RESUMEN
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/
Asunto(s)
Adenocarcinoma/genética , Adenoma/genética , Proteínas de Ciclo Celular/biosíntesis , Transformación Celular Neoplásica/genética , Neoplasias del Colon/genética , Proteínas F-Box/biosíntesis , MicroARNs/genética , Ubiquitina-Proteína Ligasas/biosíntesis , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenoma/mortalidad , Adenoma/patología , Animales , Proteínas de Ciclo Celular/genética , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Proteínas F-Box/genética , Proteína 7 que Contiene Repeticiones F-Box-WD , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Hibridación in Situ , Estimación de Kaplan-Meier , Ratones , Ratones Desnudos , Análisis de Secuencia por Matrices de Oligonucleótidos , Modelos de Riesgos Proporcionales , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
A 20-year-old male presented to the emergency department with lower abdominal pain, urinary retention, and constipation. Computed tomography (CT) revealed a large cyst on the posterior aspect of the prostate gland; he was ultimately diagnosed with a Müllerian duct cyst (MDC). Although much has been written on the radiologic diagnosis of such cysts, there is a paucity of recent literature concerning the pathological diagnosis. While older studies debated the Müllerian origin of a midline cyst abutting the poster prostate, we believe that with the advent of monoclonal PAX8 (which was positive in this lesion) and monoclonal PAX2 (which was negative), we have strong evidence that the present cyst is indeed of Müllerian origin. Further, there is debate in the literature as to whether MDC is synonymous or distinct from prostatic utricle cyst. We present an interdisciplinary analysis as to the merits and weaknesses of both sides of the debate and how data gathered from the current case could be used in a future, larger study to arrive at a more definitive conclusion.