MTHFD2 modulation impairs proliferation and migration of Malignant Pleural Mesothelioma: an in vitro study

Malignant pleural mesothelioma (MPM) is a highly aggressive tumour arising from the mesothelial cells covering the pleural space. MPM is commonly associated with asbestos exposure, its main risk factor. Currently, there are no effective treatments for MPM and the prognosis of patients is very poor. Moreover, modern targeted therapies that showed benefit in other human tumors failed in MPM, thus indicating an urgent need to identify new ways to diagnose MPM at earlier stages and increase knowledge about the mechanisms underlying carcinogenesis, progression and chemo/radio-resistance of this neoplasm. Folate metabolism is central to cell proliferation and a target of cancer therapy. Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), is an enzyme included in this pathway and it has been reported to be highly expressed in several malignancies. Although the enzymatic activity of the MTHFD2 is well understood, its role in cancer cell biology, in particular the relationship between its expression and MPM remains largely unknown. In this study, we first assessed that MTHFD2 was significantly overexpressed in MPM tissues and cell lines compared to non-malignant mesothelial tissues and cell lines. Then, we found that stable MTHFD2 knockdown by short hairpin RNAs (shRNAs) resulted in reduced MPM cell growth, clonogenic potential and migration ability in vitro. At the molecular level we observed that MTHFD2 knock-down reduced the expression of genes involved in cell cycle progression and in epithelial-to-mesenchymal transition process. On the contrary, overexpression of MTHFD2 in MPM cells resulted in enhancement of the proliferation and migration in vitro. These results indicated a possible role of MTHFD2 in MPM progression. Targeting MTHFD2 could represent a promising new therapeutic strategy.