Small Regulatory Molecules Acting Big in Cancer: Potential Role of Mito-miRs in Cancer

Author(s): Praveen Sharma, Bharat, Nilambra Dogra, Sandeep Singh*

Journal Name: Current Molecular Medicine

Volume 19 , Issue 9 , 2019

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MicroRNAs [miRNAs] are short, non-coding, single stranded RNA molecules regulating gene expression of their targets at the posttranscriptional level by either degrading mRNA or by inhibiting translation. Previously, miRNAs have been reported to be present inside the mitochondria and these miRNAs have been termed as mito-miRs. Origin of these mito-miRs may either be from mitochondrial genome or import from nucleus. The second class of mito-miRs makes it important to unravel the involvement of miRNAs in crosstalk between nucleus and mitochondria. Since miRNAs are involved in various physiological processes, their deregulation is often associated with disease progression, including cancer. The current review focuses on the involvement of miRNAs in different mitochondrial mediated processes. It also highlights the importance of exploring the interaction of miRNAs with mitochondrial genome, which may lead to the development of small regulatory RNA based therapeutic options.

Keywords: miRNAs, cancer, mitochondria, metabolism, nanoparticles, chemoresistance.

Lane N, Martin W. The energetics of genome complexity. Nature 2010; 467(7318): 929-34.
[] [PMID: 20962839]
Friedman JR, Nunnari J. Mitochondrial form and function. Nature 2014; 505(7483): 335-43.
[] [PMID: 24429632]
Pagliarini DJ, Calvo SE, Chang B, et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 2008; 134(1): 112-23.
[] [PMID: 18614015]
Antico Arciuch VG, Elguero ME, Poderoso JJ, Carreras MC. Mitochondrial regulation of cell cycle and proliferation. Antioxidants , redox signaling 2012; 16(10): 1150-80.
[] [PMID: 21967640]
Chandel NS. Mitochondrial regulation of oxygen sensing in membrane receptors, channels and transporters in pulmonary circulation. Humana Press 2010; pp. 339-54.
Finkel T. Signal transduction by reactive oxygen species. J Cell Biol 2011; 194(1): 7-15.
[] [PMID: 21746850]
Gunter TE, Yule DI, Gunter KK, Eliseev RA, Salter JD. Calcium and mitochondria. FEBS Lett 2004; 567(1): 96-102.
[] [PMID: 15165900]
Taanman JW. The mitochondrial genome: structure, transcription, translation and replication. Biochim Biophys Acta 1999; 1410(2): 103-23.
[] [PMID: 10076021]
Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 1988; 242(4884): 1427-30.
[] [PMID: 3201231]
Morris AAM, Leonard JV, Brown GK, et al. Deficiency of respiratory chain complex I is a common cause of Leigh disease. Ann Neurol 1996; 40(1): 25-30.
[] [PMID: 8687187]
Euro L, Farnum GA, Palin E, Suomalainen A, Kaguni LS. Clustering of Alpers disease mutations and catalytic defects in biochemical variants reveal new features of molecular mechanism of the human mitochondrial replicase, Pol γ. Nucleic Acids Res 2011; 39(21): 9072-84.
[] [PMID: 21824913]
Hakonen AH, Heiskanen S, Juvonen V, et al. Mitochondrial DNA polymerase W748S mutation: a common cause of autosomal recessive ataxia with ancient European origin. Am J Hum Genet 2005; 77(3): 430-41.
[] [PMID: 16080118]
Naviaux RK, Nyhan WL, Barshop BA, et al. Mitochondrial DNA polymerase γ deficiency and mtDNA depletion in a child with Alpers’ syndrome. Ann Neurol 1999; 45(1): 54-8.
[<54:AID-ART10>3.0.CO;2-B] [PMID: 9894877]
Götz A, Tyynismaa H, Euro L, et al. Exome sequencing identifies mitochondrial alanyl-tRNA synthetase mutations in infantile mitochondrial cardiomyopathy. Am J Hum Genet 2011; 88(5): 635-42.
[] [PMID: 21549344]
Pierce SB, Chisholm KM, Lynch ED, et al. Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. Proc Natl Acad Sci USA 2011; 108(16): 6543-8.
[] [PMID: 21464306]
Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 1988; 331(6158): 717-9.
[] [PMID: 2830540]
Coller HA, Khrapko K, Bodyak ND, Nekhaeva E, Herrero-Jimenez P, Thilly WG. High frequency of homoplasmic mitochondrial DNA mutations in human tumors can be explained without selection. Nat Genet 2001; 28(2): 147-50.
[] [PMID: 11381261]
Polyak K, Li Y, Zhu H, et al. Somatic mutations of the mitochondrial genome in human colorectal tumours. Nat Genet 1998; 20(3): 291-3.
[] [PMID: 9806551]
Santidrian AF, Matsuno-Yagi A, Ritland M, et al. Mitochondrial complex I activity and NAD+/NADH balance regulate breast cancer progression. J Clin Invest 2013; 123(3): 1068-81.
[] [PMID: 23426180]
Chatterjee A, Mambo E, Sidransky D. Mitochondrial DNA mutations in human cancer. Oncogene 2006; 25(34): 4663-74.
[] [PMID: 16892080]
Bandiera S, Matégot R, Girard M, Demongeot J, Henrion-Caude A. MitomiRs delineating the intracellular localization of microRNAs at mitochondria. Free Radic Biol Med 2013; 64: 12-9.
[] [PMID: 23792138]
Bandiera S, Rüberg S, Girard M, et al. Nuclear outsourcing of RNA interference components to human mitochondria. PLoS One 2011; 6(6)e20746
[] [PMID: 21695135]
Latronico MV, Condorelli G. The might of microRNA in mitochondria. Circ Res 2012; 110(12): 1540-2.
[] [PMID: 22679134]
Kren BT, Wong PY, Sarver A, Zhang X, Zeng Y, Steer CJ. MicroRNAs identified in highly purified liver-derived mitochondria may play a role in apoptosis. RNA Biol 2009; 6(1): 65-72.
[] [PMID: 19106625]
Bian Z, Li LM, Tang R, et al. Identification of mouse liver mitochondria-associated miRNAs and their potential biological functions. Cell Res 2010; 20(9): 1076-8.
[] [PMID: 20733615]
McCarthy JJ, Esser KA. MicroRNA-1 and microRNA-133a expression are decreased during skeletal muscle hypertrophy. J Appl Physiol 2007; 102(1): 306-13.
[] [PMID: 17008435]
Das S, Bedja D, Campbell N, et al. miR-181c regulates the mitochondrial genome, bioenergetics, and propensity for heart failure in vivo. PLoS One 2014; 9(5)e96820
[] [PMID: 24810628]
Barrey E, Saint-Auret G, Bonnamy B, et al. Pre-microRNA and mature microRNA in human mitochondria. PLoS One 2011; 6(5)e20220
[] [PMID: 21637849]
Thammaiah CK, Jayaram S. Role of let-7 family microRNA in breast cancer. Noncoding RNA Res 2016; 1(1): 77-82.
[] [PMID: 30159414]
Barrey E, Saint-Auret G, Bonnamy B, Damas D, Boyer O, Gidrol X. Pre-microRNA and mature microRNA in human mitochondria. PLoS One 2011; 6(5)e20220
[] [PMID: 21637849]
Boominathan L. The tumor suppressors p53, p63, and p73 are regulators of microRNA processing complex. PLoS One 2010; 5(5)e10615
[] [PMID: 20485546]
Sripada L, Tomar D, Prajapati P, Singh R, Singh AK, Singh R. Systematic analysis of small RNAs associated with human mitochondria by deep sequencing: detailed analysis of mitochondrial associated miRNA. PLoS One 2012; 7(9)e44873
[] [PMID: 22984580]
Tétreault N, De Guire V. miRNAs: their discovery, biogenesis and mechanism of action. Clin Biochem 2013; 46(10-11): 842-5.
[] [PMID: 23454500]
Soleimani A, Khazaei M, Ferns GA, Ryzhikov M, Avan A, Hassanian SM. Role of TGF-β signaling regulatory microRNAs in the pathogenesis of colorectal cancer. J Cell Physiol 2019. Epub ahead of print
[] [PMID: 30684274]
Shepherd DL, Hathaway QA, Pinti MV, et al. Exploring the mitochondrial microRNA import pathway through Polynucleotide Phosphorylase (PNPase). J Mol Cell Cardiol 2017; 110: 15-25.
[] [PMID: 28709769]
Golzarroshan B, Lin CL, Li CL, et al. Crystal structure of dimeric human PNPase reveals why disease-linked mutants suffer from low RNA import and degradation activities. Nucleic Acids Res 2018; 46(16): 8630-40.
[] [PMID: 30020492]
Warburg O. On the origin of cancer cells. Science 1956; 123(3191): 309-14.
[] [PMID: 13298683]
Weinhouse S. On respiratory impairment in cancer cells. Science 1956; 124(3215): 267-9.
[] [PMID: 13351638]
Vyas S, Zaganjor E, Haigis MC. Mitochondria and Cancer Cell 2016; 166(3): 555-66.
Fogg VC, Lanning NJ, Mackeigan JP. Mitochondria in cancer: at the crossroads of life and death. Chin J Cancer 2011; 30(8): 526-39.
[] [PMID: 21801601]
Krell J, Frampton AE, Stebbing J. MicroRNAs in the cancer clinic. Front Biosci (Elite Ed) 2013; 5: 204-13.
[] [PMID: 23276982]
Radojicic J, Zaravinos A, Vrekoussis T, et al. MicroRNA expression analysis in triple-negative (ER, PR and Her2/neu) breast cancer. Cell Cycle 2011; 10(3): 507-17.
[] [PMID: 21270527]
Yao J, Zhou E, Wang Y, Xu F, Zhang D, Zhong D. microRNA-200a inhibits cell proliferation by targeting mitochondrial transcription factor A in breast cancer. DNA Cell Biol 2014; 33(5): 291-300.
[] [PMID: 24684598]
Han B, Izumi H, Yasuniwa Y, et al. Human mitochondrial transcription factor A functions in both nuclei and mitochondria and regulates cancer cell growth. Biochem Biophys Res Commun 2011; 408(1): 45-51.
[] [PMID: 21453679]
Tomasetti M, Monaco F, Manzella N, et al. MicroRNA-126 induces autophagy by altering cell metabolism in malignant mesothelioma. Oncotarget 2016; 7(24): 36338-52.
[] [PMID: 27119351]
Yang X, Wu H, Ling T. Suppressive effect of microRNA-126 on oral squamous cell carcinoma in vitro. Mol Med Rep 2014; 10(1): 125-30.
[] [PMID: 24789258]
Berman SB, Pineda FJ, Hardwick JM. Mitochondrial fission and fusion dynamics: the long and short of it. Cell Death Differ 2008; 15(7): 1147-52.
[] [PMID: 18437161]
Simula L, Nazio F, Campello S. The mitochondrial dynamics in cancer and immune-surveillance. Semin Cancer Biol 2017; 47: 29-42. [Academic Press]
[] [PMID: 28655520]
Han Y, Cho U, Kim S, et al. Tumour microenvironment on mitochondrial dynamics and chemoresistance in cancer. Free Radic Res 2018; 52(11-12): 1271-87.
[] [PMID: 29607684]
Tan Z, Luo X, Xiao L, et al. The role of PGC1α in cancer metabolism and its therapeutic implications. Mol Cancer Ther 2016; 15(5): 774-82.
[] [PMID: 27197257]
Li F, Wang Y, Zeller KI, et al. Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol Cell Biol 2005; 25(14): 6225-34.
[] [PMID: 15988031]
Mohamed JS, Hajira A, Pardo PS, Boriek AM. MicroRNA-149 inhibits PARP-2 and promotes mitochondrial biogenesis via SIRT-1/PGC-1α network in skeletal muscle. Diabetes 2014; 63(5): 1546-59.
[] [PMID: 24757201]
Ji J, Qin Y, Ren J, et al. Mitochondria-related miR-141-3p contributes to mitochondrial dysfunction in HFD-induced obesity by inhibiting PTEN. Sci Rep 2015; 5: 16262.
[] [PMID: 26548909]
Sampson VB, Rong NH, Han J, et al. MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Res 2007; 67(20): 9762-70.
[] [PMID: 17942906]
Takwi AA, Li Y, Becker Buscaglia LE, et al. A statin-regulated microRNA represses human c-Myc expression and function. EMBO Mol Med 2012; 4(9): 896-909.
[] [PMID: 22887866]
Takaoka Y, Shimizu Y, Hasegawa H, et al. Forced expression of miR-143 represses ERK5/c-Myc and p68/p72 signaling in concert with miR-145 in gut tumors of Apc(Min) mice. PLoS One 2012; 7(8)e42137
[] [PMID: 22876303]
Mancias JD, Kimmelman AC. Mechanisms of selective autophagy in normal physiology and cancer. J Mol Biol 2016; 428(9 Pt A): 1659-80.
[] [PMID: 26953261]
Matsuda S, Nakanishi A, Minami A, Wada Y, Kitagishi Y. Functions and characteristics of PINK1 and Parkin in cancer. Front Biosci 2015; 20: 491-501.
[] [PMID: 25553463]
Chourasia AH, Boland ML, Macleod KF. Mitophagy and cancer. Cancer Metab 2015; 3: 4.
[] [PMID: 25810907]
Hu YL, DeLay M, Jahangiri A, et al. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res 2012; 72(7): 1773-83.
[] [PMID: 22447568]
Guo JY, Karsli-Uzunbas G, Mathew R, et al. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev 2013; 27(13): 1447-61.
[] [PMID: 23824538]
Cheng M, Liu L, Lao Y, et al. MicroRNA-181a suppresses parkin-mediated mitophagy and sensitizes neuroblastoma cells to mitochondrial uncoupler-induced apoptosis. Oncotarget 2016; 7(27): 42274-87.
[] [PMID: 27281615]
Frankel LB, Wen J, Lees M, et al. microRNA-101 is a potent inhibitor of autophagy. EMBO J 2011; 30(22): 4628-41.
[] [PMID: 21915098]
Xiao J, Zhu X, He B, et al. MiR-204 regulates cardiomyocyte autophagy induced by ischemia-reperfusion through LC3-II. J Biomed Sci 2011; 18(1): 35.
[] [PMID: 21631941]
Zhu H, Wu H, Liu X, et al. Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells. Autophagy 2009; 5(6): 816-23.
[] [PMID: 19535919]
Li QQ, Zhang L, Wan HY, Liu M, Li X, Tang H. CREB1-driven expression of miR-320a promotes mitophagy by down-regulating VDAC1 expression during serum starvation in cervical cancer cells. Oncotarget 2015; 6(33): 34924-40.
[] [PMID: 26472185]
Guo J, Yang Z, Yang X, et al. miR-346 functions as a pro-survival factor under ER stress by activating mitophagy. Cancer Lett 2018; 413: 69-81.
[] [PMID: 29107113]
Fei X, Qi M, Wu B, et al. 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.
[] [PMID: 22265971]
Fang R, Xiao T, Fang Z, et al. MicroRNA-143 (miR-143) regulates cancer glycolysis via targeting hexokinase 2 gene. J Biol Chem 2012; 287(27): 23227-35.
[] [PMID: 22593586]
Kim S, Lee E, Jung J, et al. microRNA-155 positively regulates glucose metabolism via PIK3R1-FOXO3a-cMYC axis in breast cancer. Oncogene 2018; 37(22): 2982-91.
[] [PMID: 29527004]
Cannino G, Di Liegro CM, Rinaldi AM. Nuclear-mitochondrial interaction. Mitochondrion 2007; 7(6): 359-66.
[] [PMID: 17822963]
Aschrafi A, Schwechter AD, Mameza MG, Natera-Naranjo O, Gioio AE, Kaplan BB. MicroRNA-338 regulates local cytochrome c oxidase IV mRNA levels and oxidative phosphorylation in the axons of sympathetic neurons. J Neurosci 2008; 28(47): 12581-90.
[] [PMID: 19020050]
Fong MY, Zhou W, Liu L, et al. Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat Cell Biol 2015; 17(2): 183-94.
[] [PMID: 25621950]
Li L, Kang L, Zhao W, et al. miR-30a-5p suppresses breast tumor growth and metastasis through inhibition of LDHA-mediated Warburg effect. Cancer Lett 2017; 400: 89-98.
[] [PMID: 28461244]
Cha YJ, Kim ES, Koo JS. Amino acid transporters and glutamine metabolism in breast cancer. Int J Mol Sci 2018; 19(3): 907.
[] [PMID: 29562706]
Gao P, Tchernyshyov I, Chang TC, et al. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 2009; 458(7239): 762-5.
[] [PMID: 19219026]
Chen S, Chen X, Shan T, et al. MiR-21-mediated Metabolic Alteration of Cancer-associated Fibroblasts and Its Effect on Pancreatic Cancer Cell Behavior. International journal of biological sciences 2018; 14(1): 100-10.
[] [PMID: 29483829]
Marchi S, Lupini L, Patergnani S, et al. Downregulation of the mitochondrial calcium uniporter by cancer-related miR-25. Curr Biol 2013; 23(1): 58-63.
[] [PMID: 23246404]
Yu C, Wang Y, Peng J, et al. Mitochondrial calcium uniporter as a target of microRNA-340 and promoter of metastasis via enhancing the Warburg effect. Oncotarget 2017; 8(48): 83831-44.
[] [PMID: 29137386]
Du C, Fang M, Li Y, Li L, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000; 102(1): 33-42.
[] [PMID: 10929711]
Cleland MM, Norris KL, Karbowski M, et al. Bcl-2 family interaction with the mitochondrial morphogenesis machinery. Cell Death Differ 2011; 18(2): 235-47.
[] [PMID: 20671748]
Vecchione A, Croce CM. Apoptomirs: small molecules have gained the license to kill. Endocr Relat Cancer 2010; 17(1): F37-50.
[] [PMID: 19815577]
Wu H, Wang J, Ma H, Xiao Z, Dong X. MicroRNA-21 inhibits mitochondria-mediated apoptosis in keloid. Oncotarget 2017; 8(54): 92914-25.
[] [PMID: 29190966]
Wang W, Yang J, Yu F, et al. MicroRNA-122-3p inhibits tumor cell proliferation and induces apoptosis by targeting Forkhead box O in A549 cells. Oncol Lett 2018; 15(2): 2695-9.
[] [PMID: 29434994]
Pant K, Yadav AK, Gupta P, Islam R, Saraya A, Venugopal SK. Butyrate induces ROS-mediated apoptosis by modulating miR-22/SIRT-1 pathway in hepatic cancer cells. Redox Biol 2017; 12: 340-9.
[] [PMID: 28288414]
Venkatadri R, Muni T, Iyer AKV, Yakisich JS. Azad. Role of apoptosis-related miRNAs in resveratrol-induced breast cancer cell death. Cell Death Dis 2017; 7(2)pe2104
[] [PMID: 26890143]
Guanen Q, Junjie S, Baolin W, et al. MiR-214 promotes cell meastasis and inhibites apoptosis of esophageal squamous cell carcinoma via PI3K/AKT/mTOR signaling pathway. Biomed Pharmacother 2018; 105: 350-61.
[] [PMID: 29864623]
Tao F, Tian X, Ruan S, Shen M, Zhang Z. miR-211 sponges lncRNA MALAT1 to suppress tumor growth and progression through inhibiting PHF19 in ovarian carcinoma. FASEB J 2018; 32(11): 6330-43.
[] [PMID: 29874124]
Koo KH, Kwon H. MicroRNA miR-4779 suppresses tumor growth by inducing apoptosis and cell cycle arrest through direct targeting of PAK2 and CCND3. Cell Death Dis 2018; 9(2): 77.
[] [PMID: 29362401]
Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. Journal of the National Cancer Institute 2008; 100(9): 672-9.
[] [PMID: 18445819]
Si W, Shen J, Zheng H, Fan W. The role and mechanisms of action of microRNAs in cancer drug resistance. Clin Epigenetics 2019; 11(1): 25.
[] [PMID: 30744689]
Ji W, Sun B, Su C. Targeting microRNAs in cancer gene therapy. Genes (Basel) 2017; 8(1): 21.
[] [PMID: 28075356]
Shah MY, Ferrajoli A, Sood AK, Lopez-Berestein G, Calin GA. microRNA therapeutics in cancer—an emerging concept. EBioMedicine 2016; 12: 34-42.
[] [PMID: 27720213]
Lindow M, Kauppinen S. Discovering the first microRNA-targeted drug. J Cell Biol 2012; 199(3): 407-12.
[] [PMID: 23109665]
Zheng SR, Guo GL, Zhai Q, Zou ZY, Zhang W. Effects of miR-155 antisense oligonucleotide on breast carcinoma cell line MDA-MB-157 and implanted tumors. Asian Pac J Cancer Prev 2013; 14(4): 2361-6.
[] [PMID: 23725141]
Zhao G, Rodriguez BL. Molecular targeting of liposomal nanoparticles to tumor microenvironment. Int J Nanomedicine 2013; 8: 61-71.
[] [PMID: 23293520]

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Year: 2019
Published on: 23 July, 2019
Page: [621 - 631]
Pages: 11
DOI: 10.2174/1566524019666190723165357
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