CFL1 expression levels as a prognostic and drug resistance marker in nonsmall cell lung cancer.
BACKGROUND
Nonsmall cell lung cancer (NSCLC) is the major determinant of overall cancer mortality worldwide. Despite progress in molecular research, current treatments offer limited benefits. Because NSCLC generates early metastasis, and this behavior requires great cell motility, herein the authors assessed the potential value of CFL1 gene (main member of the invasion/metastasis pathway) as a prognostic and predictive NSCLC biomarker.


METHODS
Metadata analysis of tumor tissue microarray was applied to examine expression of CFL1 in archival lung cancer samples from 111 patients, and its clinicopathologic significance was investigated. The robustness of the finding was validated using another independent data set. Finally, the authors assayed in vitro the role of CFL1 levels in tumor invasiveness and drug resistance using 6 human NSCLC cell lines with different basal degrees of CFL1 gene expression.


RESULTS
CFL1 levels in biopsies discriminate between good and bad prognosis at early tumor stages (IA, IB, and IIA/B), where high CFL1 levels are correlated with lower overall survival rate (P<.0001). Biomarker performance was further analyzed by immunohistochemistry, hazard ratio (P<.001), and receiver-operating characteristic curve (area=0.787; P<.001). High CFL1 mRNA levels and protein content are positively correlated with cellular invasiveness (determined by Matrigel Invasion Chamber System) and resistance (2-fold increase in drug 50% growth inhibition dose) against a list of 22 alkylating agents. Hierarchical clustering analysis of the CFL1 gene network had the same robustness for stratified NSCLC patients.


CONCLUSIONS
This study indicates that the CFL1 gene and its functional gene network can be used as prognostic biomarkers for NSCLC and could also guide chemotherapeutic interventions.
Castro
Mauro Antonio Alves
MA
Department of Biochemistry, ICBS/Federal University of Rio Grande do Sul, Porto Alegre, Brazil.
Dal-Pizzol
Felipe
F
Zdanov
Stephanie
S
Soares
Marcio
M
Müller
Carolina Beatriz
CB
Lopes
Fernanda Martins
FM
Zanotto-Filho
Alfeu
A
da Cruz Fernandes
Marilda
M
Moreira
Jose Claudio Fonseca
JC
Shacter
Emily
E
Klamt
Fábio
F
D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D051338:Cofilin 1 / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011379:Prognosis
D014408:Biomarkers, Tumor; D051338:Cofilin 1