Adam12 and lnc015192 act as ceRNAs in breast cancer by regulating miR-34a
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ABSTRACT:
PROVIDER: PRJNA437473 | ENA |
REPOSITORIES: ENA
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Project description:Long non-coding RNAs (lncRNAs) are involved in the pathology of various tumors. However, the role of lncRNA in breast cancer remains unclear. We performed microarrays to identify the differentially expressed mRNAs and lncRNAs in breast tissues with or without miR-34a knockout. In vitro and in vivo assays were preformed to explore the biological effects of the differentially expressed mRNA and lncRNA in breast cancer cells. We found that Adam12 and lnc015192 were significantly upregulated in miR-34a knockout breast tissues. Knockdown of Adam12 and lnc015192 inhibited breast cancer cells migration, invasion and epithelial-mesenchymal transition (EMT) in vitro and in vivo. Further study indicated that lnc015192 acted as a competing endogenous RNA (ceRNA) for miR-34a to regulate Adam12 expression. Taken together, our findings demonstrate how Adam12 and lnc015192 induce breast cancer metastasis and offer novel therapeutic targets for breast cancer.
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Project description:MicroRNAs (miRNAs or miRs) are small, noncoding RNAs that are implicated in the regulation of nearly all biological processes. Global miRNA biogenesis is altered in many cancers and RNA-binding proteins (RBPs) have been shown to play a role in this process, presenting a promising avenue for targeting miRNA dysregulation in disease. miR-34a exhibits tumor-suppressive functions by targeting cell cycle regulators CDK4/6 and anti-apoptotic factor Bcl-2, among other regulatory pathways such as Wnt, TGF-, and Notch signaling. Many cancers show downregulation or loss of miR-34a, and synthetic miR-34a supplementation has been shown to inhibit tumor growth in vivo; however, the post-transcriptional mechanisms by which miR-34a is lost in cancer are not entirely understood. Here, we have used a proteomics-mediated approach to identify Squamous cell carcinoma antigen recognized by T-cells 3 (SART3) as a putative pre-miR-34a-binding protein. SART3 is a spliceosome recycling factor and nuclear RBP with no previously reported role in miRNA regulation. We demonstrate that SART3 binds pre-miR-34a with specificity over pre-let-7d and begin to elucidate a new functional role for this protein in non-small lung cancer cells. Overexpression of SART3 led to increased miR-34a levels, downregulation of the miR-34a target genes CDK4 and CDK6, and cell cycle arrest in the G1 phase. In vitro binding studies showed that the RNA-recognition motifs within the SART3 sequence are responsible for selective pre-miR-34a binding. Collectively, our results present evidence for an influential role of SART3 in miR-34a biogenesis and cell cycle progression.
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