Abstract
BackgroundmiRNAs are a group of small RNA molecules regulating target genes by inducing mRNA degradation or translational repression. Aberrant expression of miRNAs correlates with various cancers. Although miR-135a has been implicated in several other cancers, its role in breast cancer is unknown. HOXA10 however, is associated with multiple cancer types and was recently shown to induce p53 expression in breast cancer cells and reduce their invasive ability. Because HOXA10 is a confirmed miR-135a target in more than one tissue, we examined miR-135a levels in relation to breast cancer phenotypes to determine if miR-135a plays role in this cancer type.MethodsExpression levels of miR-135a in tissues and cells were determined by poly (A)-RT PCR. The effect of miR-135a on proliferation was evaluated by CCK8 assay, cell migration and invasion were evaluated by transwell migration and invasion assays, and target protein expression was determined by western blotting. GFP and luciferase reporter plasmids were constructed to confirm the action of miR-135a on downstream target genes including HOXA10. Results are reported as means ± S.D. and differences were tested for significance using 2-sided Student"s t-test.ResultsHere we report that miR-135a was highly expressed in metastatic breast tumors. We found that the expression of miR-135a was required for the migration and invasion of breast cancer cells, but not their proliferation. HOXA10, which encodes a transcription factor required for embryonic development and is a metastasis suppressor in breast cancer, was shown to be a direct target of miR-135a in breast cancer cells. Our analysis showed that miR-135a suppressed the expression of HOXA10 both at the mRNA and protein level, and its ability to promote cellular migration and invasion was partially reversed by overexpression of HOXA10.ConclusionsIn summary, our results indicate that miR-135a is an onco-miRNA that can promote breast cancer cell migration and invasion. HOXA10 is a target gene for miR-135a in breast cancer cells and overexpression of HOXA10 can partially reverse the miR-135a invasive phenotype.
Highlights
MiRNAs are a group of small RNA molecules regulating target genes by inducing mRNA degradation or translational repression
Processes known to be under the control of miR-135a include megakaryocytopoiesis[10], bone and muscle development, hypertension, colorectal cancer through its target gene Adenomatous Polyposis Coli (APC)[11,12,13], epithelial ovarian cancer and endometriosis through its target gene HOXA10[14], portal vein tumor thrombus through its target gene metastasis suppressor 1 and Hodgkin disease and gastric cancer through its target JAK2[15,16]
We found that miR-135a was up-regulated in breast cancer cell line BT549 which has a highly invasive phenotype (Figure 1B)
Summary
MiRNAs are a group of small RNA molecules regulating target genes by inducing mRNA degradation or translational repression. Micro RNAs (miRNAs) are small non-coding, cellular RNAs (17-27 bp) that post-transcriptionally regulate gene expression by inducing the degradation or translational repression of target mRNAs. The discovery of miRNAs and their mode of action has revealed an entirely new level of gene regulation. The abnormal expression profiles of miRNAs have been examined in many different cancers including breast cancer [3,4] and their roles in the proliferation, apoptosis, invasion/metastasis and angiogenesis of normal and cancer cells are being investigated aggressively [5,6,7,8,9]. Its role in breast cancer is unknown
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