Saturday, June 2, 2007

Journal Club: MicroRNA-34a is a Major Contributor to p53-mediated Apoptosis- Diagnostic and Therapeutic Implications

In the latest issue of Molecular Cell, two separate groups report in back-to-back featured papers the discovery of miR-34a as a major contributor to p53-mediated apoptosis (Raver-Shapira et al. DOI: 10.1016/j.molcel.2007.05.017; Chang et al. DOI: 10.1016/j.molcel.2007.05.010). It is increasingly becoming clear that microRNAs play key regulatory roles in cancer and these studies contribute to our understanding of the mechanistic role of individual microRNAs. This opens up the prospect to use microRNAs both as diagnostics and therapeutics in cancer care management. Additionally, p53 function is implicated in many forms of cancer and a better understanding of how this “guardian of the genome” acts is desirable further informing treatment strategies.

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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By Dirk Haussecker. All rights reserved.

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