title: E-cadherin as a predictive marker of brain metastasis in non-small-cell lung cancer, and its regulation by pioglitazone in a preclinical model.
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 O(6)-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.
authors.affiliation: Department of Pathology, St. Vincent's Hospital, The Catholic University of Korea, 93-6 Chi-dong, Paldal-gu, Suwon, Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Yoo
authors.forename: Seung-Ho
authors.initials: SH
authors.lastname: Yang
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Deog Gon
authors.initials: DG
authors.lastname: Cho
authors.forename: Hoon Kyo
authors.initials: HK
authors.lastname: Kim
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Kim
authors.forename: Il Sup
authors.initials: IS
authors.lastname: Kim
authors.forename: Jae Taek
authors.initials: JT
authors.lastname: Hong
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Sung
authors.forename: Byung Chul
authors.initials: BC
authors.lastname: Son
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Lee
mesh_terms: D000368:Aged; D000818:Animals; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000473:pathology* / Q000556:secondary*; D015820:Cadherins / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D008297:Male; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D015513:Oncogene Proteins / Q000378:metabolism; D000077205:Pioglitazone; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D015820:Cadherins; D007004:Hypoglycemic Agents; D015513:Oncogene Proteins; D045162:Thiazolidinediones; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D045643:DNA Repair Enzymes; D000077205:Pioglitazone