Epigenetic down‐regulation of integrin α7 increases migratory potential and confers poor prognosis in malignant pleural mesothelioma

Abstract

Malignant pleural mesothelioma (MPM) is a devastating malignancy characterized by invasive growth and rapid recurrence. The identification and inhibition of molecular components leading to this migratory and invasive phenotype are thus essential. Accordingly, a genome-wide expression array analysis was performed on MPM cell lines and a set of 139 genes was identified as differentially expressed in cells with high versus low migratory activity. Reduced expression of the novel tumour suppressor integrin α7 (ITGA7) was found in highly motile cells. A significant negative correlation was observed between ITGA7 transcript levels and average displacement of cells. Forced overexpression of ITGA7 in MPM cells with low endogenous ITGA7 expression inhibited cell motility, providing direct evidence for the regulatory role of ITGA7 in MPM cell migration. MPM cells showed decreased ITGA7 expressions at both transcription and protein levels when compared to non-malignant mesothelial cells. The majority of MPM cell cultures displayed hypermethylation of the ITGA7 promoter when compared to mesothelial cultures. A statistically significant negative correlation between ITGA7 methylation and ITGA7 expression was also observed in MPM cells. While normal human pleura samples unambiguously expressed ITGA7, a varying level of expression was found in a panel of 200 human MPM samples. In multivariate analysis, ITGA7 expression was found to be an independent prognostic factor. Although there was no correlation between histological subtypes and ITGA7 expression, importantly, patients with high tumour cell ITGA7 expression had an increased median overall survival compared to the low- or no-expression groups (463 versus 278 days). In conclusion, our data suggest that ITGA7 is an epigenetically regulated tumour suppressor gene and a prognostic factor in human MPM.

Malignant pleural mesothelioma and mesothelial hyperplasia: A new molecular tool for the differential diagnosis

“…Most of the deregulated genes belong to signalling pathways that could drive the development of new targeted therapies, such as Gli2 , which belong to the Hedgehog pathway, whose inhibition has been reported to suppress cell growth dramatically both in vitro and in vivo, so targeting this pathway could constitute a new effective treatment approach [30]. Furthermore, we confirmed the downregulation of ITGA7 , which was reported to be epigenetically deregulated in MPM and suggested as therapeutic and prognostic marker [35], and the downregulation of NF2 , altered in almost half of MPM tumours with an important prognostic impact [34]. …”

The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma

“…The majority of MPM cell lines have considerable migratory activity, and integrin-mediated cell adhesion is reorganized during malignant progression [28, 30, 43]. In line with these data, in the current study, FAK inhibition led to a decrease in MPM migration in three out of four tested MPM cell lines.…”

“…2D video microscopy measurements were performed and analyzed as previously described [30]. Briefly, cells were seeded in 24-well plates (Corning Incorporated, Corning, NY) and cultured in DMEM medium supplemented with 10% FCS.…”

Acquired nintedanib resistance in FGFR1-driven small cell lung cancer: role of endothelin-A receptor-activated ABCB1 expression

“…Whole genome gene expression arrays were performed on 4×44K whole genome oligonucleotide-based gene expression arrays (Agilent, Santa Clara, USA) as previously described [49, 50]. For data analysis, signal intensity values were filtered according to sufficient (>20 raw expression values) and significant differences in expression by GeneSpring software (analyzed by unpaired t-test - Benjamini-Hochberg correction, p-value cut-off: 0.05).…”