Mesothelioma is a deadly cancer mainly caused by exposure to asbestos fibers. Unfortunately, mesothelioma is generally diagnosed at an already advanced stage and none of the therapeutic strategies tried so far is able to eradicate the disease. So new biomarkers that could help to identify the disease at an earlier stage are urgently needed.
Also, a more thorough understanding of the molecular mechanisms underlying mesothelioma malignant features could guide the application of more successful targeted approaches or combination strategies.
Researchers from the team of Antonio Giordano, Director and Founder of the Sbarro Health Research Organization at Philadelphia, PA (www.shro.org) and Professor of Pathology at the University of Siena, Italy, set out to address these urgent needs.
The authors analyzed the expression of tiny RNA molecules –microRNAs –which are key regulators of gene expression programmes. Through a microarray analysis, they identified a signature of 48 microRNAs that are differentially expressed between the normal mesothelial tissue and the mesothelioma specimens, provided by Luca Luzzi and Cristiana Bellan from the University of Siena.
A subset of these microRNAs was further studied through an alternate method (qRT-PCR) and their differential expression was also validated in an extended case series. Within this list of new potential candidate biomarkers, able to distinguish cancer from normal tissue, the authors also identified microRNAs previously associated to mesothelioma, such as miR-145 which is implicated in mesothelioma development and resistance to chemotherapy, further supporting their role as a classifiers of benign versus malignant mesothelial tissues.
Among the candidates, the authors zoomed in on miR-320a because its family members showed the same trend of deregulation in mesothelioma even if located on different chromosomes, which suggests that a common upstream mechanism leads to their dysregulation.
The authors showed that miR-320a targets PDL1, a well known player of the antitumoral immune response and target of recently developed immunotherapy strategies. Interestingly, the authors previously found that miR-320a is in turn a target of the p53 tumor suppressor, being directly upregulated upon stress cues. P53, which is often inactive in mesothelioma because of alterations in its pathway, is able to downregulate PDL1 expression through the action of other microRNAs.
"Our findings suggest that a defective response to stress owed to p53 inactivation might contribute, through a consequent microRNA-defective regulation, to develop immunosuppressive features thereby favoring mesothelioma escape from organismal immunosurveillance" says Caterina Costa of the National Cancer Institute of Naples, Pascale Foundation, first author of the study published September 14 on Cell Death and Disease, a renowned scientific journal of Springer Nature.
Once again, our studies of this deadly cancer point to a crucial role of tumor suppressor genes, which are poorly actionable."
Francesca Pentimalli corresponding author of the study from the Pascale Institute and Adjunct Professor at the Sbarro Institute, Temple University of Philadelphia
"We hope that the identification of these microRNAs and their mechanisms of action will lead to the identification of biomarkers that could help us to diagnose mesothelioma at an earlier stage and to identify new urgently needed therapeutic strategies" concludes Luciano Mutti President of the Italian Group on the Study and Therapy of Mesothelioma and Adjunct Professor at the Sbarro Institute.
Costa, C., et al. (2020) P53-regulated miR-320a targets PDL1 and is downregulated in malignant mesothelioma. Cell Death & Disease. doi.org/10.1038/s41419-020-02940-w.