RGD Reference Report - MicroRNA-18a attenuates DNA damage repair through suppressing the expression of ataxia telangiectasia mutated in colorectal cancer. - Rat Genome Database

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MicroRNA-18a attenuates DNA damage repair through suppressing the expression of ataxia telangiectasia mutated in colorectal cancer.

Authors: Wu, Chung-Wah  Dong, Yu-Juan  Liang, Qiao-Yi  He, Xin-Qi  Ng, Simon S M  Chan, Francis K L  Sung, Joseph J Y  Yu, Jun 
Citation: Wu CW, etal., PLoS One. 2013;8(2):e57036. doi: 10.1371/journal.pone.0057036. Epub 2013 Feb 21.
RGD ID: 150340701
Pubmed: PMID:23437304   (View Abstract at PubMed)
PMCID: PMC3578802   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0057036   (Journal Full-text)


BACKGROUND: miR-18a is one of the most up-regulated miRNAs in colorectal cancers (CRC) based on miRNA profiling. In this study, we examined the functional significance of miR-18a in CRC.
METHODS: Expression of miR-18a was investigated in 45 CRC patients. Potential target genes of miR-18a were predicted by in silico search and confirmed by luciferase activity assay and Western blot. DNA damage was measured by comet assay. Gene function was measured by cell viability, colony formation and apoptosis assays.
RESULTS: The up-regulation of miR-18a was validated and confirmed in 45 primary CRC tumors compared with adjacent normal tissues (p<0.0001). Through in silico search, the 3'UTR of Ataxia telangiectasia mutated (ATM) contains a conserved miR-18a binding site. Expression of ATM was down-regulated in CRC tumors (p<0.0001) and inversely correlated with miR-18a expression (r = -0.4562, p<0.01). Over-expression of miR-18a in colon cancer cells significantly reduced the luciferase activity of the construct with wild-type ATM 3'UTR but not that with mutant ATM 3'UTR, inferring a direct interaction of miR-18a with ATM 3'UTR. This was further confirmed by the down-regulation of ATM protein by miR-18a. As ATM is a key enzyme in DNA damage repair, we evaluated the effect of miR-18a on DNA double-strand breaks. Ectopic expression of miR-18a significantly inhibited the repair of DNA damage induced by etoposide (p<0.001), leading to accumulation of DNA damage, increase in cell apoptosis and poor clonogenic survival.
CONCLUSION: miR-18a attenuates cellular repair of DNA double-strand breaks by directly suppressing ATM, a key enzyme in DNA damage repair.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
colorectal cancer  IEP 150340701mRNA:decreased expression:mucosa of rectum (human)RGD 
colorectal cancer  ISOATM (Homo sapiens)150340701; 150340701mRNA:decreased expression:mucosa of rectum (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Atm  (ATM serine/threonine kinase)

Genes (Mus musculus)
Atm  (ataxia telangiectasia mutated)

Genes (Homo sapiens)
ATM  (ATM serine/threonine kinase)


Additional Information