title: Downregulation of nitrogen permease regulator like-2 activates PDK1-AKT1 and contributes to the malignant growth of glioma cells.
abstract: Nitrogen permease regulator like-2(NPRL2) is a candidate tumor suppressor gene(TSG) located on chromosome 3p21.3 and deletions frequently occur in this region, leading to canceration. Recently, molecular pathologic researches have provided valuable insights into the downregulation of NPRL2 in carcinogenesis in some types of cancers. However, very little is known about genetic changes of NPRL2 involved in glioma. Here, for the first time, we aimed to understand the expression levels, functions and mechanisms of NPRL2 for progression of glioma. We clearly demonstrated that NPRL2 expression was decreased in glioma and was negatively correlated with the histologic grade. The upregulation of NPRL2 expression in glioma cells inhibited proliferation by inducing G0/G1 cell cycle arrest in vitro and suppressed the growth of xenotransplanted tumors. In contrast, siRNA-mediated knockdown of NPRL2 promoted glioma growth. The anti-cancer effects of NPRL2 were involved in dephosphorylation of PDK1Tyr9and downstream AKT1Thr308resulting in inactivation of the PDK1-AKT1 signaling pathway, this ultimately increased the expression of p21 and p27, and inactivated CDK2 and CDK4. Our data confirmed NPRL2 was downregulated in gliomas. More importantly, NPRL2 was able to inhibit cell proliferation in vitro and repress tumorigenicity in vivo, suggesting its role as a tumor suppressor. Our data provide a basis for the further development of a promising therapeutic target for glioma. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Huang
authors.affiliation: Department of Orthopaedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Si
authors.initials: S
authors.lastname: Cheng
authors.affiliation: Department of neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.|Chongqing Key Laboratory of Neurology, Chongqing, China.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Mi
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.|Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Zongye
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Zongyi
authors.initials: Z
authors.lastname: Xie
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. chengyuan023@aliyun.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016543:Central Nervous System Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C492816:NPRL2 protein, human; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D025521:Tumor Suppressor Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: NPRL2; TUSC4; glioma; proliferation; tumorigenesis