Global Gene Expression Profiling Of Human Pleural Mesotheliomas: Identification of Matrix Metalloproteinase 14 (MMP-14) as Potential Tumour Target

Abstract

BackgroundThe goal of our study was to molecularly dissect mesothelioma tumour pathways by mean of microarray technologies in order to identify new tumour biomarkers that could be used as early diagnostic markers and possibly as specific molecular therapeutic targets.MethodologyWe performed Affymetrix HGU133A plus 2.0 microarray analysis, containing probes for about 39,000 human transcripts, comparing 9 human pleural mesotheliomas with 4 normal pleural specimens. Stringent statistical feature selection detected a set of differentially expressed genes that have been further evaluated to identify potential biomarkers to be used in early diagnostics. Selected genes were confirmed by RT-PCR. As reported by other mesothelioma profiling studies, most of genes are involved in G2/M transition. Our list contains several genes previously described as prognostic classifier. Furthermore, we found novel genes, never associated before to mesotheliom that could be involved in tumour progression. Notable is the identification of MMP-14, a member of matrix metalloproteinase family. In a cohort of 70 mesothelioma patients, we found by a multivariate Cox regression analysis, that the only parameter influencing overall survival was expression of MMP14. The calculated relative risk of death in MM patients with low MMP14 expression was significantly lower than patients with high MMp14 expression (P = 0.002).ConclusionsBased on the results provided, this molecule could be viewed as a new and effective therapeutic target to test for the cure of mesothelioma.

Overexpressed genes in malignant pleural mesothelioma: implications in clinical management

“…Survivin overexpression in MPM has been confirmed in different independent cohort of mesothelioma patients (7)(8)(9)11,47,53). Survivin is a multifunctional protein that plays critical roles in several crucial cell processes: several studies described its anti-apoptotic function (49,98,99), a role in microtubule dynamics, in cell proliferation, in cell migration and control bipolar spindle formation (100).…”

“…In recent years, a number of aberrantly expressed genes were suggested, but with a poor consistency among studies. In 2012, in order to find a consensus among nine independent transcriptome studies carried out between 2000 and 2010 (1)(2)(3)(4)(5)(6)(7)(8)(9), it has been performed a review and a data mining (10) and it has been identified a group of 96 overexpressed genes in MPM compared to non-malignant tissues and cell lines. This group of genes have been further evaluated in 2015 through a gene expression study performed on an independent cohort of mesothelioma tissues compared to non-malignant tissues: the overexpression of 51 genes ( Table 1) have been confirmed (11).…”

c-Myc modulation: a key role in melanoma drug response

“…36 These molecules are able to efflux cytotoxic drugs, affecting the resistance of cancer cells to apoptosis in the context of treatment. However, several reports provide evidence that ABC transporters might also promote cell survival independently of cytotoxic drug efflux, suggesting together with our findings that further experiments are needed to address this issue in melanoma.…”

“…The entire procedure for qRT-PCR analysis-primer design, reactions, amplicon specificity and determination of gene target expression levels-was performed as previously described. 36 Statistical analysis of the c-Myc expression levels were performed using GraphPad Prism 5.0 Ò statistical software (GraphPad Software Inc., La Jolla, CA). Paired t test was used for comparison of 2 paired groups.…”

Bisphenol A effects on gene expression in adipocytes from children: association with metabolic disorders

“…Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as an internal control. The entire procedure for quantitative RT-PCR (qRT-PCR) analysis -including primer design, reactions, amplicon specificity, and determination of gene target expression levels -was performed as previously described (Crispi et al 2009). …”