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/

miRNA-503 Promotes Tumor Progression and Is Associated with Early Recurrence and Poor Prognosis in Human Colorectal Cancer

“…2a), even though the biological function in cell proliferation is obviously significant. These results might indicate that the other miR-503 target gene, FBXW7 [27], is also involved in the regulation of proliferation in CRC cells.…”

“…High expression of miR-503 is significantly associated with shorter OS [19], since miR-503 inhibits the G2/M DNA damage checkpoint by suppressing reprimo, which is a downstream protein of tumor suppressor p53 [26]. Recently, Li et al [27] showed that miR-182 and miR-503 cooperatively targeted F-box/WD repeat-containing protein 7 (FBXW7), which normally functions as a cell cycle regulator in CRC cells. They also demonstrated that miR-503 contributed to the malignant transformation of colonic adenoma to adenocarcinoma, and high expression of miR-503 in CRC tended to shorten OS [27].…”

“…Recently, Li et al [27] showed that miR-182 and miR-503 cooperatively targeted F-box/WD repeat-containing protein 7 (FBXW7), which normally functions as a cell cycle regulator in CRC cells. They also demonstrated that miR-503 contributed to the malignant transformation of colonic adenoma to adenocarcinoma, and high expression of miR-503 in CRC tended to shorten OS [27]. The results of that study are consistent with those of the present study, in which miR-503 was gradually upregulated according to the adenoma-carcinoma sequence and high miR-503 expression was associated with malignant potential, in particular tumor growth (large and highly invasive tumor).…”

Fbw7 and its counteracting forces in stem cells and cancer: Oncoproteins in the balance

“…miR-223 is also inversely correlated with Fbw7 expression in human oesophageal cancer [78]. miR-182 and miR-503 together reduce Fbw7 expression in colon adenoma AAC1 cells and increase their tumourigenicity in nude mice [79]. miR-92 represses Fbw7 expression and stabilises c-Myc in B cells, although this must be balanced by an increase in its "sister" miR (encoded by the same polycistronic transcript), miR-19, to repress apoptosis if this is to cause malignant transformation [68].…”

microRNA-503 suppresses the migration, proliferation and colony formation of prostate cancer cells by targeting tumor protein D52 like 2

“…Previous studies have identified that miR-503 is abnormally expressed in retinal glioblastoma, adenoma, breast cancer, non-small cell lung cancer and hepatic cancer. Furthermore, it has been demonstrated that miR-503 targets phosphoinositide-3-kinase, p85 or inhibitor of nuclear factor κB kinase subunit β, regulates the Rho guanine nucleotide exchange factor 19, DDHD domain containing 2 and F-box and WD repeat domain containing 7 genes and initiates apoptosis, thus promoting the growth and differentiation of tumors and inhibiting the invasion and metastasis of tumors (18,(26)(27)(28)(29)(30)(31). This indicates that miR-503 serves important roles in different types of cancer.…”