The human genome encodes several hundred
microRNA (
miRNA) genes that produce small (21-23n) single strand regulatory
RNA molecules. Although abnormal expression of
miRNAs has been linked to
cancer progression, the mechanisms of this dysregulation are poorly understood.
Malignant mesothelioma (MM) of pleura is an aggressive and highly lethal
cancer resistant to conventional
therapies. We and others previously linked loss of the 9p21.3 chromosome in MM with short time to
tumor recurrence. In this study, we report that MM cell lines derived from patients with more aggressive disease fail to express miR-31, a
microRNA recently linked with suppression of
breast cancer metastases. We further demonstrate that this loss is due to homozygous deletion of the miR-31-encoding gene that resides in 9p21.3. Functional assessment of miR-31 activity revealed its ability to inhibit proliferation, migration, invasion, and clonogenicity of MM cells. Re-introduction of miR-31 suppressed the cell cycle and inhibited expression of multiple factors involved in cooperative maintenance of DNA replication and cell cycle progression, including pro-survival
phosphatase PPP6C, which was previously associated with
chemotherapy and
radiation therapy resistance, and maintenance of
chromosomal stability. PPP6C, whose
mRNA is distinguished with three miR-31-binding sites in its 3'-untranslated region, was consistently down-regulated by miR-31 introduction and up-regulated in clinical MM specimens as compared with matched normal tissues. Taken together, our data suggest that
tumor-suppressive propensity of miR-31 can be used for development of new
therapies against
mesothelioma and other
cancers that show loss of the 9p21.3 chromosome.