MicroRNA-195 Controls MICU1 Expression and Tumor Growth in Ovarian Cancer

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2020 Aug 28

PMID 32851774

Citations 28

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

The roles of mitochondria in global and local intracellular calcium signalling.

Cartes-Saavedra B, Ghosh A, Hajnoczky G Nat Rev Mol Cell Biol. 2025; .

PMID: 39870977 DOI: 10.1038/s41580-024-00820-1.

Micro RNA profiles in colostrum exosomes obtained from primiparous or multiparous dairy cows.

Terre M, Aris A, Garcia-Fruitos E, Fabregas F, Bach A Front Vet Sci. 2024; 11:1463342.

PMID: 39545260 PMC: 11561390. DOI: 10.3389/fvets.2024.1463342.

Long Non-coding RNA FOXD2-AS1 Silencing Inhibits Malignant Behaviors of Ovarian Cancer Cells Via miR-324-3p/SOX4 Signaling Axis.

Xiang Y, Cheng X, Li H, Xu W, Zhang W Reprod Sci. 2024; .

PMID: 39455487 DOI: 10.1007/s43032-024-01719-0.

Mitochondrial calcium uniporter channel gatekeeping in cardiovascular disease.

Stevens T, Cohen H, Garbincius J, Elrod J Nat Cardiovasc Res. 2024; 3(5):500-514.

PMID: 39185387 PMC: 11343476. DOI: 10.1038/s44161-024-00463-7.

Multi-omic profiling of breast tumor microenvironment uncovers a role of mitochondrial calcium gatekeepers.

Tzeng Y, Chu P, Yong S, Hsu T, Tseng L, Hou M J Cancer. 2024; 15(12):3663-3674.

PMID: 38911376 PMC: 11190767. DOI: 10.7150/jca.95979.

References

Cimmino A, Calin G, Fabbri M, Iorio M, Ferracin M, Shimizu M . miR-15 and miR-16 induce apoptosis by targeting BCL2. Proc Natl Acad Sci U S A. 2005; 102(39):13944-9. PMC: 1236577. DOI: 10.1073/pnas.0506654102. View

Ward P, Thompson C . Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012; 21(3):297-308. PMC: 3311998. DOI: 10.1016/j.ccr.2012.02.014. View

Marchi S, Corricelli M, Branchini A, Vitto V, Missiroli S, Morciano G . Akt-mediated phosphorylation of MICU1 regulates mitochondrial Ca levels and tumor growth. EMBO J. 2018; 38(2). PMC: 6331721. DOI: 10.15252/embj.201899435. View

Cai H, Zhao H, Tang J, Wu H . Serum miR-195 is a diagnostic and prognostic marker for osteosarcoma. J Surg Res. 2014; 194(2):505-510. DOI: 10.1016/j.jss.2014.11.025. View

Mallilankaraman K, Doonan P, Cardenas C, Chandramoorthy H, Muller M, Miller R . MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. Cell. 2012; 151(3):630-44. PMC: 3486697. DOI: 10.1016/j.cell.2012.10.011. View

Lin Y, Wu J, Chen H, Mao Y, Liu Y, Mao Q . Cyclin-dependent kinase 4 is a novel target in micoRNA-195-mediated cell cycle arrest in bladder cancer cells. FEBS Lett. 2012; 586(4):442-7. DOI: 10.1016/j.febslet.2012.01.027. View

Heneghan H, Miller N, Kelly R, Newell J, Kerin M . Systemic miRNA-195 differentiates breast cancer from other malignancies and is a potential biomarker for detecting noninvasive and early stage disease. Oncologist. 2010; 15(7):673-82. PMC: 3228012. DOI: 10.1634/theoncologist.2010-0103. View

Hui W, Yuntao L, Lun L, WenSheng L, Chaofeng L, Haiyong H . MicroRNA-195 inhibits the proliferation of human glioma cells by directly targeting cyclin D1 and cyclin E1. PLoS One. 2013; 8(1):e54932. PMC: 3557299. DOI: 10.1371/journal.pone.0054932. View

Paupe V, Prudent J . New insights into the role of mitochondrial calcium homeostasis in cell migration. Biochem Biophys Res Commun. 2017; 500(1):75-86. PMC: 5930976. DOI: 10.1016/j.bbrc.2017.05.039. View

10.

Fei X, Qi M, Wu B, Song Y, Wang Y, Li T . MicroRNA-195-5p suppresses glucose uptake and proliferation of human bladder cancer T24 cells by regulating GLUT3 expression. FEBS Lett. 2012; 586(4):392-7. DOI: 10.1016/j.febslet.2012.01.006. View

11.

Wang H, Ren S, Xu Y, Miao W, Huang X, Qu Z . MicroRNA-195 reverses the resistance to temozolomide through targeting cyclin E1 in glioma cells. Anticancer Drugs. 2018; 30(1):81-88. PMC: 6287895. DOI: 10.1097/CAD.0000000000000700. View

12.

Monteith G, Prevarskaya N, Roberts-Thomson S . The calcium-cancer signalling nexus. Nat Rev Cancer. 2017; 17(6):367-380. DOI: 10.1038/nrc.2017.18. View

13.

Kim Y, Kim E, Jeon D, Liu J, Kim H, Choi J . Differential microRNA expression signatures and cell type-specific association with Taxol resistance in ovarian cancer cells. Drug Des Devel Ther. 2014; 8:293-314. PMC: 3938445. DOI: 10.2147/DDDT.S51969. View

14.

Ye R, Wei B, Li S, Liu W, Liu J, Qiu L . Expression of miR-195 is associated with chemotherapy sensitivity of cisplatin and clinical prognosis in gastric cancer. Oncotarget. 2017; 8(57):97260-97272. PMC: 5722560. DOI: 10.18632/oncotarget.21919. View

15.

Shanmughapriya S, Tomar D, Dong Z, Slovik K, Nemani N, Natarajaseenivasan K . FOXD1-dependent MICU1 expression regulates mitochondrial activity and cell differentiation. Nat Commun. 2018; 9(1):3449. PMC: 6115453. DOI: 10.1038/s41467-018-05856-4. View

16.

Chen H, Untiveros G, McKee L, Perez J, Li J, Antin P . Micro-RNA-195 and -451 regulate the LKB1/AMPK signaling axis by targeting MO25. PLoS One. 2012; 7(7):e41574. PMC: 3402395. DOI: 10.1371/journal.pone.0041574. View

17.

Deng H, Guo Y, Song H, Xiao B, Sun W, Liu Z . MicroRNA-195 and microRNA-378 mediate tumor growth suppression by epigenetical regulation in gastric cancer. Gene. 2013; 518(2):351-9. DOI: 10.1016/j.gene.2012.12.103. View

18.

Gomez de Cedron M, Ramirez de Molina A . Microtargeting cancer metabolism: opening new therapeutic windows based on lipid metabolism. J Lipid Res. 2015; 57(2):193-206. PMC: 4727429. DOI: 10.1194/jlr.R061812. View

19.

Brenner B, Hoshen M, Purim O, David M, Ashkenazi K, Marshak G . MicroRNAs as a potential prognostic factor in gastric cancer. World J Gastroenterol. 2011; 17(35):3976-85. PMC: 3199555. DOI: 10.3748/wjg.v17.i35.3976. View

20.

Hsu P, Sabatini D . Cancer cell metabolism: Warburg and beyond. Cell. 2008; 134(5):703-7. DOI: 10.1016/j.cell.2008.08.021. View