title: Protein phosphatase PHLPP induces cell apoptosis and exerts anticancer activity by inhibiting Survivin phosphorylation and nuclear export in gallbladder cancer.
abstract: Many factors regulate cancer cell apoptosis, among which Survivin has a strong anti-apoptotic effect and PHLPP is a tumor suppressor gene that can induce significant apoptosis. However, the relationship between PHLPP and Survivin in gallbladder carcinoma (GBC) has not been reported. This study found that PHLPP expression is decreased and Survivin expression is increased in GBC tissues and cell lines. Their expression levels showed an inverse relationship and were associated with poor prognosis of GBC patients. Loss of PHLPP can increase the level of phosphorylated Survivin and induce the nuclear export of Survivin, which thus inhibit cell apoptosis and promote cell proliferation in GBC cells. The process that PHLPP regulates Survivin phosphorylation and intracellular localization is involved in AKT activity. Re-overexpression of PHLPP in GBC cells can decrease AKT phosphorylation level. Reduced expression of PHLPP in GBC is associated with high expression of miR-495. Increasing PHLPP expression or inhibiting miR-495 expression can induce apoptosis and suppress tumor growth in GBC xenograft model in nude mice. The results revealed the role and mechanism of PHLPP and Survivin in GBC cells and proposed strategies for gene therapies targeting the miR-495 / PHLPP / AKT / Survivin regulatory pathway.
authors.affiliation: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China.
authors.forename: Yinghe
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China.
authors.forename: Xiaoya
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yi
authors.affiliation: Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Junnian
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China.
authors.forename: Zhangxiao
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China.
authors.forename: Zhihan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China.
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.affiliation: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Shen
authors.affiliation: Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China.|Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China.
authors.forename: Changqing
authors.initials: C
authors.lastname: Su
mesh_terms: D021581:Active Transport, Cell Nucleus; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D005706:Gallbladder Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009687:Nuclear Proteins / Q000008:administration & dosage* / Q000235:genetics*; D010749:Phosphoprotein Phosphatases / Q000008:administration & dosage* / Q000235:genetics*; D010766:Phosphorylation; D011379:Prognosis; D011897:Random Allocation; D000077022:Survivin; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009687:Nuclear Proteins; D000077022:Survivin; C400601:PHLPP1 protein, human; D010749:Phosphoprotein Phosphatases
keywords: Survivin; apoptosis; cell signaling; gallbladder carcinoma; protein phosphatase