Journal
EMBO REPORTS
Volume 21, Issue 10, Pages -Publisher
WILEY
DOI: 10.15252/embr.201948483
Keywords
chemoresistance; glycolysis; MICU1; CBARA1; miR-195; Ovarian cancer
Categories
Funding
- National Institutes of Health [2CA136494, CA213278]
- Peggy and Charles Stephenson Cancer Center at the University of Oklahoma Health Sciences Center
- Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [P20 GM103639]
- Peggy and Charles Stephenson Endowed Chair fund
- National Cancer Institute Cancer Center Support Grant [P30CA225520]
- National Institutes of Health: National Center for Advancing Translational Sciences (NCATS) [UL1TR000067]
- Clinical and Translational Science Awards (CTSA) grant
- Oklahoma Tobacco Settlement Endowment Trust
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MICU1 is a mitochondrial inner membrane protein that inhibits mitochondrial calcium entry; elevatedMICU1 expression is characteristic of many cancers, including ovarian cancer.MICU1 induces both glycolysis and chemoresistance and is associated with poor clinical outcomes. However, there are currently no available interventions to normalize aberrantMICU1 expression. Here, we demonstrate that microRNA-195-5p (miR-195) directly targets the 3 ' UTRof theMICU1mRNAand repressesMICU1 expression. Additionally, miR-195 is under-expressed in ovarian cancer cell lines, and restoring miR-195 expression reestablishes nativeMICU1 levels and the associated phenotypes. Stable expression of miR-195 in a human xenograft model of ovarian cancer significantly reduces tumor growth, increases tumor doubling times, and enhances overall survival. In conclusion, miR-195 controlsMICU1 levels in ovarian cancer and could be exploited to normalize aberrantMICU1 expression, thus reversing both glycolysis and chemoresistance and consequently improving patient outcomes.
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