Reprogramming of miRNA networks in cancer and leukemia

Abstract

We studied miRNA profiles in 4419 human samples (3312 neoplastic, 1107 nonmalignant), corresponding to 50 normal tissues and 51 cancer types. The complexity of our database enabled us to perform a detailed analysis of microRNA (miRNA) activities. We inferred genetic networks from miRNA expression in normal tissues and cancer. We also built, for the first time, specialized miRNA networks for solid tumors and leukemias. Nonmalignant tissues and cancer networks displayed a change in hubs, the most connected miRNAs. hsa-miR-103/106 were downgraded in cancer, whereas hsa-miR-30 became most prominent. Cancer networks appeared as built from disjointed subnetworks, as opposed to normal tissues. A comparison of these nets allowed us to identify key miRNA cliques in cancer. We also investigated miRNA copy number alterations in 744 cancer samples, at a resolution of 150 kb. Members of miRNA families should be similarly deleted or amplified, since they repress the same cellular targets and are thus expected to have similar impacts on oncogenesis. We correctly identified hsa-miR-17/92 family as amplified and the hsa-miR-143/145 cluster as deleted. Other miRNAs, such as hsa-miR-30 and hsa-miR-204, were found to be physically altered at the DNA copy number level as well. By combining differential expression, genetic networks, and DNA copy number alterations, we confirmed, or discovered, miRNAs with comprehensive roles in cancer. Finally, we experimentally validated the miRNA network with acute lymphocytic leukemia originated in Mir155 transgenic mice. Most of miRNAs deregulated in these transgenic mice were located close to hsa-miR-155 in the cancer network

Interleukin-27 inhibits pediatric B-acute lymphoblastic leukemia cell spreading in a preclinical model

“…As shown in Figure 2d Finally, we tested the ability of IL-27 to modulate the expression of a set of miRNA implicated in human tumorigenesis. [21][22][23] These experiments showed that IL-27 treatment caused downregulation of miR-155 in all B-ALL cell samples tested (5 to 13.5-fold, Figure 2e). Downregulation of miR301, 222 and let7e and upregulation of miR212 and 148b was also observed in two or three samples (not shown), whereas all the other cancerrelated miRNAs included in the PCR array kit were not significantly modulated (not shown).…”

Clinical and prognostic significance of miR-155 and miR-146a expression levels in formalin-fixed/paraffin-embedded tissue of patients with diffuse large B-cell lymphoma

“…miR-146a expression levels were up-regulated in miR-155 transgenic mice when compared to the control wild-type mice. This suggests that miR-155 and miR-146a are involved in one complex microRNA network (35).…”

Integrative nucleophosmin mutation-associated microRNA and gene expression pattern analysis identifies novel microRNA - target gene interactions in acute myeloid leukemia

“…Furthermore, a recent study inferring miRNA networks from miRNA expression data in normal tissue or cancer also suggested a link between the miR-29 and miR-30 family. 42 In normal tissue as well as in AML, the expression patterns of miR-29 and miR-30 family members are closely related, thereby implying co-regulation and a potential collaborative tumor-suppressor mechanism. Therefore, a miRNA-based therapy using miR-30c, as already suggested for the miR-29 family, 18 and its ability to induce chemosensitivity, might be an interesting approach for the treatment of AML.…”