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Team IDs MicroRNA Network Differences in Cancer, Normal Tissues

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – MicroRNA expression networks tend to become more fragmented in cancerous tissues than in healthy tissues, according to a study appearing in the latest issue of Genome Research, with the extent and nature of miRNA network changes varying by tissue and cancer type.

An international research team used miRNA expression data on more than 4,400 cancer or normal tissue samples to come up with networks outlining genetic interactions between miRNAs in 50 normal tissues and 51 cancer types. Their findings suggest miRNA networks tend to be more cohesive and well connected in normal tissues, whereas cancer miRNA networks — particularly those in solid tumors — are often rewired to create breakaway sub-networks of miRNAs.

"In solid cancers there can be a few, or more, groups of such misbehaved miRNAs, while in leukemias we found only one or two," senior author Carlo Croce, director of the human cancer genetics program at Ohio State University's Comprehensive Cancer Center, said in a statement. "The miRNAs we discovered can now be used as targets for drug development, or to pinpoint candidate proteins, which, in turn, they regulate."

Several studies have implicated specific miRNAs or small sets of RNAs in cancer, the researchers noted. But much of the evidence so far has come from research on individual miRNAs in isolation rather than as part of an inter-related system.

"MicroRNAs were always considered as singles, generally unrelated to each other in the miRNA world," Croce said. "We did not know much about how miRNAs cooperate."

In an effort to get a better sense of these interactions, the researchers used a clustering algorithm to develop genetic networks based on miRNA expression data for 4,419 samples: including 2,532 solid cancer and 780 leukemia samples representing 51 cancer types and 1,107 normal samples representing 50 tissues.

Indeed, the team found that the overall structure of the networks and the individual miRNA interactions varied depending on tissue and cancer type.

Among the most commonly rewired miRNAs were some previously that were either implicated in cancer itself or in governing processes that tend to go amiss in cancer, such as signal transduction.

And whereas miRNAs typically fell into single, complete networks in normal tissues, the researchers explained, miRNAs in the cancer samples formed what they call "disjointed" networks with disconnected miRNA sub-groups. At the same time, the most connected or "hub" miRNAs shifted in the cancers relative to normal tissues.

"Groups of miRNAs go awry and exit from the 'social network' altogether," Croce said in a statement.

In general, the researchers found more extensive re-wiring in solid cancer networks than in leukemia networks, which they suspect might be a consequence of "diverging pathogenetic mechanisms that include differing oncogenic miRNA networks" in solid cancers and leukemia. "In the former complex chromosomal rearrangements are frequent," they wrote, "whereas in the latter translocations often represent the major driving force."

The researchers also began investigating how copy number changes relate to miRNA network patterns for a subset of the cancer samples. Down the road, they also plan to integrate miRNA network information with cell signaling pathway patterns to get a more complete picture of how these processes interact in cells from normal tissues and in various types of cancer.

Together, such findings are expected to provide a better understanding of the cellular processes that are altered in cancer and reveal potential targets for combating these changes.

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