TY - JOUR
T1 - MicroRNA-195 controls MICU1 expression and tumor growth in ovarian cancer
AU - Rao, Geeta
AU - Dwivedi, Shailendra Kumar Dhar
AU - Zhang, Yushan
AU - Dey, Anindya
AU - Shameer, Khader
AU - Karthik, Ramachandran
AU - Srikantan, Subramanya
AU - Hossen, Md Nazir
AU - Wren, Jonathan D.
AU - Madesh, Muniswamy
AU - Dudley, Joel T.
AU - Bhattacharya, Resham
AU - Mukherjee, Priyabrata
N1 - Funding Information:
This work was supported by National Institutes of Health Grants 2CA136494, CA213278. We thank the Peggy and Charles Stephenson Cancer Center at the University of Oklahoma Health Sciences Center for a seed grant and also acknowledge an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (P20 GM103639) for the use of Histology and Immunohistochemistry Core, which provided immunohistochemistry and image analysis service. This research was also supported by Peggy and Charles Stephenson Endowed Chair fund to PM. We thank the Laboratory for Molecular Biology and Cytometry Research at OUHSC for the use of the Core Facility which provided DNA sequencing and flow cytometry service; use of the core facility was supported in part by the National Cancer Institute Cancer Center Support Grant P30CA225520 awarded to the University of Oklahoma Stephenson Cancer Center. KS and JTD acknowledge support from the National Institutes of Health: National Center for Advancing Translational Sciences (NCATS, grant number UL1TR000067); and Clinical and Translational Science Awards (CTSA) grant. Research reported in this publication was supported in part by the Oklahoma Tobacco Settlement Endowment Trust awarded to the University of Oklahoma//Stephenson Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Oklahoma Tobacco Settlement Endowment Trust.
Funding Information:
This work was supported by National Institutes of Health Grants 2CA136494, CA213278. We thank the Peggy and Charles Stephenson Cancer Center at the University of Oklahoma Health Sciences Center for a seed grant and also acknowledge an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health (P20 GM103639) for the use of Histology and Immunohistochemistry Core, which provided immunohistochemistry and image analysis service. This research was also supported by Peggy and Charles Stephenson Endowed Chair fund to PM. We thank the Laboratory for Molecular Biology and Cytometry Research at OUHSC for the use of the Core Facility which provided DNA sequencing and flow cytometry service; use of the core facility was supported in part by the National Cancer Institute Cancer Center Support Grant P30CA225520 awarded to the University of Oklahoma Stephenson Cancer Center. KS and JTD acknowledge support from the National Institutes of Health: National Center for Advancing Translational Sciences (NCATS, grant number UL1TR000067); and Clinical and Translational Science Awards (CTSA) grant. Research reported in this publication was supported in part by the Oklahoma Tobacco Settlement Endowment Trust awarded to the University of Oklahoma//Stephenson Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Oklahoma Tobacco Settlement Endowment Trust.
Publisher Copyright:
© 2020 The Authors
PY - 2020/10/5
Y1 - 2020/10/5
N2 - 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.
AB - 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.
KW - MICU1/CBARA1
KW - Ovarian cancer
KW - chemoresistance
KW - glycolysis
KW - miR-195
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UR - http://www.scopus.com/inward/citedby.url?scp=85089863689&partnerID=8YFLogxK
U2 - 10.15252/embr.201948483
DO - 10.15252/embr.201948483
M3 - Article
C2 - 32851774
AN - SCOPUS:85089863689
VL - 21
JO - EMBO Reports
JF - EMBO Reports
SN - 1469-221X
IS - 10
M1 - e48483
ER -