| BACKGROUND:Lung cancer represents the leading cause of cancer-related death every yearworldwide. Non-small cell lung cancer (NSCLC) represents75–85%of all lungcancer cases. The median survival time for patients with untreated metastaticNSCLC is only4–5months. Up to now, the evaluation of NSCLC prognosis largelydepends on TNM staging and clinical experience of oncologists. Hereditary factorsin genesis and progression of NSCLC have been attached great importance duringthese years. Single nucleotide polymorphism (SNP) could distinctly reflectindividual’s genetic background and easily be detected, providing a broad prospectfor risk and prognosis appraisal of NSCLC. Monocarboxylate transporters (MCTs) are among the most important plasmamembrane transporters that export the accumulating lactic acid produced by tumorcells. It has been suggested that MCTs were highly expressed in tumors. Thetranslocation to plasma membrane of MCTs1-4requires a chaperone, CD147, alsoknown as EMMPRIN, the overexpression of which have been demonstratedassociated with malignancy of several kinds of tumors. Consequently, the aim of ourstudy is to investigate functional SNPs in MCTs and CD147and their relation withprognosis of patients with NSCLC, and to demonstrate the component ofMCT-CD147complex and its role in clinical outcome of NSCLC.METHODS AND RESULTS:Firstly,13functional SNPs in SLC16A1, SLC16A7, SLC16A3and basigin hasbeen selected and genotyping was performed using MassARRAY platform basedon MALDI-TOF mass spectrometry technology. The clinical findings,epidemiological and follow-up data were analyzed statistically to investigate therelation between SNPs and clinical outcome of patients with NSCLC. We found thatpatients carrying homozygous variant and heterozygous variant genotype ofrs4919859in basigin had a significantly lower risk of death than those carrying wildhomozygous (HR=0.70，P=0.043). In squamous cell lung cancer patients,compared with wild type genotype, those carrying mutant on rs1049434in SLC16A1had lower risk of death (HR=0.75, P=0.048). Secondly, expressions of MCT1,MCT4and CD147in tumor tissues and their corresponding normal tissues in334NSCLC were detected with immunohistochemistry. The prognostic significance ofMCT1and CD147expression was analyzed by using multivariate Cox proportionalhazards analysis. The results showed that both MCT1and CD147were highlyexpressed in the plasma membrane of tumor tissue, and there was a significantlycorrelation between their expression levels (P <0.001), while MCT4was located incytoplasm. Meanwhile, we found a negative correlation between the expression levels of MCT1and CD147and survival rate of NSCLC patients.Immunofluorescence staining suggested that MCT1and CD147could be combinedinto a complex in lung cancer cells. Third, MTT assay and plate clone formationassay demonstrated that three lung cancer cell lines A549, SPC-A-1and PLA-801-Cwere significantly inhibited in the proliferation by MCT1and CD147siRNAs in asynergetic manner, and was accelerated in the proliferation by MCT1-CD147overexpression.CONCLUSIONS:Several SNPs (rs4919859, rs1049434) were remarkably associated withprognosis of NSCLC patients. MCT1-CD147complex significantly contributes topoor prognosis of NSCLC patients partially through promoting cell proliferation.The results of our study can be evidences for further study of MCTs-CD147complexin NSCLC genesis and development, and MCT1and CD147may be provided asprognostic markers for NSCLC patients. |
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