title: CK2α, over-expressed in human malignant pleural mesothelioma, regulates the Hedgehog signaling pathway in mesothelioma cells.
abstract: BACKGROUND
  The Hedgehog (Hh) signaling pathway has been implicated in stem cell maintenance and its activation is aberrant in several types of cancer including mesothelioma. Protein kinase CK2 affects several cell signaling pathways through the mechanism of phosphorylation.
  
  
  METHODS
  Protein and mRNA levels of CK2α and Gli1 were tested by quantitative RT-PCR and immunohistochemistry staining in mesothelioma samples and cell lines. Down-regulated Gli1 expression and transcriptional activity were demonstrated by RT-PCR, Western blot and luciferase reporter assay.
  
  
  RESULTS
  In this study, we show that CK2α is over-expressed and a positive regulator of Hegdehog/Gli1 signaling in human malignant pleural mesothelioma. First of all, we found that the mRNA levels of CK2α and Gli1 were broadly elevated and correlated (n = 52, r = 0.401, P < 0.05), compared with LP9 (a normal mesothelial cell line). We then investigated their expression at the protein level, and found that all the 7 mesothelioma cell lines tested showed positive staining in CK2α and Gli1 immunohistochemistry. Correlation analysis by Pearson test for CK2α and Gli1 expression in the 75 mesothelioma tumors and the 7 mesothelioma cell lines showed that the two protein expression was significantly correlated (n = 82, r = 0.554, P < 0.01). Furthermore, we demonstrated that Gli1 expression and transcriptional activity were down-regulated after CK2α was silenced in two mesothelioma cell lines (H28 and H2052). CK2α siRNA also down-regulated the expression of Hh target genes in these cell lines. Moreover, treatment with a small-molecule CK2α inhibitor CX-4945 led to dose-dependent inhibition of Gli1 expression and transcriptional activity. Conversely, forced over-expression of CK2α resulted in an increase in Gli1 transcriptional activity in H28 cells.
  
  
  CONCLUSIONS
  Thus, we report for the first time that over-expressed CK2α positively regulate Hh/Gli1 signaling in human mesothelioma.
authors.affiliation: Department of Thoracic Surgery, The Fifth Hospital of Dalian, Dalian, 116021, P.R. China. zhangshulin830814@yahoo.com.|Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. zhangshulin830814@yahoo.com.
authors.forename: Shulin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. Yi-Lin.Yang@ucsfmedctr.org.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Yang
authors.affiliation: Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. Yucheng.Wang@ucsfmedctr.org.
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. Yb2759@gmail.com.|Department of Thoracic Surgery, Beijing Chao-Yang Hospital, Affiliated with Capital University of Medical Science, Beijing, P.R. China. Yb2759@gmail.com.
authors.forename: Bin
authors.initials: B
authors.lastname: You
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. Yuyuan.Dai@ucsfmedctr.org.
authors.forename: Yuyuan
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. Geraldine.c.chan@gmail.com.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Chan
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. david.hsieh4@gmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Hsieh
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. kimij@cc.ucsf.edu.
authors.forename: Il-Jin
authors.initials: IJ
authors.lastname: Kim
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. ltfang@gmail.com.
authors.forename: Li Tai
authors.initials: LT
authors.lastname: Fang
authors.affiliation: Division of Diagnostic Pathology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. Alfred.Au@ucsfmedctr.org.
authors.forename: Alfred
authors.initials: A
authors.lastname: Au
authors.affiliation: Tissue Core, Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. hubert.stoppler@ucsf.edu.
authors.forename: Hubert J
authors.initials: HJ
authors.lastname: Stoppler
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. Zhidong.Xu@ucsfmedctr.org.
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. David.Jablons@ucsfmedctr.org.
authors.forename: David M
authors.initials: DM
authors.lastname: Jablons
authors.affiliation: Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94143, USA. Liang.You@ucsfmedctr.org.
authors.forename: Liang
authors.initials: L
authors.lastname: You
mesh_terms: D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008654:Mesothelioma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000086002:Mesothelioma, Malignant; D010997:Pleural Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D053823:Hedgehog Proteins; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; C570325:CSNK2A1 protein, human; D047390:Casein Kinase II