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MicroRNA-195 controls MICU1 expression and tumor growth in ovarian cancer
Geeta Rao1, Shailendra Kumar Dhar Dwivedi2, Yushan Zhang1
1Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Abstract:
MICU1 is a mitochondrial inner membrane protein that inhibits mitochondrial calcium entry; elevated MICU1 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 aberrant MICU1 expression. Here, we demonstrate that microRNA-195-5p (miR-195) directly targets the 3' UTR of the MICU1 mRNA and represses MICU1 expression. Additionally, miR-195 is under-expressed in ovarian cancer cell lines, and restoring miR-195 expression reestablishes native MICU1 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 controls MICU1 levels in ovarian cancer and could be exploited to normalize aberrant MICU1 expression, thus reversing both glycolysis and chemoresistance and consequently improving patient outcomes.
Insights
MicroRNA-195-5p (miR-195) targets MICU1, a protein linked to ovarian cancer progression. Restoring miR-195 levels in ovarian cancer reduces tumor growth and improves survival.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Mitochondrial calcium uptake regulator 1 (MICU1) is elevated in ovarian cancer, promoting glycolysis and chemoresistance.
- High MICU1 expression correlates with poor clinical outcomes in ovarian cancer patients.
- Current therapeutic strategies to normalize MICU1 expression are lacking.
Purpose of the Study:
- To investigate the regulatory role of microRNA-195-5p (miR-195) on MICU1 expression in ovarian cancer.
- To evaluate the therapeutic potential of restoring miR-195 levels in ovarian cancer models.
Main Methods:
- Bioinformatic analysis to predict miR-195 targeting of MICU1 mRNA.
- In vitro studies using ovarian cancer cell lines to assess miR-195 and MICU1 expression.
- In vivo studies using a human ovarian cancer xenograft model.
Main Results:
- miR-195 directly targets the 3' UTR of MICU1 mRNA, repressing its expression.
- miR-195 is significantly under-expressed in ovarian cancer cell lines.
- Restoring miR-195 normalized MICU1 levels and reversed associated phenotypes.
- Stable miR-195 expression in vivo reduced tumor growth, increased doubling time, and improved survival.
Conclusions:
- miR-195 acts as a tumor suppressor by regulating MICU1 in ovarian cancer.
- Restoring miR-195 expression offers a potential therapeutic strategy to normalize MICU1, reversing glycolysis and chemoresistance.
- Targeting miR-195 could improve patient outcomes in ovarian cancer.
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