Identification of a microRNA landscape targeting the PI3K/Akt signaling pathway in inflammation-induced colorectal carcinogenesis.
Inflammation can contribute to tumor formation; however, markers that predict progression are still lacking. In the present study, the well-established azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mouse model of colitis-associated cancer was used to analyze microRNA (miRNA) modulation accompanying inflammation-induced tumor development and to determine whether inflammation-triggered miRNA alterations affect the expression of genes or pathways involved in cancer. A miRNA microarray experiment was performed to establish miRNA expression profiles in mouse colon at early and late time points during inflammation and/or tumor growth. Chronic inflammation and carcinogenesis were associated with distinct changes in miRNA expression. Nevertheless, prediction algorithms of miRNA-mRNA interactions and computational analyses based on ranked miRNA lists consistently identified putative target genes that play essential roles in tumor growth or that belong to key carcinogenesis-related signaling pathways. We identified PI3K/Akt and the insulin growth factor-1 (IGF-1) as major pathways being affected in the AOM/DSS model. DSS-induced chronic inflammation downregulates miR-133a and miR-143/145, which is reportedly associated with human colorectal cancer and PI3K/Akt activation. Accordingly, conditioned medium from inflammatory cells decreases the expression of these miRNA in colorectal adenocarcinoma Caco-2 cells. Overexpression of miR-223, one of the main miRNA showing strong upregulation during AOM/DSS tumor growth, inhibited Akt phosphorylation and IGF-1R expression in these cells. Cell sorting from mouse colons delineated distinct miRNA expression patterns in epithelial and myeloid cells during the periods preceding and spanning tumor growth. Hence, cell-type-specific miRNA dysregulation and subsequent PI3K/Akt activation may be involved in the transition from intestinal inflammation to cancer.
GIGA-Research, Human Genetics Unit, University of Liège, Liège, Belgium;
Claire
C
Josse
Nassim
N
Bouznad
Pierre
P
Geurts
Alexandre
A
Irrthum
Vân Anh
VA
Huynh-Thu
Laurence
L
Servais
Alexandre
A
Hego
Philippe
P
Delvenne
Vincent
V
Bours
Cécile
C
Oury
D000818:Animals; D001397:Azoxymethane / Q000009:adverse effects; D063646:Carcinogenesis / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D035683:MicroRNAs; D016264:Dextran Sulfate; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D001397:Azoxymethane
colorectal cancer; computational analyses; inflammation; microRNA; mouse model