Study shows microRNA let-7 plays a key role in restricting neuroblastoma -
Much progress has been made in the treatment of neuroblastoma, the most common cancer infants and toddlers. But advanced cases are often fatal, and children who survive often face physical challenges and long intellectual life related to their treatment. A study by researchers at Dana-Farber / Cancer and Blood Disorders Children's Center in Boston, believes that a microRNA called let-7 plays a central role in the fight against neuroblastoma and could concentrate its efforts to find a target, non-toxic alternative to chemotherapy.
Published by Nature (Advance online) July 6, the study unifies several theories about neuroblastoma and has implications for other solid tumors where let-7 is lost as Wilms' tumor, lungs also, breast, ovarian and cervical cancers, says first author John Powers, Ph.D., of the Division of hematology / oncology pediatric Hospital Boston children .
the let-7 family of microRNAs (bits of genetic code that regulate genes) is known to be involved in the differentiation of stem cells and tumor suppression. Recent research has involved LIN28B, a protein that inhibits let-7 maturation in neuroblastoma. But the new study, by work on cells and data analysis of neuroblastoma patients, found that LIN28B is only one of cancer mechanisms that involve let-7 deletion.
"We show that inhibition of let-7 is the heart of the development of this disease," says Powers. "So critical in fact that neuroblastoma uses at least three different ways to eliminate it."
Powers and colleagues first demonstrated that the genetic amplification of MYCN oncogene - producing thousands of copies of its mRNA - helps to sequester neuroblastoma let-7, apart from the traffic.
"children with MYCN-amplification event, which occurs in about 25 percent of cases, have the poorest prognosis," says Powers, a senior researcher in the laboratory of George Q. Daley, MD , PhD, director of the stem Cell transplantation program at Dana-Farber / Boston children. "a big question in the search for neuroblastoma was, why do you need so MYCN mRNA? We found that MYCN is expressed at high levels it is able to absorb otherwise functional let-7. "
Second, the researchers showed that chromosomal deletions associated with neuroblastoma (in 11q regions and 3p) are home to several let-7 family members and that the genetic loss of let-7 tracks also with poor results.
"genetic loss of let-7 has not been widely appreciated in neuroblastoma," says Powers. "people knew about chromosomal losses and sought a tumor suppressor, but they were mainly looking for genes encoding proteins, microRNAs not. "
Interestingly, data from 202 patients with neuroblastoma have shown that loss of chromosome let -7 rarely occurred in patients with MYCN amplification. Both events promote cancer, both repress let-7 were almost mutually exclusive, which means most of the involved neuroblastoma either.
"From the perspective of cancer, you have to deal with let-7," Powers said. "If not amplified MYCN is, the tumor instead just loses it genetically. In both cases, let-7 is attenuated. "
Similarly, if let-7 is removed by chromosomal loss, MYCN amplification is unnecessary for the cancer to spread." Once the tumor disrupted let-7 genetically, it does not need to amplify MYCN because he did not need a sponge let-7, "Powers said.
Powers believes that the strategies the 7 letters of restoration could provide a new approach to low toxicity to neuroblastoma and other cancers in which let-7 is lost. Let 7 itself could potentially be a drug, if supply problems (common to all RNA treatments) can be overcome.
The results of the team, if replicated in a larger number of patient samples, could also help establish genetic typing of neuroblastoma, predict disease severity based on LIN28B levels, loss let-7 gene and MYCN amplification and perhaps guide a precision medicine approach.
Powers also hope to apply the results to create better mouse models of neuroblastoma. Current models do not take account of let-7, he said.
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