title: Expression and transcriptional profiling of the LKB1 tumor suppressor in cervical cancer cells.
abstract: OBJECTIVE
  To characterize the biological activities of LKB1, examine LKB1 protein expression and identify LKB1-regulated genes that may serve as therapeutic targets in cervical cancer.
  
  
  METHODS
  Proliferation of cervical cancer HeLa cells expressing LKB1 was examined. LKB1 expression in normal cervical tissues and cervical cancers was assessed by immunohistochemistry. Gene expression profiles of cervical cancer HeLa cells stably expressing LKB1 were analyzed by microarray. Differentially expressed genes were analyzed using Gene Ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) PATHWAY database. Quantitative RT-PCR was used to validate the microarray data. The expression of lipid phosphatase inositol polyphosphate 4-phosphatase type II (INPP4B) was confirmed by western blotting.
  
  
  RESULTS
  Expression of LKB1 inhibited HeLa cell proliferation, activated AMPK and was lost in more than 50% of cervical carcinomas. More than 200 genes were differentially expressed between HeLa cells with and without LKB1. Bioinformatics analysis with GO annotation indicated that LKB1 plays a role in receiving diverse stimuli and converting them into molecular signals. KEGG PATHWAY analysis showed that 8 pathways were significantly regulated. These include arginine and proline metabolism and inositol phosphate metabolism. The differential expression of 7 randomly selected genes was confirmed by quantitative RT-PCR. Furthermore, the steady-state level of INPP4B protein was up-regulated in LKB1-overexpressing cells.
  
  
  CONCLUSIONS
  This study establishes LKB1 as an important tumor suppressor in cervical cancer and sheds light on a novel signaling pathway regulated by LKB1.
authors.affiliation: Department of Microbiology, Shandong University School of Medicine, Jinan, Shandong, China; Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01532, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Microbiology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Hanxiang
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pathology, Shandong University School of Medicine, Jinan, Shandong, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Microbiology, Shandong University School of Medicine, Jinan, Shandong, China. Electronic address: zhaowm@sdu.edu.cn.
authors.forename: Weiming
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01532, USA; Cancer Research Center, Shandong University School of Medicine, Jinan, Shandong, China. Electronic address: Jason.chen@umassmed.edu.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Chen
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics*; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms / Q000235:genetics*
chemical_list: D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases
keywords: Cervical carcinoma; Gene expression profiling; INPP4B; LKB1; Phosphatidyl inositol signaling