Abstract
Malignant pleural mesothelioma (MPM) is associated with asbestos exposure. Asbestos can induce chronic inflammation which in turn can lead to silencing of tumour suppressor genes. Wnt signaling pathway can be affected by chronic inflammation and is aberrantly activated in many cancers including colon and MPM. SFRP genes are antagonists of Wnt pathway, and SFRPs are potential tumour suppressors in colon, gastric, breast, ovarian, and lung cancers and mesothelioma. This study investigated the expression and DNA methylation of SFRP genes in MPM cells lines with and without demethylation treatment. Sixty-six patient FFPE samples were analysed and have showed methylation of SFRP2 (56%) and SFRP5 (70%) in MPM. SFRP2 and SFRP5 tumour-suppressive activity in eleven MPM lines was confirmed, and long-term asbestos exposure led to reduced expression of the SFRP1 and SFRP2 genes in the mesothelium (MeT-5A) via epigenetic alterations. Finally, DNA methylation of SFRPs is detectable in MPM patient plasma samples, with methylated SFRP2 and SFRP5 showing a tendency towards greater abundance in patients. These data suggested that SFRP genes have tumour-suppresive activity in MPM and that methylated DNA from SFRP gene promoters has the potential to serve as a biomarker for MPM patient plasma.
Highlights
Malignant pleural mesothelioma (MPM) is an aggressive and invariably fatal malignancy associated with asbestos exposure
Results indicated that expression of at least two SFRP genes was reactivated in every MPM cell line (Figure 1(a) right), which is a strong indication of DNA hypermethylation
DNA methylation, cell growth, and colony formation results indicate that SFRP2 and SFRP5 both act as tumour suppressors of MPM and are silenced by DNA hypermethylation
Summary
Malignant pleural mesothelioma (MPM) is an aggressive and invariably fatal malignancy associated with asbestos exposure. The exact mechanism by which asbestos exposure leads to MPM carcinogenesis is not yet understood. A much better understanding of the mechanism by which asbestos exposure leads to MPM is needed, so that the molecular players in the mechanism can be used as new molecular targets for diagnosis and treatment of MPM [1, 2]. It has been shown that asbestos exposure does not directly transform primary human mesothelial cells in tissue culture and instead induces inflammation [6,7,8,9]. Chronic inflammation caused by exposure of serosal surfaces to asbestos fibres is likely to represent a central factor in the carcinogenesis of MPM [10, 11]
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