Tumorigenesis: Keeping a good thing down

signaling update home

SOURCE:

Myc-induced tumorigenesis causes widespread repression of microRNAs, suggesting that re-expression of microRNAs could block the growth of Myc-positive tumors.

Previous papers have reported the capacity of the oncogene MYC to increase the expression of the microRNA (miR) cluster miR-17–92. However, Andrei Thomas-Tikhonenko, Joshua Mendell and colleagues now show that widespread repression of miRs seems to be the norm during MYC-induced tumorigenesis.

Using two models of MYC-induced tumorigenesis — human P493-6 B cells that are immortalized with Epstein–Barr virus and express a tetracycline-regulated form of MYC, and lymphomas formed by mouse p53-null bone-marrow cells that are infected with a MYC–oestrogen receptor (ER) retroviral construct, in which the MYC protein is regulated by tamoxifen — the authors analysed the fate of miR expression in conditions of high and low MYC activity using custom-built miR microarrays from human and mouse. Surprisingly, most miRs were downregulated in both models, with only the miR-17–92 cluster being consistently upregulated.

To further confirm these findings the authors analysed miR expression in P493-6 cells and MYC–ER tumours under conditions of high and low MYC expression using RNA blots. Because many of the miRs are encoded by several related transcripts, the authors developed stringent conditions in order to detect individual family members. In addition, they analysed expression levels of miRs in human tumours using previously published microarray profiles from MYC-expressing Burkitt lymphoma cells. These experiments consistently showed miR repression in response to MYC.

MYC is known to bind to specific gene promoters to repress their transcription. Using a complex series of chromatin immunoprecipitation (ChIP)- and PCR-based approaches the authors were able to show that MYC bound to the 5' end (most probably the promoters) of 11 out of 16 of the sequences encoding the repressed miRs.

So, why are these miRs repressed? To assess this, the authors used retroviral green fluorescent protein (GFP) constructs to re-express individual miRs in either p53-null mouse bone-marrow cells expressing MYC or murine lymphomas expressing the oncogene v-abl. Infection rates were kept to 50% of cells, as determined by GFP expression, and a mixture of GFP-positive and GFP-negative cells were injected into immunocompromised mice. In theory, if the re-expression of an miR suppresses MYC-induced (or v-abl-induced) tumorigenesis, then fewer GFP-positive cells should be present in resulting tumours. Indeed, this was observed in tumours that ectopically expressed miR-34a, miR-150, miR-195/miR-497 and miR-15a/miR-16-1. Interestingly, expression of these miRs repressed growth in both MYC- and v-abl-expressing cells, whereas miR-26a inhibited only MYC-expressing cells and miR-22 only v-abl-expressing cells. Therefore, several of the miRs that MYC represses can suppress tumour growth.

These findings indicate that further studies on the effects of MYC and other oncogenes on the expression of miRs during tumorigenesis are warranted. They also indicate that re-expression of specific miRs could have therapeutic potential.

Nicola McCarthy

References

Chang, T.-C. et al. Widespread microRNA repression by Myc contributes to tumorigenesis. Nature Genet. 40, 43–50 (2008) | Article | PubMed |