The microRNAs, or miRNAs, control global protein output, by regulating translation of protein coding genes. During the last five years many groups, including ours, have been actively involved in the discovery of miRNA deregulation in cancer cells. Now much of the effort is focused on the elucidation of functional miRNA pathways and therefore on the identification of key miRNA targets. miRNA can be either regulating, or regulated by, cancer genes: in fact protein targets have been revealed for some cancer miRNAs (i.e. miR-17/92, miR-21) and in other instances miRNAs have been positioned downstream of pivotal tumor proteins (i.e. miR-34 and p53). Typically, each miRNA has been studied for its single contribution to differential expression or to predictive molecular signatures. But the effects of microRNAs are likely to be complex for two reasons: 1) the action of miRNA activity is exerted in a one-to-many fashion, i.e. each miRNA can control translation of tens or even hundreds of different coding messenger RNAs; 2) conversely, each single protein-coding mRNA can be controlled by more than one non-coding miRNA. Therefore, we propose a paradigm shift to the study of miRNAs role in cancer by applying a “whole cell” systems biology approach. We will build a miRNA gene network by using both public and a large body of unpublished expression datasets. In primis, we will infer a network reflecting the miRNome of normal cells and tissues. Preliminary results demonstrating the feasibility and information content of such a network are included in this grant application. The complete miRNA network in normal tissues will be the first goal of our project and will become our reference. To date no such genetic network is known, thus our work is of absolute novelty. In parallel, we will build miRNA networks relative to different oncologic conditions. By comparing the reference normal network to the cancer networks we will reach the second goal of our work: the identification of the variations in miRNA networks relating to cancer states. We will infer networks for each step in cancer progression: from benign tumors to overtly metastatic states. Third, we will revise and assay the miRNA re-programming events identified during the project in cancer and leukemia by using both bioinformatics and molecular/cellular techniques. Cellular assays will test the true extent of these miRNAs’ function, cooperation and target genes. The aim of our proposal is in fact that of unravelling the critical and coordinated steps in the miRNA program required to express the full pathological potential of cancer cells.
The genetic network of microRNAs in cancer
VOLINIA, Stefano
2009
Abstract
The microRNAs, or miRNAs, control global protein output, by regulating translation of protein coding genes. During the last five years many groups, including ours, have been actively involved in the discovery of miRNA deregulation in cancer cells. Now much of the effort is focused on the elucidation of functional miRNA pathways and therefore on the identification of key miRNA targets. miRNA can be either regulating, or regulated by, cancer genes: in fact protein targets have been revealed for some cancer miRNAs (i.e. miR-17/92, miR-21) and in other instances miRNAs have been positioned downstream of pivotal tumor proteins (i.e. miR-34 and p53). Typically, each miRNA has been studied for its single contribution to differential expression or to predictive molecular signatures. But the effects of microRNAs are likely to be complex for two reasons: 1) the action of miRNA activity is exerted in a one-to-many fashion, i.e. each miRNA can control translation of tens or even hundreds of different coding messenger RNAs; 2) conversely, each single protein-coding mRNA can be controlled by more than one non-coding miRNA. Therefore, we propose a paradigm shift to the study of miRNAs role in cancer by applying a “whole cell” systems biology approach. We will build a miRNA gene network by using both public and a large body of unpublished expression datasets. In primis, we will infer a network reflecting the miRNome of normal cells and tissues. Preliminary results demonstrating the feasibility and information content of such a network are included in this grant application. The complete miRNA network in normal tissues will be the first goal of our project and will become our reference. To date no such genetic network is known, thus our work is of absolute novelty. In parallel, we will build miRNA networks relative to different oncologic conditions. By comparing the reference normal network to the cancer networks we will reach the second goal of our work: the identification of the variations in miRNA networks relating to cancer states. We will infer networks for each step in cancer progression: from benign tumors to overtly metastatic states. Third, we will revise and assay the miRNA re-programming events identified during the project in cancer and leukemia by using both bioinformatics and molecular/cellular techniques. Cellular assays will test the true extent of these miRNAs’ function, cooperation and target genes. The aim of our proposal is in fact that of unravelling the critical and coordinated steps in the miRNA program required to express the full pathological potential of cancer cells.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
