Saturday, June 2, 2007
Journal Club: MicroRNA-34a is a Major Contributor to p53-mediated Apoptosis- Diagnostic and Therapeutic Implications
Both groups set out to discover p53-regulated microRNAs by comparing microRNA profiles of p53-containing with p53-deficient cell lines, and found that miR-34a is particularly responsive to the presence of p53. Identification of functional p53 binding sites then confirmed that p53 directly acts as a transcriptional regulator of miR-34a expression. Through microRNA-inhibition and overexpression strategies both groups finally come to the conclusion that the p53-dependent response to genotoxic (= carcinogenic) insult is significantly effected by miR-34a activation which in turn regulates a number of genes involved in programmed cell death (apoptosis) and cancer progression. Strikingly, a major importance of miR-34a in mediating this response is further suggested by the finding by Joshua Mendell’s group (Chang et al.) that in all the 15 pancreatic cancer cell lines tested, miR-34a was significantly downregulated or even deleted.
These findings have important implications for the development of microRNAs both as diagnostics and cancer therapeutics. As such, the status of miR-34a could be used to predict the response of a tumour to a chemotherapeutic agent. miR-34a may also be used as part of microRNA diagnostics measuring a number of microRNAs for cancer screening purposes. Profiles showing low miR-34a may be indicative of the presence of a tumour. Maybe most intriguing would be the delivery of miR-34a mimics, either as synthetic siRNAs or in expressed form, to promote the apoptosis of cancer cells. Tt remains to be seen, however, which cancer types respond best to such a strategy and different degrees of efficiencies were reported in the different model systems used in the two papers.
A handful of companies may be interested in converting these ideas into real products. Rosetta Genomics (ticker: ROSG), a microRNA company of Israel, is certainly one of them and was heavily involved in the Shapira-Raver et al. studies. This company is founded on the discovery of proprietary microRNAs and have further licensed other microRNAs for diagnostic purposes from other institutions, most notably the Max-Planck Institutes of Germany, the Rockefeller and the MIT. It is not clear to me, however, who claims the rights to miR-34a, possibly the MIT given that David Bartel’s group first reported miR-34a following bioinformatic predictions (Lim et al. Science 299: 1540). Among other projects, Rosetta is currently developing microRNA diagnostics for Cancers of Unknown Primary (CUP) and pancreatic cancer diagnostics, the latter in collaboration with Asuragen, a privately held company of Austin, Texas. As these in-licensed microRNAs, however, are for diagnostic purposes only, it is well possible that other RNAi companies will get involved in miR-34a-based RNAi Therapeutics, as miR-34a would essentially be delivered in the form of RNAi effectors. David Bartel and the MIT e.g. have a close relationship with Alnylam (ticker: ALNY), which in turn owns many of the fundamental RNAi patents and therapeutic rights to many important microRNAs discovered by their scientific co-founder Thomas Tuschl of Rockefeller University.
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