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Researchers ID MicroRNA Signatures Involved in Cancer Progression

NEW YORK (GenomeWeb News) – MicroRNA signatures shift on the road to multiple myeloma, new research suggests, altering the expression of proteins involved in oncogenesis and malignancy.
A team of American and Italian researchers used a genome-wide approach to search for miRNA signatures associated with multiple myeloma. The findings, appearing online this week in the Proceedings of the National Academy of Sciences, indicate that specific miRNAs herald myeloma progression — from normal blood plasma cells to a benign condition that can precede myeloma to multiple myeloma itself. These patterns, in turn, can reveal biological pathways involved in myeloma development and progression.
“Our findings define an miRNA signature related to expression and regulation of proteins associated with malignant transformation of [plasma cells],” the authors wrote. “These results indicate an additional level of control by this class of regulatory molecules in the multistep process associated with malignant transformation of [plasma cells].”
Multiple myeloma, a blood cancer that affects a group of white blood cells called plasma cells, has been linked to several complex genetic changes including chromosomal translocations, duplications, or deletions.
Plasma cells have a role in immune system function, eventually going on to produce antibodies. Individuals with multiple myeloma have abnormal, malignant plasma cells, making them susceptible to bacterial infections, fatigue, bone pain or breaks, and anemia.
In some cases, the condition appears to arise spontaneously. In others it starts as a condition known as monoclonal gammopathy of undetermined significance, or MGUS. In an effort to understand the series of steps and pathological events occurring in the transition from normal plasma cells to MGUS to myeloma, the researchers focused on the miRNA profile of each.
Because these non-coding RNAs help regulate biological processes by preventing translation of specific messenger RNAs, the team suspected that miRNAs might play a role in this transition — and provide clues about the pathways that become altered during plasma cell malignancy.
And, the author noted, understanding miRNA profiles in each cell type could reveal new avenues for myeloma treatment. “[F]urther studies are needed to identify critical pathways in [multiple myeloma] pathogenesis that could be targeted by pharmacological intervention to improve outcomes for this still incurable disease,” they wrote.
Using a combination of miRNA microarrays and quantitative real time PCR, the researchers captured snapshots of the miRNA expression in multiple myeloma cell lines and patient samples. They compared these with the miRNAs present in plasma cells representing MGUS and normal plasma cells lines.
They discovered distinct miRNA profiles in each of the conditions, with MGUS and myeloma cells sharing some miRNAs that were absent under normal conditions. For example, the researchers identified 41 miRNAs that were up-regulated in MGUS cells compared to normal plasma cells and seven that were down-regulated.
Among the miRNAs that were up-regulated during MGUS: miR-21, miR-181a, and the miR-106b~25 — miRNAs that have been previously linked with multiple myeloma, B and T cell differentiation, and oncogenesis, respectively.
While MGUS and myeloma cells both exhibited up-regulation of miR-21 and other shared miRNA, the expression of other miRNA differed between the two conditions. For instance, the switch from benign to malignant cells coincided with up-regulation of miR-32 and the miR-17~92 cluster.
Within the myeloma-specific miR-17~92 cluster, the researchers noted, two miRNAs — miR-19a and miR-19b — are dramatically up-regulated during multiple myeloma. These miRNAs appear to be capable of down-regulating a gene called SOCS-1. Because SOCS-1 silencing has been linked to multiple myeloma in the past, the researchers speculated that SOCS-1 silencing might activate pathways that lead to myeloma progression.
Similarly, the researchers were able to make predictions about other miRNA targets and use that information to begin unraveling other multiple myeloma pathways. They also began testing hypotheses about myeloma-related pathways by antagonizing some of the miRNAs identified in the study. For instance, they found that antagonizing miR-19a and b and miR-181a and b in mice containing human myeloma cells decreased tumor growth in these animals.
“These data may suggest that miRNAs could have a therapeutic potential in antagonizing the growth of transformed [plasma cells],” the authors wrote.

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