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Adam12 and lnc015192 act as ceRNAs in breast cancer by regulating miR-34a

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE111587 | GEO | 2018/08/01

REPOSITORIES: GEO

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Project description:Previous studies have evaluated the role of miRNAs in the initiation and progression of cancer. MiR-34a was found to be downregulated in several tumors, including medulloblastoma. We here analysed the function of miR-34a in vivo by targeted transgenesis to generate mice with constitutive deletion of the miR-34a gene, which resulted in the absence of mir-34a in all analysed tissues. Nevertheless, these mice were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters performed by the German Mouse Clinic revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significant downregulation as compared to human cerebellum. Re-expression of mir-34a in human medulloblastoma cells in vitro reduced cell viability, cell proliferation and induced apoptosis. Among the targets downregulated by miR-34a in human medulloblastoma cells were NMYC and SIRT1. Activation of the Shh pathway by targeted overexpression of SmoA1 causes medulloblastoma in mice, which is dependent on the presence and upregulation of NMYC. Analysis of miR-34a in ND2:SmoA1-derived medulloblastomas revealed significant suppression of miR-34a compared to normal cerebellum. Crossbreeding these mice with miR-34a knockout mice significantly accelerated medulloblastoma growth in mice deficient for miR-34a. Interestingly, NMYC and SIRT1 were highly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastoma. Strategies aiming to re-express miR-34a in tumors could therefore represent an efficient therapy option. For genome-wide expression analysis total RNA from brain and thymus of three or four male miR34a and four control mice was isolated using RNeasy Midi kit (Qiagen, Hilden, Germany). The cDNA microarrays were generated, hybridized and analysed as described (Horsch et al 2009). Two chip hybridizations were performed with total RNA for each individual mutant mouse against a reference RNA pool of the same organ.

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Adam12 and lnc015192 act as ceRNAs in breast cancer by regulating miR-34a

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