Laboratory Investigation

Journal of Neuro-Oncology

, Volume 109, Issue 2, pp 219-227

E-cadherin as a predictive marker of brain metastasis in non-small-cell lung cancer, and its regulation by pioglitazone in a preclinical model

  • Jin Young YooAffiliated withDepartment of Pathology, St. Vincent’s Hospital, The Catholic University of Korea
  • , Seung-Ho YangAffiliated withDepartment of Neurosurgery, St. Vincent’s Hospital, The Catholic University of Korea Email author 
  • , Jung Eun LeeAffiliated withDepartment of Neurosurgery, St. Vincent’s Hospital, The Catholic University of Korea
  • , Deog Gon ChoAffiliated withDepartment of Thoracic Surgery, St. Vincent’s Hospital, The Catholic University of Korea
  • , Hoon Kyo KimAffiliated withDepartment of Internal Medicine, St. Vincent’s Hospital, The Catholic University of Korea
  • , Sung Hwan KimAffiliated withDepartment of Radiation Oncology, St. Vincent’s Hospital, The Catholic University of Korea
  • , Il Sup KimAffiliated withDepartment of Neurosurgery, St. Vincent’s Hospital, The Catholic University of Korea
  • , Jae Taek HongAffiliated withDepartment of Neurosurgery, St. Vincent’s Hospital, The Catholic University of Korea
  • , Jae Hoon SungAffiliated withDepartment of Neurosurgery, St. Vincent’s Hospital, The Catholic University of Korea
    • , Byung Chul SonAffiliated withDepartment of Neurosurgery, St. Vincent’s Hospital, The Catholic University of Korea
    • , Sang Won LeeAffiliated withDepartment of Neurosurgery, St. Vincent’s Hospital, The Catholic University of Korea

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Abstract

It remains unclear whether patients with non-small-cell lung cancer (NSCLC) develop brain metastasis during or after standard therapy. We attempted to identify biological markers that predict brain metastasis, and investigated how to modulate expression of such markers. A case–control study of patients who were newly diagnosed with NSCLC and who had developed brain metastasis during follow-up was conducted between 2004 and 2009. These patients were compared with a control group of patients who had NSCLC but no evidence of brain metastasis. Immunohistochemical analysis of expression of Ki-67, p53, Bcl-2, Bax, vascular endothelial growth factor, epidermal growth factor receptor, caspase-3, and E-cadherin was conducted. The methylation status of the genes for O6-methylguanine-DNA-methyltransferase, tissue inhibitor of matrix metalloproteinase (TIMP)-2, TIMP-3, and death-associated protein-kinase was also determined, by use of a methylation-specific polymerase chain reaction. A significantly increased risk of developing brain metastasis was associated with the presence of primary tumors with low E-cadherin expression in patients with NSCLC. We also investigated the effects of pioglitazone, a peroxisome proliferator-activated receptor γ-activating drug, in tumor-bearing mouse models. We found that E-cadherin expression was proportional to pioglitazone exposure time. Interestingly, pioglitazone pretreatment before cancer cell inoculation prevented loss of E-cadherin expression and reduced expression of MMP9 and fibronectin, compared with the control group. E-cadherin expression could be a predictor of brain metastasis in patients with NSCLC. Preventive treatment with pioglitazone may be useful for modulating E-cadherin expression.

Keywords

Biomarker Brain metastasis NSCLC PPARγ Prevention E-cadherin