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MiR-155 regulates the ability of circulating cancer cells to colonize and establish metastasis

ABSTRACT: Abstract: Metastases are established through a complex multistep process by which tumor cells disseminate from the primary tumor and expand at distant sites. Traditionally, studies on metastasis have focused on proteins and protein-coding genes, but recently microRNAs (miRNAs) have achieved increasing interest. miRNAs involved in the metastatic process are poorly defined, and while the use of clinical tissue samples or in vitro assessment for study of the first phases of the metastatic process is not feasible; such processes may be studies using in vivo models created by inoculation of human cell lines into mice. We have used such a model system consisting of three isogenic human cancer cell lines that are equally tumorigenic in mice, but while two of these cell lines give rise to metastasis at different rates, the last one disseminates single cells that remain dormant in distant organs. Using a global LNA- based miRNA microarray platform, 28 miRNAs were found to be significantly altered between the metastatic and non-metastatic cell lines, with mir-155 being the miRNA exhibiting the largest difference in expression level and central in a network analysis. Examining the potential targets of miR-155 identified calumenin, solute carrier family 26 (sulfate transporter) member 2 (SLC26A2), Integrin αV, and CD73, which showed an inverse expression pattern to miR-155 in the metastatic and non-metastatic cell lines as determined by immunocytochemical staining. The miRNAs identified in this study could be markers of the ability of cancer cells to colonize at distant organs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE37719 | GEO | 2012/05/03

SECONDARY ACCESSION(S): PRJNA163093

REPOSITORIES: GEO

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Project description:MicroRNAs (miRNAs) are small (21-25 nucleotide in length) non-coding RNA molecules that negatively regulate protein expression. They are linked to cancer development and maintenance. In this work, studying gene expression profiles of 340 mammalian miRNAs with DNA microarrays, we selected 10 miRNAs gene features able to distinguish primary from secondary glioblastoma type; furthermore we verified that miR-21 and miR-155 up-regulatation seems to characterize the glioblastoma tumour state since it was found up-regulated in all samples analyzed compared to adult brain noneoplastic tissue. Since miR-21 function in glioblastoma cells was addressed previously we concentrated our efforts on miR-155 function. We found that miR-155 levels were markedly elevated both in primary and secondary glioblastomas tumours, in glioblastoma cell cultures and in 4 glioblastoma cell lines (U87, A172, LN229, and LN308) compared with adult brain tissue, CHP212-neuroblastoma cell lines and DAOY-1-medulloblastoma cell line. Since one of the miR-155 target was gamma-aminobutyric acid (GABA) A receptor (GABRA1) we verified if there was a relation between miR-155 up-regulation and GABRA1 expression. We demonstrated that, in cultured glioblastoma cells, knockdown of miR-155, which lower miR-155 expression to normal level, restore the normal expression of the gamma-aminobutyric acid (GABA) A receptor (GABRA1), making glioblastoma cells responsive to GABA cell cycle inhibiting signals. Our data suggest that aberrantly over-expressed miR-155 contribute to the malignant phenotype of the glioblastoma cells, promoting their unlimited growth. Keywords: miRNA expression profile We studied the expression profiles of 340 miRNAs in 97 glioblastoma tissues, of which 66 were primary glioblastomas and 27 were secondary glioblastomas. We have 66 replicates of primary glioblastoma and 27 replicates of secondary glioblastoma, each hybridized with the respective adult non-neoplastic brain tissue as a control.

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MiR-155 regulates the ability of circulating cancer cells to colonize and establish metastasis

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