Protein phosphatase PHLPP induces cell apoptosis and exerts anticancer activity by inhibiting Survivin phosphorylation and nuclear export in gallbladder cancer
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Yinghe Qiu1,*, Xiaoya Li1,*, Bin Yi1,*, Junnian Zheng2, Zhangxiao Peng1, Zhihan Zhang1, Mengchao Wu1, Feng Shen1 and Changqing Su1,2
1 Department of Molecular Oncology & Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital & National Center of Liver Cancer, Second Military Medical University, Shanghai, China
2 Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical College, Xuzhou, Jiangsu, China
* These authors have contributed equally to this work
Changqing Su, email:
Keywords: gallbladder carcinoma, protein phosphatase, survivin, apoptosis, cell signaling
Received: February 03, 2015 Accepted: March 03, 2015 Published: March 30, 2015
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.
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