Abstract
Dysregulated microRNA (miRNA) expression was profiled through a miRNA array comparison between human colorectal cancer tumors and their adjacent normal tissues. Specifically, using laser capture micro-dissection, miR-133a was shown to be significantly downregulated in primary colorectal cancer specimens compared with matched adjacent normal tissue. Ectopic expression of miR-133a significantly suppressed colorectal cancer cell growth in vitro and in vivo. Cell-cycle analysis revealed that miR-133a induced a G0/G1-phase arrest, concomitant with the upregulation of the key G1-phase regulator p21(Cip1). We further revealed that miR-133a markedly increased p53 protein and induced p21(Cip1) transcription. Studies in silico revealed that the 3'UTR of the ring finger and FYVE-like domain containing E3-ubiquitin protein ligase (RFFL), which regulates p53 protein, contains an evolutionarily conserved miR-133a binding site. miR-133a repressed RFFL-3'UTR reporter activity and reduced RFFL protein levels, indicating that miR-133a directly bound to RFFL mRNA and inhibited RFFL translation. Moreover, miR-133a sensitized colon cancer cells to doxorubicin and oxaliplatin by enhancing apoptosis and inhibiting cell proliferation. These data add weight to the significance of miR-133a in the development of CRC. miR-133a serves as a potential tumor suppressor upstream of p53 in colorectal cancer and may sensitize cells to therapeutics.
Highlights
Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer-related death in the world, with an estimated incidence of 1.2 million new cases and a mortality of more than 600,000 deaths annually [1]
We found that miR-133a was significantly downregulated in CRCs based on the array data (GSE45349)
Among the 89 pairs of CRC tissues specimens examined, 80 (89.9%) tumor tissues showed significantly lower miR133a expression when compared with matched adjacent normal tissues (36 of 44, 81.8%, P < 0.001 for cohort I; and 44 of 45, 97.8%, P < 0.001 for cohort II; Fig. 1A1 and 2, Supplementary Table S4), with a median difference of 0.15fold [interquartile range (IQR), 0.46–0.05] in cohort I and 0.05-fold (IQR, 0.13–0.02) in cohort II, respectively. miR133a was first identified as a muscle-specific miRNA [6]
Summary
Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer-related death in the world, with an estimated incidence of 1.2 million new cases and a mortality of more than 600,000 deaths annually [1]. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). It is estimated that miRNAs can regulate up to 50% human genes translation [3]. MiRNAs epigenetically regulate fundamental cellular processes such as cell proliferation, apoptosis, differentiation, and migration, which strongly indicates that they may function as potential oncogenes or tumor suppressors in cancer development. An investigation into the mechanism of the dysregulated miRNAs in pathogenesis of CRCs can help identify novel molecular events and signal pathways for the development of anticancer therapy. We recently identified dysregulated miRNAs in human CRC through comparison between tumors and their adjacent normal tissues by miRNA array (GSE45349). We aim to clarify miR-133a biologic function, molecular basis, and target gene in CRCs
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