Tumor Suppressor Functions of miR-133a in Colorectal Cancer

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 microdissection, 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 G 0 /G 1 -phase arrest, concomitant with the upregulation of the key G 1 -phase regulator p21Cip1 . We further revealed that miR-133a markedly increased p53 protein and induced p21 Cip1 transcription. Studies in silico revealed that the 3 0 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 0 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.

Impairment of growth of gastric carcinoma by miR-133-mediated Her-2 inhibition

“…The suppression of miR-133 has recently been reported in bladder cancer, prostate cancer, and colorectal carcinoma [17][18][19]. However, the direct target genes for miR-133 in these studies are different, for example, Her-2 in bladder cancer and prostate cancer, or E3-ubiquitin protein ligase (RFFL) in colorectal carcinoma.…”

CD47, a multi-facetted target for cancer immunotherapy

“…CD47 expression is also subject to post-transcriptional regulation by micro RNAs (miRNAs). Aberrant overexpression of CD47 correlates with downregulation of miRNA133a in esophageal squamous cell carcinoma and colorectal cancer (Suzuki et al, 2012;Dong et al, 2013). Reporter construct studies validated the ability of miR-133a to directly inhibit CD47 transcription in vitro.…”

“…Finally, the transfection or injection of miR-133a, known to regulate CD47 expression, into mouse tumor xenografts significantly inhibited tumor outgrowth (Suzuki et al, 2012;Dong et al, 2013). Thus, siRNA or miRNA-mediated down-regulation of CD47 is a potentially interesting approach, which will however need to be performed using tumorselective delivery systems in order to prevent systemic side-effects.…”

Involvement of MicroRNA-133a in the Development of Arteriosclerosis Obliterans of the Lower Extremities via RhoA Targeting

“…These findings indicate that miR-133a may take part in the onset of ASO by regulating the function of HASMCs. miR-133a has been demonstrated to inhibit proliferation 14,15) , migration 16,17) , invasion [17][18][19] and differentiation 20,21) and promote apoptosis 17,22) in various types of cells. In addition, miR-133a has been shown to suppress proliferation and promote apoptosis in osteosarcoma cells by targeting Bcl-xL and Mcl-1 14) .…”