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Abstract
It has been postulated that a small number of Cancer Stem Cells (CSCs) buried in tumour mass drive cancer growth and impart cancer drug resistance. However, their eradication has not been achieved so far as the mechanistic understanding of CSCs’ role in cancer development and growth is limited. The cholesterol accumulation and efflux processes have been shown to play an important role in maintaining cell’s integrity and its sensitivity towards drugs, as altered cholesterol pathways contribute to cancer drug resistance. Emerging pieces of evidence have indicated miRNAs as regulators of CSCs, and also as regulators of cholesterol pathways in cancer cells, but a link between the two has not been fully established so far. In this review, we have collated key signalling pathways and published evidence emphasising the involvement of miRNAs and cholesterol in CSCs related drug resistance. Additionally, we have used bioinformatics analysis to identify miRNAs that may modulate cholesterol pathways in CSCs at a molecular level to contribute to cancer drug resistance. Our results show that two miRNAs (hsa-miR-34a-5p and hsa-miR-373-3p) interact and bind to two known Breast CSC markers (CD44 and CD24) and mediate the expression of several cholesterol-related genes (INSIG2, APOL2, CYP51A1, HDLB, and DHCR7). Furthermore, survival analysis of the breast cancer patients’ gene expression data revealed that higher expression of these genes is associated with poor disease-free survival. We, therefore, propose that targeting these two miRNAs could possibly provide a way to alter cell’s response to drugs via modulating cholesterol pathways in CSCs.
Keywords: Cancer stem cells, breast cancer, miRNAs, cholesterol, cancer drug resistance, hematopoietic stem cells.
[http://dx.doi.org/10.1038/nm.4409] [PMID: 28985214]
[http://dx.doi.org/10.1038/s41568-018-0056-x] [PMID: 30228301]
[http://dx.doi.org/10.1038/nrc2499] [PMID: 18784658]
[http://dx.doi.org/10.1016/j.stemcr.2018.07.010] [PMID: 30122444]
[http://dx.doi.org/10.1038/nrc796] [PMID: 12044012]
[http://dx.doi.org/10.1038/nrc1590] [PMID: 15803154]
[http://dx.doi.org/10.1038/nrc1232] [PMID: 14737120]
[http://dx.doi.org/10.1038/nrd4253] [PMID: 24981363]
[http://dx.doi.org/10.18632/oncoscience.159] [PMID: 26097879]
[http://dx.doi.org/10.2307/3570892] [PMID: 13776896]
[http://dx.doi.org/10.1038/199079a0] [PMID: 14047954]
[http://dx.doi.org/10.1126/science.560061] [PMID: 560061]
[http://dx.doi.org/10.1083/jcb.201202014] [PMID: 22869594]
[http://dx.doi.org/10.1126/science.1226929] [PMID: 23087000]
[http://dx.doi.org/10.1002/cyto.a.22206] [PMID: 22997049]
[http://dx.doi.org/10.3390/biomedicines6030077] [PMID: 30018256]
[PMID: 1708632]
[http://dx.doi.org/10.1101/gad.1143403] [PMID: 14701873]
[http://dx.doi.org/10.1016/j.ccr.2004.10.015] [PMID: 15607963]
[http://dx.doi.org/10.1038/nature04980] [PMID: 16862118]
[http://dx.doi.org/10.1016/j.ccr.2008.07.005] [PMID: 18691547]
[http://dx.doi.org/10.1016/0145-2126(79)90041-9] [PMID: 316485]
[http://dx.doi.org/10.1016/0165-4608(82)90092-9] [PMID: 6749282]
[http://dx.doi.org/10.1182/blood-2003-12-4369] [PMID: 15331442]
[http://dx.doi.org/10.1038/344251a0] [PMID: 2179728]
[http://dx.doi.org/10.1038/nature05384] [PMID: 17122771]
[http://dx.doi.org/10.1073/pnas.0703478104] [PMID: 17548814]
[http://dx.doi.org/10.1002/glia.10094] [PMID: 12203386]
[http://dx.doi.org/10.1158/0008-5472.CAN-08-0364] [PMID: 18519691]
[http://dx.doi.org/10.1038/sj.cdd.4402283] [PMID: 18049477]
[http://dx.doi.org/10.1158/0008-5472.CAN-06-2030] [PMID: 17283135]
[http://dx.doi.org/10.3390/molecules17066196] [PMID: 22634835]
[http://dx.doi.org/10.1073/pnas.0530291100] [PMID: 12629218]
[http://dx.doi.org/10.7150/ijbs.23586] [PMID: 30443182]
[http://dx.doi.org/10.1093/carcin/bgz182] [PMID: 31742606]
[http://dx.doi.org/10.3390/cancers12051325] [PMID: 32455980]
[http://dx.doi.org/10.1242/jcs.02741] [PMID: 16390867]
[PMID: 26516408]
[http://dx.doi.org/10.1007/978-1-61779-246-5]
[http://dx.doi.org/10.1371/journal.pone.0020636] [PMID: 21695188]
[http://dx.doi.org/10.2174/1574888X13666180810120012] [PMID: 30095061]
[http://dx.doi.org/10.1038/oncsis.2015.35] [PMID: 26619402]
[http://dx.doi.org/10.1038/s41392-020-0110-5] [PMID: 32296030]
[http://dx.doi.org/10.1038/287795a0] [PMID: 6776413]
[http://dx.doi.org/10.1101/gad.938601] [PMID: 11731473]
[http://dx.doi.org/10.1016/j.ceb.2017.10.004] [PMID: 29268141]
[http://dx.doi.org/10.1038/nature03100] [PMID: 15549094]
[http://dx.doi.org/10.3390/jdb4030023] [PMID: 27547735]
[PMID: 25691811]
[http://dx.doi.org/10.1242/dev.120154] [PMID: 26839340]
[http://dx.doi.org/10.1016/j.tcb.2007.06.007] [PMID: 17845852]
[http://dx.doi.org/10.1101/gad.1543607] [PMID: 17504941]
[http://dx.doi.org/10.1126/science.1104135] [PMID: 15618519]
[http://dx.doi.org/10.1073/pnas.0509927103] [PMID: 16371461]
[http://dx.doi.org/10.1038/nature02061] [PMID: 14603322]
[http://dx.doi.org/10.1006/dbio.1999.9335] [PMID: 10433824]
[http://dx.doi.org/10.1016/j.devcel.2015.08.001] [PMID: 26305592]
[http://dx.doi.org/10.1038/ng1196-357] [PMID: 8896572]
[http://dx.doi.org/10.2174/138920112802502114] [PMID: 21605074]
[http://dx.doi.org/10.1038/nature01972] [PMID: 14520411]
[http://dx.doi.org/10.1016/S0092-8674(00)81268-4] [PMID: 8681379]
[PMID: 9192811]
[PMID: 9187099]
[http://dx.doi.org/10.1038/nrc1229] [PMID: 14737121]
[http://dx.doi.org/10.1038/ng916] [PMID: 12068298]
[http://dx.doi.org/10.1073/pnas.84.19.6899] [PMID: 3477813]
[http://dx.doi.org/10.1101/cshperspect.a028175] [PMID: 27881449]
[http://dx.doi.org/10.1038/nature07737] [PMID: 19169242]
[http://dx.doi.org/10.1038/emboj.2008.172] [PMID: 18756266]
[http://dx.doi.org/10.1093/carcin/bgn230] [PMID: 19028702]
[http://dx.doi.org/10.1073/pnas.0611682104] [PMID: 17360475]
[http://dx.doi.org/10.1002/emmm.200900039] [PMID: 20049737]
[http://dx.doi.org/10.1158/0008-5472.CAN-06-0054] [PMID: 16778178]
[http://dx.doi.org/10.1016/j.cub.2006.11.033] [PMID: 17196391]
[http://dx.doi.org/10.1634/stemcells.2007-0166] [PMID: 17628016]
[http://dx.doi.org/10.4161/org.4.2.5851] [PMID: 19279717]
[PMID: 22367735]
[http://dx.doi.org/10.1038/nrm2654] [PMID: 19305417]
[http://dx.doi.org/10.1016/S0092-8674(02)00679-7] [PMID: 11955446]
[http://dx.doi.org/10.1002/bies.20757] [PMID: 18404694]
[http://dx.doi.org/10.1016/j.gene.2008.12.008] [PMID: 19135507]
[http://dx.doi.org/10.2217/14796694.1.6.787]
[http://dx.doi.org/10.1101/gad.1686208] [PMID: 18765787]
[http://dx.doi.org/10.1128/MCB.00992-14] [PMID: 25348713]
[http://dx.doi.org/10.1056/NEJMoa040258] [PMID: 15306667]
[http://dx.doi.org/10.1038/7747] [PMID: 10192393]
[http://dx.doi.org/10.1128/MCB.19.8.5696] [PMID: 10409758]
[http://dx.doi.org/10.1126/science.275.5307.1787] [PMID: 9065402]
[PMID: 9515795]
[PMID: 9537226]
[http://dx.doi.org/10.1016/S0002-9440(10)65148-6] [PMID: 10433945]
[http://dx.doi.org/10.1073/pnas.1314239110] [PMID: 24277854]
[http://dx.doi.org/10.1016/j.ctrv.2017.11.002] [PMID: 29169144]
[http://dx.doi.org/10.1038/leu.2008.384] [PMID: 19148141]
[http://dx.doi.org/10.1038/sj.onc.1208303] [PMID: 15592505]
[http://dx.doi.org/10.4161/cam.1.2.4488] [PMID: 19329884]
[http://dx.doi.org/10.1126/science.284.5415.770] [PMID: 10221902]
[http://dx.doi.org/10.21037/sci.2018.02.02] [PMID: 29682512]
[http://dx.doi.org/10.1158/0008-5472.CAN-05-1069] [PMID: 16166334]
[http://dx.doi.org/10.1038/modpathol.3800785] [PMID: 17507991]
[http://dx.doi.org/10.1038/nm0797-730] [PMID: 9212098]
[PMID: 14522905]
[http://dx.doi.org/10.1007/s12015-007-0023-5] [PMID: 17873349]
[http://dx.doi.org/10.1634/stemcells.2006-0442] [PMID: 17158237]
[http://dx.doi.org/10.1016/j.devcel.2005.09.010] [PMID: 16256737]
[http://dx.doi.org/10.1038/ng0296-154] [PMID: 8563753]
[http://dx.doi.org/10.1182/blood.V89.6.1922] [PMID: 9058712]
[http://dx.doi.org/10.1038/nrc1592] [PMID: 15803157]
[http://dx.doi.org/10.1016/0092-8674(91)90111-B] [PMID: 1831692]
[http://dx.doi.org/10.4149/neo_2009_05_371] [PMID: 19580337]
[http://dx.doi.org/10.1158/0008-5472.CAN-08-4312] [PMID: 19276344]
[http://dx.doi.org/10.1517/14728222.2011.566216] [PMID: 21391891]
[http://dx.doi.org/10.1038/srep24704] [PMID: 27108536]
[http://dx.doi.org/10.1016/j.cell.2004.08.005] [PMID: 15315754]
[http://dx.doi.org/10.1016/0092-8674(91)90382-9] [PMID: 1904008]
[http://dx.doi.org/10.1038/ncb2099] [PMID: 20818389]
[http://dx.doi.org/10.1186/1476-4598-10-10] [PMID: 21276221]
[PMID: 12183433]
[http://dx.doi.org/10.1186/1471-2407-12-406] [PMID: 22967049]
[http://dx.doi.org/10.1038/nrm2763] [PMID: 19738629]
[http://dx.doi.org/10.1101/gad.13.20.2678] [PMID: 10541554]
[http://dx.doi.org/10.1038/16476] [PMID: 9923679]
[http://dx.doi.org/10.1186/bcr1760] [PMID: 17711569]
[http://dx.doi.org/10.1172/JCI39374] [PMID: 19884659]
[http://dx.doi.org/10.1073/pnas.0905653106] [PMID: 19805294]
[http://dx.doi.org/10.3390/ijms12031595] [PMID: 21673909]
[http://dx.doi.org/10.1093/hmg/ddi111] [PMID: 15809278]
[http://dx.doi.org/10.1038/nature01587] [PMID: 12714971]
[http://dx.doi.org/10.1532/IJH97.05013] [PMID: 16105758]
[http://dx.doi.org/10.1016/j.eururo.2006.11.020] [PMID: 17134822]
[http://dx.doi.org/10.2353/ajpath.2007.060754] [PMID: 17392175]
[http://dx.doi.org/10.1186/s40659-017-0140-9] [PMID: 28969709]
[http://dx.doi.org/10.1007/s12013-014-0459-6] [PMID: 25543329]
[http://dx.doi.org/10.1016/j.breast.2005.10.001] [PMID: 16286232]
[http://dx.doi.org/10.1007/s10549-005-1411-7] [PMID: 15980988]
[http://dx.doi.org/10.3322/caac.21262] [PMID: 25651787]
[http://dx.doi.org/10.1073/pnas.191367098] [PMID: 11553815]
[http://dx.doi.org/10.1146/annurev.me.30.020179.001031] [PMID: 400484]
[http://dx.doi.org/10.1056/NEJMra021902] [PMID: 12432047]
[http://dx.doi.org/10.1371/journal.pone.0005329] [PMID: 19390630]
[http://dx.doi.org/10.1186/bcr2256] [PMID: 19426500]
[http://dx.doi.org/10.1073/pnas.0703071104] [PMID: 17566110]
[http://dx.doi.org/10.1007/s10549-009-0524-9] [PMID: 19731012]
[http://dx.doi.org/10.1186/bcr1855] [PMID: 18241344]
[http://dx.doi.org/10.1016/j.ccr.2007.01.013] [PMID: 17349583]
[http://dx.doi.org/10.1038/onc.2010.591] [PMID: 21242971]
[http://dx.doi.org/10.1074/jbc.271.33.20009] [PMID: 8702718]
[http://dx.doi.org/10.1016/j.ctrv.2018.07.004] [PMID: 30029203]
[http://dx.doi.org/10.1016/S0140-6736(05)67887-7] [PMID: 16360786]
[http://dx.doi.org/10.1007/s10549-018-4935-3] [PMID: 30168014]
[http://dx.doi.org/10.3390/molecules23092193] [PMID: 30200262]
[http://dx.doi.org/10.1158/0008-5472.CAN-13-1080] [PMID: 23832666]
[http://dx.doi.org/10.1038/ncomms10442] [PMID: 26858125]
[http://dx.doi.org/10.1158/0008-5472.CAN-16-2129] [PMID: 28202520]
[http://dx.doi.org/10.1038/onc.2011.338] [PMID: 21822303]
[http://dx.doi.org/10.1158/0008-5472.CAN-15-3490] [PMID: 28202523]
[http://dx.doi.org/10.1158/0008-5472.CAN-16-1022] [PMID: 28108512]
[http://dx.doi.org/10.1038/s41523-017-0016-8] [PMID: 28649657]
[http://dx.doi.org/10.1056/NEJMcibr043143] [PMID: 15564551]
[http://dx.doi.org/10.18632/oncotarget.3047] [PMID: 25717032]
[http://dx.doi.org/10.1186/1476-4598-13-213] [PMID: 25216750]
[http://dx.doi.org/10.1016/j.bbrc.2018.05.139] [PMID: 29792857]
[http://dx.doi.org/10.1016/j.ctrv.2013.09.008] [PMID: 24090504]
[http://dx.doi.org/10.1016/j.redox.2018.04.015] [PMID: 29729523]
[http://dx.doi.org/10.1155/2016/2746457]
[http://dx.doi.org/10.1007/s00432-010-0913-9] [PMID: 20499251]
[http://dx.doi.org/10.1158/1078-0432.CCR-08-1479] [PMID: 19509181]
[http://dx.doi.org/10.1007/s10549-011-1692-y] [PMID: 21818590]
[http://dx.doi.org/10.1016/j.biopha.2013.04.005] [PMID: 23721823]
[http://dx.doi.org/10.1016/j.stem.2007.08.014] [PMID: 18371393]
[http://dx.doi.org/10.1158/1078-0432.CCR-09-1532] [PMID: 20103682]
[http://dx.doi.org/10.1111/j.1349-7006.2009.01151.x] [PMID: 19385968]
[http://dx.doi.org/10.2174/1381612822666161027120043] [PMID: 28231756]
[http://dx.doi.org/10.1515/hsz-2016-0308] [PMID: 28095367]
[http://dx.doi.org/10.3892/ol.2019.10304] [PMID: 31289483]
[http://dx.doi.org/10.1007/s00018-009-8750-1] [PMID: 19153653]
[http://dx.doi.org/10.18632/genesandcancer.202] [PMID: 32577155]
[http://dx.doi.org/10.1186/s12943-018-0765-5] [PMID: 29471827]
[http://dx.doi.org/10.1007/978-1-4939-6524-3_1]
[http://dx.doi.org/10.1261/rna.068692.118] [PMID: 30333195]
[http://dx.doi.org/10.1261/rna.2191905] [PMID: 16177138]
[http://dx.doi.org/10.1016/j.cub.2005.10.048] [PMID: 16289642]
[http://dx.doi.org/10.1016/j.cell.2005.07.031] [PMID: 16122423]
[http://dx.doi.org/10.1038/nrg3965] [PMID: 26077373]
[http://dx.doi.org/10.1371/journal.pone.0006783] [PMID: 19710908]
[http://dx.doi.org/10.1016/j.tem.2016.10.003] [PMID: 27810172]
[http://dx.doi.org/10.1158/2159-8290.CD-15-0893] [PMID: 26865249]
[http://dx.doi.org/10.1007/s10545-017-0018-6] [PMID: 28229250]
[http://dx.doi.org/10.1002/ddr.21275] [PMID: 26310899]
[http://dx.doi.org/10.1002/jcp.27885] [PMID: 30537109]
[http://dx.doi.org/10.1016/j.canlet.2018.01.027] [PMID: 29331418]
[http://dx.doi.org/10.1038/onc.2010.167] [PMID: 20498642]
[http://dx.doi.org/10.1080/15384101.2019.1638182] [PMID: 31286834]
[http://dx.doi.org/10.1038/s41417-018-0035-0] [PMID: 30032164]
[http://dx.doi.org/10.1042/bse0500161] [PMID: 21967057]
[http://dx.doi.org/10.1046/j.1365-2826.2002.00836.x] [PMID: 12213137]
[http://dx.doi.org/10.1111/cas.12656] [PMID: 25783790]
[http://dx.doi.org/10.1038/ncomms8318] [PMID: 26065921]
[http://dx.doi.org/10.1038/cddis.2016.438] [PMID: 28102845]
[http://dx.doi.org/10.1128/MCB.10.1.28] [PMID: 1688465]
[http://dx.doi.org/10.1038/onc.2014.236] [PMID: 25088204]
[http://dx.doi.org/10.1089/scd.2015.0100] [PMID: 26154167]
[http://dx.doi.org/10.1074/jbc.M806041200] [PMID: 18790736]
[http://dx.doi.org/10.1016/j.ccr.2009.10.014] [PMID: 19962668]
[http://dx.doi.org/10.1016/j.tem.2010.08.008] [PMID: 20880716]
[http://dx.doi.org/10.1016/j.celrep.2016.09.021] [PMID: 27705805]
[http://dx.doi.org/10.1016/j.celrep.2019.05.104]
[http://dx.doi.org/10.1038/343425a0] [PMID: 1967820]
[http://dx.doi.org/10.1111/febs.15018] [PMID: 31350867]
[http://dx.doi.org/10.18632/oncotarget.14740] [PMID: 28118603]
[http://dx.doi.org/10.1186/s12885-018-4757-z] [PMID: 30143015]
[http://dx.doi.org/10.1186/bcr3063] [PMID: 22115051]
[http://dx.doi.org/10.1200/JCO.2016.70.3116] [PMID: 28380313]
[http://dx.doi.org/10.1074/jbc.RA118.004442] [PMID: 30089652]
[http://dx.doi.org/10.1093/jnci/85.8.632] [PMID: 8096875]
[http://dx.doi.org/10.1023/A:1025751631115] [PMID: 14572157]
[http://dx.doi.org/10.1290/0502016.1] [PMID: 16223335]
[http://dx.doi.org/10.2174/138920007779315044] [PMID: 17266523]
[http://dx.doi.org/10.4161/cbt.26603] [PMID: 24145140]
[http://dx.doi.org/10.1038/sj.bjc.6601863] [PMID: 15150577]
[http://dx.doi.org/10.1038/bjc.2014.385] [PMID: 25025965]
[http://dx.doi.org/10.1200/JCO.2010.31.5200] [PMID: 21422422]
[http://dx.doi.org/10.2147/BCTT.S140265] [PMID: 28744156]
[http://dx.doi.org/10.1158/0008-5472.CAN-19-1184] [PMID: 32718996]
[http://dx.doi.org/10.1111/cas.14587] [PMID: 32713162]
[http://dx.doi.org/10.1038/s41598-017-14364-2] [PMID: 29062075]
[http://dx.doi.org/10.1016/j.molcel.2007.05.010] [PMID: 17540599]
[http://dx.doi.org/10.1038/nbt.1618] [PMID: 20351690]
[http://dx.doi.org/10.1016/0092-8674(90)90694-A] [PMID: 1694723]
[http://dx.doi.org/10.1039/D0BM00015A] [PMID: 32319481]
[http://dx.doi.org/10.1002/jcb.28608] [PMID: 30916815]
[http://dx.doi.org/10.18632/oncotarget.3394] [PMID: 25826085]
[http://dx.doi.org/10.1016/j.biomaterials.2016.07.040] [PMID: 27512943]
[http://dx.doi.org/10.1016/j.ymthe.2019.09.008] [PMID: 31604677]
[http://dx.doi.org/10.3390/ijms20184420] [PMID: 31500376]
[http://dx.doi.org/10.1093/nar/gkn851] [PMID: 18996891]
[http://dx.doi.org/10.1038/nm.2284] [PMID: 21240262]
[http://dx.doi.org/10.1038/ncb1681] [PMID: 18193036]
[http://dx.doi.org/10.1093/nar/gkx1144] [PMID: 29194489]
[http://dx.doi.org/10.1093/nar/gkx247] [PMID: 28407145]
[http://dx.doi.org/10.4103/0974-7788.76794] [PMID: 21455458]
[http://dx.doi.org/10.1002/iub.1461] [PMID: 26662938]
[http://dx.doi.org/10.1111/j.1349-7006.2011.01936.x] [PMID: 21443541]
[http://dx.doi.org/10.18632/aging.101974] [PMID: 31138773]
[http://dx.doi.org/10.1002/jcp.22345] [PMID: 20665705]
[http://dx.doi.org/10.1038/cddis.2014.237] [PMID: 24901046]
[http://dx.doi.org/10.1096/fba.2019-00081] [PMID: 32123859]
[http://dx.doi.org/10.3892/or.2014.3111] [PMID: 24676454]
[http://dx.doi.org/10.1128/MCB.01031-10] [PMID: 20974809]
[http://dx.doi.org/10.1073/pnas.1002922107] [PMID: 20615952]
[http://dx.doi.org/10.1016/j.plipres.2004.10.001] [PMID: 15748653]
[PMID: 33491740]
[http://dx.doi.org/10.3390/cells9081819] [PMID: 32751976]
[http://dx.doi.org/10.1093/jnci/djq361] [PMID: 20935265]
[http://dx.doi.org/10.2147/OTT.S21431] [PMID: 21792314]
[http://dx.doi.org/10.3803/EnM.2017.32.1.6] [PMID: 28116873]
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