MRP3 gene expression correlates with NRF2 mutations in lung squamous cell carcinomas

Abstract

The expression of multidrug-resistant protein-3 (MRP3), a membrane-bound transporter, has been linked to drug resistance in non-small cell lung cancers (NSCLCs). Recently, we reported that NRF2 gene (NFE2L2) mutations are correlated with poor prognosis for lung squamous cell carcinomas. We hypothesized that tumor MRP3 expression may be correlated with the mutation status of upstream regulators, including NRF2, in NSCLC patients. MRP3 mRNA levels were analyzed by quantitative real-time polymerase chain reaction (qPCR) in 67 surgically-treated lung squamous cell cancer cases from the Nagoya City University Hospital and normalized by β-actin mRNA levels. Fourteen NRF2 mutation cases were included. The mean MRP3/β-actin mRNA levels did not differ according to age (≤65 vs. >65 years), Brinkman index (≤400 vs. >400) or the pathological stage of the lung squamous cell carcinoma. MRP3/β-actin mRNA levels were significantly higher in men (1.200±1.524) than in women (0.179±0.083; p=0.0036). In addition, the MRP3/β-actin mRNA levels were significantly higher in NRF2 mutants (2.598±2.373) than in wild-type NRF2 mutants (0.734±0.820; p=0.0002). These data support the hypothesis that the expression of MRP3 is induced by NRF2 activation in lung squamous cell cancers.