title: PPM1D exerts its oncogenic properties in human pancreatic cancer through multiple mechanisms.
abstract: 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.
authors.affiliation: Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 YiShan Road, Shanghai, Shanghai, 200233, China. wubo7421@sohu.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 YiShan Road, Shanghai, Shanghai, 200233, China.
authors.forename: Bo-Min
authors.initials: BM
authors.lastname: Guo
authors.affiliation: Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 YiShan Road, Shanghai, Shanghai, 200233, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Kang
authors.affiliation: Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 YiShan Road, Shanghai, Shanghai, 200233, China.
authors.forename: Xian-Zhao
authors.initials: XZ
authors.lastname: Deng
authors.affiliation: Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 YiShan Road, Shanghai, Shanghai, 200233, China.
authors.forename: You-Ben
authors.initials: YB
authors.lastname: Fan
authors.affiliation: Institution of Interventional and Vascular surgery, Tongji University, 301 Middle Yan Chang Rd, Shanghai, 200072, China. zxpkxy@126.com.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 YiShan Road, Shanghai, Shanghai, 200233, China. akxing8258@sina.com.
authors.forename: Kai-Xing
authors.initials: KX
authors.lastname: Ai
mesh_terms: D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D006801:Humans; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry*
chemical_list: D051017:Apoptosis Regulatory Proteins; D011518:Proto-Oncogene Proteins; C090468:TP53BP2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; C000607458:PPM1D protein, human; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C
keywords: ASPP2; P53; PPM1D; Pancreatic cancer; Wnt/β-catenin