MicroRNA profiling of carcinogen-induced rat colon tumors and the influence of dietary spinach.
METHODS
MicroRNA (miRNA) profiles are altered in chronic conditions such as cardiovascular disease, diabetes, neurological disorders, and cancer. A systems biology approach was used to examine, for the first time, miRNAs altered in rat colon tumors induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), a heterocyclic amine carcinogen from cooked meat.


RESULTS
Among the most highly dysregulated miRNAs were those belonging to the let-7 family. Subsequent computational modeling and target validation identified c-Myc and miRNA-binding proteins Lin28A/Lin28B (Lin28) as key players, along with Sox2, Nanog, and Oct-3/4. These targets of altered miRNAs in colon cancers have been implicated in tumor recurrence and reduced patient survival, in addition to their role as pluripotency factors. In parallel with these findings, the tumor-suppressive effects of dietary spinach given postinitiation correlated with elevated levels of let-7 family members and partial normalization of c-myc, Sox2, Nanog, Oct-3/4, HmgA2, Dnmt3b, and P53 expression.


CONCLUSIONS
We conclude that the let-7/c-Myc/Lin28 axis is dysregulated in heterocyclic amine-induced colon carcinogenesis, and that the tumor suppressive effects of dietary spinach are associated with partial normalization of this pathway.
Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA.
Mansi A
MA
Parasramka
W Mohaiza
WM
Dashwood
Rong
R
Wang
Amir
A
Abdelli
George S
GS
Bailey
David E
DE
Williams
Emily
E
Ho
Roderick H
RH
Dashwood
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000178:diet therapy* / Q000235:genetics*; D003198:Computer Simulation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D007093:Imidazoles / Q000633:toxicity; D008297:Male; D035683:MicroRNAs; D016601:RNA-Binding Proteins / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D018724:Spinacia oleracea
D002273:Carcinogens; D007093:Imidazoles; C578027:Lin28A protein, rat; C548145:MIRNLET7 microRNA, rat; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine