Unknown,Transcriptomics,Genomics,Proteomics

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DOCK1 gene derived hsa_circ_0020397 RNA is over-expressed in luminal mammary tumors and it is involved in the epithelial differentiation, growth and motility of the neoplastic cell

ABSTRACT: Circular-RNAs are an emerging group of regulatory molecules involved in the control of numerous cellular processes and may play a role in the growth and diffusion of various types of tumors. In the present study, we define the expression of 15 selected circular-RNAs, which may be involved in the process of epithelial-to-mesenchymal-transition, using a panel of 18 breast cancer cell-lines recapitulating the heterogeneity of the tumor and consisting of three distinct groups according to the mesenchymal/epithelial phenotype. The circular RNA deriving from the DOCK1 gene (hsa_circ_0020397) is characterized by the most interesting expression profile, as it is undetectable in triple-negative mesenchymal cell-lines, while it is easily measurable in epithelial cell-lines independent of their positivity to estrogen receptor or the HER2 membrane receptor. Whole-genome RNA-sequencing experiments performed on the triple-negative/mesenchymal MDA-MB-231 and MDA-MB-157 cell-lines engineered to over-express hsa_circ_0020397 demonstrate that the circular-RNA controls the expression of 110 common genes. Pathway analysis of these genes indicate that over-expression of the circular-RNA differentiates the two mesenchymal cell-lines along the epithelial pathway and increase cell-to-cell adhesion. This is accompanied by a growth inhibitory effect and a reduction in the random/directional motility of the two cell-lines. The up-regulated AGR2, ENPP1 and PPP1R9A genes as well as the down-regulated APOE, AQP3, CD99L2 and IGFBP4 genes show an opposite regulation by circDOCK1 silencing in CAMA1 luminal cells.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER: Marco Bolis

PROVIDER: E-MTAB-10819 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Vascular endothelial growth factor is a multifunctional cytokine playing important roles in angiogenesis, tumor progression and metastasis. Alternative splicing results in the production of several different isoforms of VEGF. We have previously generated human breast cancer cells overexpressing VEGF165 or VEGF189 isoforms (referred to as the V165 and V189 clones, respectively) and showed that VEGF189-transfected cells were less tumorigenic. In this study, we used bioluminescence imaging to analyze the metastasis capacity of breast cancer cell lines (MDA-MB-321) overexpressing VEGF isoforms in nude mice. V165, V189 and control cV clones were transfected with a luciferase plasmid to generate bioluminescent clones (the V165-B, V189-B and cV clones, respectively). These clones were then injected into the left heart ventricle of nude mice. Analysis of the location of metastases shows that V189-B cells induced fewer metastases in lung and bone than V165-B and cV-B cells. Moreover, there was a delay on metastasis appearance in mice receiving VEGF V189-B clone, consistent with increase survival in these mice. We investigated the possible mechanisms underlying these effects and found that VEGF189 increased adhesion and decreased cell invasion and survival in vitro. In the other side, transcriptomic analyses shown expression of genes, implicated in breast cancer and metastatic dissemination, in VEGF165 overexpressing cells. After in silico analyses of genes differentially expressed between V189 and V165 cells,we used Q-PCR assays to quantify mRNA levels of some gene of interest in 120 breast tumors from patients with or without metastasis and/or specially lung metastasis. We found that genes have prognostical significance and /or showed an influence on relapse-free survival. These data provide the first evidence that different VEGF isoforms have different effects on breast cancer cell line invasion and colonization. Human MDA-MB-231 breast cancer cells were used to generate stable transfected clones overexpressing VEGF165 isoform, VEGF189 isoform, or control vector (referred to as 42ctl8, 13ctl3 and PCIctl3, respectively). Analysis of the metastasis capacity of these clones in nude mice.

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DOCK1 gene derived hsa_circ_0020397 RNA is over-expressed in luminal mammary tumors and it is involved in the epithelial differentiation, growth and motility of the neoplastic cell

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