MicroRNA-195 controls MICU1 expression and tumor growth in ovarian cancer

Geeta Rao; Shailendra Kumar Dhar Dwivedi; Yushan Zhang; Anindya Dey; Khader Shameer; Ramachandran Karthik; Subramanya Srikantan; Md Nazir Hossen; Jonathan D. Wren; Muniswamy Madesh; Joel T. Dudley; Resham Bhattacharya; Priyabrata Mukherjee

doi:10.15252/embr.201948483

MicroRNA-195 controls MICU1 expression and tumor growth in ovarian cancer

Geeta Rao, Shailendra Kumar Dhar Dwivedi, Yushan Zhang, Anindya Dey, Khader Shameer, Ramachandran Karthik, Subramanya Srikantan, Md Nazir Hossen, Jonathan D. Wren, Muniswamy Madesh, Joel T. Dudley, Resham Bhattacharya, Priyabrata Mukherjee

Division of Renal Diseases

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	e48483
Journal	EMBO Reports
Volume	21
Issue number	10
DOIs	https://doi.org/10.15252/embr.201948483
State	Published - Oct 5 2020

Keywords

MICU1/CBARA1
Ovarian cancer
chemoresistance
glycolysis
miR-195

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Genetics

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MicroRNA-195 controls MICU1 expression and tumor growth in ovarian cancer. / Rao, Geeta; Dwivedi, Shailendra Kumar Dhar; Zhang, Yushan; Dey, Anindya; Shameer, Khader; Karthik, Ramachandran; Srikantan, Subramanya; Hossen, Md Nazir; Wren, Jonathan D.; Madesh, Muniswamy; Dudley, Joel T.; Bhattacharya, Resham; Mukherjee, Priyabrata.

In: EMBO Reports, Vol. 21, No. 10, e48483, 05.10.2020.

Research output: Contribution to journal › Article › peer-review

Rao, Geeta ; Dwivedi, Shailendra Kumar Dhar ; Zhang, Yushan ; Dey, Anindya ; Shameer, Khader ; Karthik, Ramachandran ; Srikantan, Subramanya ; Hossen, Md Nazir ; Wren, Jonathan D. ; Madesh, Muniswamy ; Dudley, Joel T. ; Bhattacharya, Resham ; Mukherjee, Priyabrata. / MicroRNA-195 controls MICU1 expression and tumor growth in ovarian cancer. In: EMBO Reports. 2020 ; Vol. 21, No. 10.

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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.",

keywords = "MICU1/CBARA1, Ovarian cancer, chemoresistance, glycolysis, miR-195",

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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

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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.

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