CK2α, over-expressed in human malignant pleural mesothelioma, regulates the Hedgehog signaling pathway in mesothelioma cells

Journal of Experimental & Clinical Cancer Research

Liang You¹  David M Jablons¹  Zhidong Xu¹  Hubert J Stoppler⁴  Alfred Au⁵  Li Tai Fang¹  Il-Jin Kim¹  David Hsieh¹  Geraldine Chan¹  Yuyuan Dai¹  Bin You³  Yucheng Wang²  Yi-Lin Yang¹  Shulin Zhang¹ 

[1] Thoracic Oncology Laboratory, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco 94143, CA, USA;Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco 94143, CA, USA;Department of Thoracic Surgery, Beijing Chao-Yang Hospital, Affiliated with Capital University of Medical Science, Beijing, P.R. China;Tissue Core, Comprehensive Cancer Center, University of California San Francisco, San Francisco 94143, CA, USA;Division of Diagnostic Pathology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco 94143, CA, USA

关键词: Mesothelioma;    IHC;    Gli1;    Hedgehog;    CK2α;   

Others  :  1136010
DOI  :  10.1186/s13046-014-0093-6

 received in 2014-08-14, accepted in 2014-10-22,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Zhang et al.; licensee BioMed Central Ltd.

【 图 表 】

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