A research team reported that microRNAs (miRNAs) are differentially regulated between malignant pleural mesotheliomas that are positive for MDM2 compared to ones that are MDM2-negative. The study, published in the journal Oncotarget, is titled “microRNAs are differentially regulated between MDM2-positive and negative malignant pleural mesothelioma.”
Malignant mesothelioma is a rare, aggressive tumor that forms on the thin protective tissues that cover the lungs and abdomen, usually in people who have been directly exposed to high levels of asbestos. Asbestos is a natural but toxic mineral that was frequently used in many industries. Once inside the body, asbestos microscopic fibers are unable to be processed or expelled, leading to harmful inflammation and scarring of the mesothelium, a thin membrane that forms the lining of several body cavities.
The current treatment of choice for malignant pleural mesothelioma (the pleura includes the two thin layers of tissue that protect and cushion the lungs) is the combination of cisplatin and pemetrexed; however, a positive response for this therapeutic combination is only detected in 40 percent of patients, with a progression-free survival of 5.7 months.
The TP53 gene, a key tumor suppressor, is one of the most mutated genes in tumors; however, TP53 mutations are extremely rare in malignant pleural mesothelioma. Two key regulators of TP53 are MDM2 and P14/ARF (CDKN2A). In a previous study, the research team showed that patients with MDM2-positive malignant pleural mesothelioma exhibited a significant decrease in overall survival and progression-free survival when compared to MDM2-negative malignant pleural mesothelioma patients, potentially by decreasing TP53 activity/stability.
Now, researchers investigated the role of miRNAs as key regulators of gene activity on this mechanism. To this end, the team studied 24 formalin-fixed paraffin-embedded (FFPE) tumor samples for miRNA expression. Specifically, researchers investigated the expression of 800 miRNAs using the nCounter technique (NanoString).
The team found that 136 miRNAs were significantly differentially expressed in MDM2-positive and -negative tumors. In MDM2-expressing mesotheliomas, researchers detected down-regulated expression of 17 miRNAs regulating TP53, 18 miRNAs regulating MDM2, and 11 miRNAs directly regulating CDKN2A.
In conclusion, the results suggested that MDM2 expression impacts miRNAs expression levels in malignant pleural mesothelioma, with MDM2-expressing mesotheliomas exhibiting a specific down-regulation of miRNAs involved in TP53-signaling. These findings contribute to a better understanding of malignant pleural mesothelioma tumor biology, which is important for the development of novel therapeutic strategies.