title: Genetic amplification of PPME1 in gastric and lung cancer and its potential as a novel therapeutic target.
abstract: Protein phosphatase methylesterase 1 (PPME1) is a protein phosphatase 2A (PP2A)-specific methyl esterase that negatively regulates PP2A through demethylation at its carboxy terminal leucine 309 residue. Emerging evidence shows that the upregulation of PPME1 is associated with poor prognosis in glioblastoma patients. By performing an array comparative genomic hybridization analysis to detect copy number changes, we have been the first to identify PPME1 gene amplification in 3.8% (5/131) of Chinese gastric cancer (GC) samples and 3.1% (4/124) of Chinese lung cancer (LC) samples. This PPME1 gene amplification was confirmed by fluorescence in situ hybridization analysis and is correlated with elevated protein expression, as determined by immunohistochemistry analysis. To further investigate the role of PPME1 amplification in tumor growth, short-hairpin RNA-mediated gene silencing was employed. A knockdown of PPME1 expression resulted in a significant inhibition of cell proliferation and induction of cell apoptosis in PPME1-amplified human cancer cell lines SNU668 (GC) and Oka-C1 (LC), but not in nonamplified MKN1 (GC) and HCC95 (LC) cells. The PPME1 gene knockdown also led to a consistent decrease in PP2A demethylation at leucine 309, which was correlated with the downregulation of cellular Erk and AKT phosphorylation. Our data indicate that PPME1 could be an attractive therapeutic target for a subset of GCs and LCs.
authors.affiliation: Innovation Center China; Asia & Emerging Market iMed; AstraZeneca Innovation Medicines and Early Development; Shanghai, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Innovation Center China; Asia & Emerging Market iMed; AstraZeneca Innovation Medicines and Early Development; Shanghai, PR China.
authors.forename: Sufang
authors.initials: S
authors.lastname: Han
authors.affiliation: Innovation Center China; Asia & Emerging Market iMed; AstraZeneca Innovation Medicines and Early Development; Shanghai, PR China.
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Qian
authors.affiliation: Innovation Center China; Asia & Emerging Market iMed; AstraZeneca Innovation Medicines and Early Development; Shanghai, PR China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Su
authors.affiliation: Innovation Center China; Asia & Emerging Market iMed; AstraZeneca Innovation Medicines and Early Development; Shanghai, PR China.
authors.forename: Shuqiong
authors.initials: S
authors.lastname: Fan
authors.affiliation: Innovation Center China; Asia & Emerging Market iMed; AstraZeneca Innovation Medicines and Early Development; Shanghai, PR China.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Fu
authors.affiliation: Innovation Center China; Asia & Emerging Market iMed; AstraZeneca Innovation Medicines and Early Development; Shanghai, PR China.
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Innovation Center China; Asia & Emerging Market iMed; AstraZeneca Innovation Medicines and Early Development; Shanghai, PR China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Yin
authors.affiliation: Innovation Center China; Asia & Emerging Market iMed; AstraZeneca Innovation Medicines and Early Development; Shanghai, PR China.
authors.forename: Zeren
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Innovation Center China; Asia & Emerging Market iMed; AstraZeneca Innovation Medicines and Early Development; Shanghai, PR China.
authors.forename: Jingchuan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Innovation Center China; Asia & Emerging Market iMed; AstraZeneca Innovation Medicines and Early Development; Shanghai, PR China.
authors.forename: De-Hua
authors.initials: DH
authors.lastname: Yu
authors.affiliation: Innovation Center China; Asia & Emerging Market iMed; AstraZeneca Innovation Medicines and Early Development; Shanghai, PR China.
authors.forename: Qunsheng
authors.initials: Q
authors.lastname: Ji
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D045744:Cell Line, Tumor; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D034741:RNA, Small Interfering; D002265:Carboxylic Ester Hydrolases; C119357:protein phosphatase methylesterase-1
keywords: PP2A; PPME1amplification; gastric cancer; lung cancer; shRNA-knockdown