Abstract
Emerging evidence indicate that microRNAs (miRNAs) may play important roles in cancer. Aberrant expression of miRNAs has been frequently identified in different human malignancies, including colorectal cancer (CRC). However, the mechanism by which deregulated miRNAs impact the development of CRC remains largely elusive. In this study, we show that miR-124 is significantly down-regulated in CRC compared to adjacent non-tumor colorectal tissues. MiR-124 suppresses the expression of STAT3 by directly binding to its 3′-untranslated region (3′-UTR). Overexpression of miR-124 led to increased apoptosis of CRC cells and reduced tumor growth in vitro and in vivo. Knocking down STAT3 expression by specific siRNA suppressed the growth of CRC cells in vitro and in vivo, resembling that of miR-124 overexpression. Moreover, overexpression of STAT3 in miR-124-transfected CRC cells effectively rescued the inhibition of cell proliferation caused by miR-124. These data suggest that miR-124 serves as a tumor suppressor by targeting STAT3, and call for the use of miR-124 as a potential therapeutic tool for CRC, where STAT3 is often hyper-activated.
Highlights
Colorectal cancer (CRC) is the third leading cause of deaths among all human malignancies [1,2]
MiR-124 is Down-regulated in Human CRC To examine the expression profile of miR-124 in CRC, we performed quantitative real-time RT-PCR using TaqMan assay in 90 paired tumor and normal colorectal specimens
In mouse models of hepatocellular carcinoma, miR-124 is involved in an inflammatory feedback loop where it suppresses the expression of IL-6R and reduces STAT3 activation in transformed cells [39]
Summary
Colorectal cancer (CRC) is the third leading cause of deaths among all human malignancies [1,2]. Most CRCs arise sporadically, with sequential mutations in APC/b-catennin, K-Ras, COX-2, and p53 signaling along the process of cancer initiation, progression and metastasis [3,4,5]. In addition to cancer cellintrinsic mechanisms mediated by these oncogenes and tumor suppressor genes, interaction between cancer cells and other cells in tumor stroma plays important roles in shaping the development of cancers [6]. STAT3 is a critical link between tumor cells and their microenvironments by regulating both tumor growth and tumorassociated inflammation [8,9]. STAT3 plays important roles in tumor growth and progression [10]. Conditional deletion of STAT3 in colonic epithelial cells and in hepatocytes resulted in reduced tumor development in mice [10,14].
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