Pro-tumorigenic effects of miR-31 loss in mesothelioma.
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.
Ivanov
Sergey V
SV
Department of Otolaryngology, Vanderbilt School of Medicine, Nashville, Tennessee 37232, USA. sergey.v.ivanov@vanderbilt.edu
Goparaju
Chandra M V
CM
Lopez
Peter
P
Zavadil
Jiri
J
Toren-Haritan
Ginat
G
Rosenwald
Shai
S
Hoshen
Moshe
M
Chajut
Ayelet
A
Cohen
Dalia
D
Pass
Harvey I
HI
D001483:Base Sequence; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D017353:Gene Deletion; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D008654:Mesothelioma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D015203:Reproducibility of Results; D016615:Telomere / Q000235:genetics
D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D010749:Phosphoprotein Phosphatases; C106079:protein phosphatase 6
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