulatory Proteins - metabolism
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cancer Research
Carcinogenesis - metabolism
Cell Biology
Cell Line, Tumor
Cell Movement
Down-Regulation
Humans
Neoplasm Invasiveness
Oncology
p38 Mitogen-Activated Protein Kinases - chemistry
Pancreatic cancer
Pancreatic Neoplasms - metabolism
Pancreatic Neoplasms - pathology
Phosphoprotein Phosphatases - metabolism
Phosphorylation
Protein Phosphatase 2C
Proto-Oncogene Proteins - metabolism
Virology
Wnt Signaling Pathway
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Summary:Protein phosphatase, Mg 2+ /Mn 2+ dependent, 1D (PPM1D) is emerging as an oncogene by virtue of its negative control on several tumor suppressor pathways. However, the clinical significance of PPM1D in pancreatic cancer (PC) has not been defined. In this study, we determined PPM1D expression in human PC tissues and cell lines and their irrespective noncancerous controls. We subsequently investigated the functional role of PPM1D in the migration, invasion, and apoptosis of MIA PaCa-2 and PANC-1 PC cells in vitro and explored the signaling pathways involved. Furthermore, we examined the role of PPM1D in PC tumorigenesis in vivo. Our results showed that PPM1D is overexpressed in human PC tissues and cell lines and significantly correlated with tumor growth and metastasis. PPM1D promotes PC cell migration and invasion via potentiation of the Wnt/β-catenin pathway through downregulation of apoptosis-stimulating of p53 protein 2 (ASPP2). In contrast to PPM1D, our results showed that ASPP2 is downregulated in PC tissues. Additionally, PPM1D suppresses PC cell apoptosis via inhibition of the p38 MAPK/p53 pathway through both dephosphorylation of p38 MAPK and downregulation of ASPP2. Furthermore, PPM1D promotes PC tumor growth in vivo. Our results demonstrated that PPM1D is an oncogene in PC.
ISSN:1360-8185
1573-675X
DOI:10.1007/s10495-015-1211-4