As work accelerates in the field of microRNAs, it is becoming increasingly apparent that these small RNAs play a significant role in various biological processes.
Last November, Rockefeller Universityâ€™s Markus Stoffel published in Nature data demonstrating that the evolutionarily conserved and islet-specific microRNA miR-375 regulates insulin secretion. Two months later, Whitehead Institute researcher David Bartel published data in Cell suggesting that miRNAs may be responsible for regulating up to one-third of all human genes (see RNAi News, 1/21/2005).
Now ,a researcher a Yale University has shown that the let-7 miRNA may help suppress lung cancer in humans, and is hoping his work will attract the interest of drug developers.
Frank Slack, assistant professor in the department of molecular, cellular, and developmental biology at Yale, has published a paper in this weekâ€™s Cell indicating that let-7 may act as a tumor suppressor through its inhibition of the human oncogene RAS.
According to Slack, this research began last year through a collaboration with Mark Gerstein, a bioinformaticist at Yale, to develop an algorithm to predict miRNA targets. â€œWe supplied him with some rules, and his lab generated an algorithm that would search 3â€™ UTRs in all C. elegans genes,â€ he told RNAi News this week. This work was published last week in Developmental Cell.
Slack used Gersteinâ€™s algorithm to identify C. elegans RAS as a potential target for the let-7 miRNA. â€œFollowing a series of genetic experiments and some reporter-gene analyses, we were able to validate that, in fact, RAS was very likely to be a target of the microRNA,â€ Slack said.
â€œThis was satisfying to us because it explained why the let-7 microRNA has the phenotype that it does if you knock it out â€" in various cells in C. elegans, if you can knock out let-7 microRNA, the cells fail to stop dividing and they donâ€™t â€¦ differentiate when they should.â€
Based on his observations in C. elegans, Slack took the next logical step and looked to see if similar results could be obtained in human cells.
â€œThe fact that cells continued to divide in let-7 mutants suggested that [the microRNA] was somehow involved in repressing the cell cycle, and that if there was a human equivalent [microRNA] it would perhaps be a tumor suppressor,â€ Slack explained. â€œWe looked at human RAS genes â€¦ and we were able to [determine that] human RAS was regulated by human let-7.â€
Slack added that he and his colleagues at Yale were particularly pleased with these data because â€œthe initial observations were made in a simple model organism, and we were able to show â€¦ that what we observed [in C. elegans] was even true in human cells. Even more satisfying was [the fact that] we were able to connect our findings with some observations that the gene we were studying â€¦ was involved in various cancers.â€
Specifically, it appears that let-7 may play a role in lung cancer, according to the Cell paper.
â€œAt the same time we were doing our work, David Brown, [a senior scientist] at Ambion [and] collaborator on [the Cell] paper, was performing microRNA-profiling experiments,â€ Slack explained. Brown and colleagues at Ambion â€œbuilt a chip that has all of the known microRNAs on it.â€ With RNA samples from tumors and normal adjacent tissue, they used the chips to â€œidentify microRNAs that were misregulated in the tumor relative to the normal tissue,â€ Slack said.
â€œThey found that let-7 in particular was consistently down-regulated in lung cancer,â€ he said, noting that the tumor samples were taken from patients with squamous cell carcinoma.
â€œWhat we were able to show with David Brown was that whenever let-7 is down in these tumors, RAS is up-regulated,â€ he said. â€œThere was a negative correlation between the presence of let-7 and the presence of RAS.â€
Slack said that these observations suggest that a potential therapy for cancers associated with RAS expression, such as lung cancer, might be found in let-7. Late last year â€œwe [took] out a provisional patent on the idea of using microRNAs to control oncogenes like RAS, and weâ€™re looking for an industry partner to take that forward,â€ he said.
â€œAmbion hasnâ€™t shown any interest in that,â€ he noted, adding that Yaleâ€™s technology-transfer office has been â€œsending feelers out to various companies to see if theyâ€™re interested, and I believe some companies have asked to see the patent.â€
In the meantime, Slack said his lab is in the process of exploring whether administering let-7 to mice with RAS mutations can stop tumor growth. â€œIf that works, I think [the technology] has a good chance of some company picking it up.â€ He said that he expects data from these experiments to start being ready around the end of the year.