title: Sequential expression of miR-182 and miR-503 cooperatively targets FBXW7, contributing to the malignant transformation of colon adenoma to adenocarcinoma.
abstract: Genetic changes in colon cancer are known to parallel the tissue abnormalities associated with the disease, namely adenoma and adenocarcinoma. The role of microRNA dysregulation in dysplastic progression, however, is not well understood. Here, we show that miR-182 and miR-503 undergo sequential up-regulation and drive the progression of colon adenoma to adenocarcinoma by cooperatively down-regulating the tumour suppressor FBXW7. We identified that increased expression of miR-182 is a feature of adenomas. A subsequent increase in miR-503 expression works cooperatively with miR-182 to induce transformation of an adenoma to adenocarcinoma. We show that introducing miR-503 into AAC1 cells, which are derived from a benign adenoma, confers tumourigenic potential. We also demonstrated that blocking both miR-182 and miR-503 in HCT116 colon cancer cells resulted in increased FBXW7 expression and significantly reduced tumour size in xenograft models. We confirmed relevance of these results in patients by examining the expression levels of miR-182 and miR-503 in over 200 colon cancer patients with 12 year survival outcome data. Decreased patient survival was correlated with elevated expression of both miRNAs, suggesting that elevated levels of both miR-182 and miR-503 define a novel prognostic biomarker for colon cancer patients. In conclusion, we show that a sequential expression of miR-182 and miR-503 in benign adenoma cooperatively regulates the tumour suppressor FBXW7, contributing to the malignant transformation of colon adenoma to adenocarcinoma and miR-182 and miR-503 may prove to be novel therapeutic targets. Array data are available at: http://www.oncomir.umn.edu/
authors.affiliation: Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Li
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sarver
authors.forename: Rohini
authors.initials: R
authors.lastname: Khatri
authors.forename: Praveensingh B
authors.initials: PB
authors.lastname: Hajeri
authors.forename: Iris
authors.initials: I
authors.lastname: Kamenev
authors.forename: Amy J
authors.initials: AJ
authors.lastname: French
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Steer
authors.forename: Subbaya
authors.initials: S
authors.lastname: Subramanian
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000236:Adenoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis* / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D044783:F-Box Proteins / Q000096:biosynthesis* / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D016016:Proportional Hazards Models; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C545473:MIRN503 microRNA, human; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; D044767:Ubiquitin-Protein Ligases
keywords: FBXW7; colon adenoma; colon cancer; malignant transformation; miR-182; miR-503; microRNAs