Editing MicroRNA (section)

===DNA repair and cancer===
Many miRNAs can directly target and inhibit [[cell cycle]] genes to control [[cell proliferation]]. A new strategy for tumor treatment is to inhibit tumor cell proliferation by repairing the defective miRNA pathway in tumors.<ref>{{cite journal|url=
https://scitechdaily.com/scientists-develop-a-new-powerful-cancer-fighting-weapon/amp/|title=Scientists Develop a New, Powerful Cancer-Fighting Weapon|date=September 13, 2022|access-date=September 15, 2022|author=[[Peking University]]|journal=Cell |volume=185 |issue=11 |pages=1888–1904.e24 |publisher=[[SciTech (magazine)|SciTech Daily]]|doi=10.1016/j.cell.2022.04.030|pmid=35623329 |s2cid=249070106 |doi-access=free}}</ref>
Cancer is caused by the accumulation of [[mutation]]s from either DNA damage or uncorrected errors in [[DNA replication]].<ref>{{cite journal | vauthors = Loeb KR, Loeb LA | title = Significance of multiple mutations in cancer | journal = Carcinogenesis | volume = 21 | issue = 3 | pages = 379–385 | date = March 2000 | pmid = 10688858 | doi = 10.1093/carcin/21.3.379 | doi-access = free }}</ref> Defects in [[DNA repair]] cause the accumulation of mutations, which can lead to cancer.<ref>{{cite book | vauthors = Lodish H, Berk A, Kaiser CA, Krieger M, Bretscher A, Ploegh H, Amon A, Martin KC |title=Molecular Cell Biology |date=2016 |publisher=W. H. Freeman and Company |location=New York |isbn=978-1-4641-8339-3 |page=203 |edition=8th}}</ref> Several genes involved in DNA repair are regulated by microRNAs.<ref>{{cite journal | vauthors = Hu H, Gatti RA | title = MicroRNAs: new players in the DNA damage response | journal = Journal of Molecular Cell Biology | volume = 3 | issue = 3 | pages = 151–158 | date = June 2011 | pmid = 21183529 | pmc = 3104011 | doi = 10.1093/jmcb/mjq042 }}</ref>

[[Germline]] mutations in DNA repair genes cause only 2–5% of [[colon cancer]] cases.<ref>{{cite journal | vauthors = Jasperson KW, Tuohy TM, Neklason DW, Burt RW | title = Hereditary and familial colon cancer | journal = Gastroenterology | volume = 138 | issue = 6 | pages = 2044–58 | date = June 2010 | pmid = 20420945 | pmc = 3057468 | doi = 10.1053/j.gastro.2010.01.054 }}</ref> However, altered expression of microRNAs, causing DNA repair deficiencies, are frequently associated with cancers and may be an important [[causality|causal]] factor. Among 68 sporadic colon cancers with reduced expression of the [[DNA mismatch repair]] protein [[MLH1]], most were found to be deficient due to [[epigenetic methylation]] of the [[CpG site|CpG]] island of the [[MLH1]] gene.<ref>{{cite journal | vauthors = Truninger K, Menigatti M, Luz J, Russell A, Haider R, Gebbers JO, Bannwart F, Yurtsever H, Neuweiler J, Riehle HM, Cattaruzza MS, Heinimann K, Schär P, Jiricny J, Marra G | title = Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer | journal = Gastroenterology | volume = 128 | issue = 5 | pages = 1160–71 | date = May 2005 | pmid = 15887099 | doi = 10.1053/j.gastro.2005.01.056 | doi-access = free }}</ref> However, up to 15% of MLH1-deficiencies in sporadic colon cancers appeared to be due to over-expression of the microRNA miR-155, which represses MLH1 expression.<ref>{{cite journal | vauthors = Valeri N, Gasparini P, Fabbri M, Braconi C, Veronese A, Lovat F, Adair B, Vannini I, Fanini F, Bottoni A, Costinean S, Sandhu SK, Nuovo GJ, Alder H, Gafa R, Calore F, Ferracin M, Lanza G, Volinia S, Negrini M, McIlhatton MA, Amadori D, Fishel R, Croce CM | title = Modulation of mismatch repair and genomic stability by miR-155 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 15 | pages = 6982–87 | date = April 2010 | pmid = 20351277 | pmc = 2872463 | doi = 10.1073/pnas.1002472107 | bibcode = 2010PNAS..107.6982V | doi-access = free }}</ref>

In 29–66%<ref name=Zhang>{{cite journal | vauthors = Zhang W, Zhang J, Hoadley K, Kushwaha D, Ramakrishnan V, Li S, Kang C, You Y, Jiang C, Song SW, Jiang T, Chen CC | title = miR-181d: a predictive glioblastoma biomarker that downregulates MGMT expression | journal = Neuro-Oncology | volume = 14 | issue = 6 | pages = 712–19 | date = June 2012 | pmid = 22570426 | pmc = 3367855 | doi = 10.1093/neuonc/nos089 }}</ref><ref>{{cite journal | vauthors = Spiegl-Kreinecker S, Pirker C, Filipits M, Lötsch D, Buchroithner J, Pichler J, Silye R, Weis S, Micksche M, Fischer J, Berger W | title = O6-Methylguanine DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients | journal = Neuro-Oncology | volume = 12 | issue = 1 | pages = 28–36 | date = January 2010 | pmid = 20150365 | pmc = 2940563 | doi = 10.1093/neuonc/nop003 }}</ref> of [[glioblastomas]], DNA repair is deficient due to epigenetic methylation of the [[O-6-methylguanine-DNA methyltransferase|MGMT]] gene, which reduces protein expression of MGMT. However, for 28% of glioblastomas, the MGMT protein is deficient, but the MGMT promoter is not methylated.<ref name=Zhang /> In glioblastomas without methylated MGMT promoters, the level of microRNA miR-181d is [[inversely correlated]] with protein expression of MGMT and the direct target of miR-181d is the MGMT [[mRNA]] 3'UTR (the [[three prime untranslated region]] of MGMT mRNA).<ref name=Zhang /> Thus, in 28% of glioblastomas, increased expression of miR-181d and reduced expression of DNA repair enzyme MGMT may be a causal factor.

[[HMGA]] proteins (HMGA1a, HMGA1b and HMGA2) are implicated in cancer, and expression of these proteins is regulated by microRNAs. HMGA expression is almost undetectable in differentiated adult tissues, but is elevated in many cancers. HMGA proteins are [[polypeptides]] of ~100 amino acid residues characterized by a modular sequence organization. These proteins have three highly positively charged regions, termed [[AT hook]]s, that bind the minor groove of AT-rich DNA stretches in specific regions of DNA. Human neoplasias, including thyroid, prostatic, cervical, colorectal, pancreatic and ovarian carcinomas, show a strong increase of HMGA1a and HMGA1b proteins.<ref>{{cite journal | vauthors = Sgarra R, Rustighi A, Tessari MA, Di Bernardo J, Altamura S, Fusco A, Manfioletti G, Giancotti V | title = Nuclear phosphoproteins HMGA and their relationship with chromatin structure and cancer | journal = FEBS Letters | volume = 574 | issue = 1–3 | pages = 1–8 | date = September 2004 | pmid = 15358530 | doi = 10.1016/j.febslet.2004.08.013 | bibcode = 2004FEBSL.574....1S | s2cid = 28903539 }}</ref> Transgenic mice with HMGA1 targeted to lymphoid cells develop aggressive lymphoma, showing that high HMGA1 expression is associated with cancers and that HMGA1 can act as an oncogene.<ref>{{cite journal | vauthors = Xu Y, Sumter TF, Bhattacharya R, Tesfaye A, Fuchs EJ, Wood LJ, Huso DL, Resar LM | title = The HMG-I oncogene causes highly penetrant, aggressive lymphoid malignancy in transgenic mice and is overexpressed in human leukemia | journal = Cancer Research | volume = 64 | issue = 10 | pages = 3371–75 | date = May 2004 | pmid = 15150086 | doi = 10.1158/0008-5472.CAN-04-0044 | doi-access = free }}</ref> HMGA2 protein specifically targets the promoter of [[ERCC1]], thus reducing expression of this DNA repair gene.<ref>{{cite journal | vauthors = Borrmann L, Schwanbeck R, Heyduk T, Seebeck B, Rogalla P, Bullerdiek J, Wisniewski JR | title = High mobility group A2 protein and its derivatives bind a specific region of the promoter of DNA repair gene ERCC1 and modulate its activity | journal = Nucleic Acids Research | volume = 31 | issue = 23 | pages = 6841–51 | date = December 2003 | pmid = 14627817 | pmc = 290254 | doi = 10.1093/nar/gkg884 }}</ref> ERCC1 protein expression was deficient in 100% of 47 evaluated colon cancers (though the extent to which HGMA2 was involved is not known).<ref>{{cite journal | vauthors = Facista A, Nguyen H, Lewis C, Prasad AR, Ramsey L, Zaitlin B, Nfonsam V, Krouse RS, Bernstein H, Payne CM, Stern S, Oatman N, Banerjee B, Bernstein C | title = Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer | journal = Genome Integrity | volume = 3 | issue = 1 | pages = 3 | date = April 2012 | pmid = 22494821 | pmc = 3351028 | doi = 10.1186/2041-9414-3-3 | doi-access = free }}</ref>

Single Nucleotide polymorphisms (SNPs) can alter the binding of miRNAs on 3'UTRs for example the case of hsa-mir181a and hsa-mir181b on the CDON tumor suppressor gene.<ref>{{cite journal | vauthors = Gibert B, Delloye-Bourgeois C, Gattolliat CH, Meurette O, Le Guernevel S, Fombonne J, Ducarouge B, Lavial F, Bouhallier F, Creveaux M, Negulescu AM, Bénard J, Janoueix-Lerosey I, Harel-Bellan A, Delattre O, Mehlen P | title = Regulation by miR181 family of the dependence receptor CDON tumor suppressive activity in neuroblastoma | journal = Journal of the National Cancer Institute | volume = 106 | issue = 11 | date = November 2014 | pmid = 25313246 | doi = 10.1093/jnci/dju318 | doi-access = free }}</ref>