A Spanish research team has recently published evidence which may provide the first direct functional link between differential expression of mRNA-specific translational regulators and tumor development.

The researchers showed that CPEB4 (cytoplasmic polyadenylation element binding protein 4), an RNA binding protein that mediates the polyadenylation and translation of mRNA transcripts, may play a very important role in the genesis of both glioblastomas and pancreatic ductal adenocarcinomas (PDAs), two malignant carcinomas with the least favorable clinical outcomes among cancers.

After observing that CPEB4 was overexpressed in both types of cancers, it was shown that knocking down this expression leads to an impressive decrease in tumor size and tumor weight in xenografted mice (immune-compromised mice that have had their flanks injected with cancerous cells, to allow tumor growth outside of a specific organ structure), and that cancerous proliferation and vascularization are also decreased substantially.

To explain how this anti-tumorigenic effect was possible, the researchers went on to more specifically characterize the nature of CPEB4’s normal role in the cell. It was shown that CPEB4 normally associates with a large number of mRNA sequences which contain a very specific “CPE activation arrangement,” which acts to recruit the polyadenylation complex. Thus, the association of CPEB4 and these mRNAs serves to promote the translation of the mRNA transcripts into functional proteins. The factors which are encoded or influenced by these specific RNAs appear to include a number of tumorigenesis-related products, including chromatin-remodeling proteins, cyclins, RAS-related molecules, stress and inflammation factors, and an assortment of other signaling molecules. By knocking out CPEB4, the increase in all of these factors in tumor cells seems to be ablated, resulting in an absence of tumor formation.

For a cancerous tumor to develop, an assortment of mutations to the underlying genetic material must occur, and the locations of these mutations generally differ greatly between tumors. However, certain types of genes are more likely to contribute to the eventual emergence of cancer when mutated; these are often broadly grouped into the categories “oncogenes” and “tumor suppressor genes.” When genes from the oncogenic group are upregulated, the chances of cancer development increase, whereas downregulation of genes from the tumor suppressor group yields the same results. It is ultimately the accumulation of such mutations that allows a cancerous tumor to form, and eventually develop the properties characteristic of most cancers: angiogenesis, growth factor self-sufficiency, metastasis, loss of apoptosis and senescence, etc.

In these terms, the gene which encodes CPEB4 may not necessarily be defined as an oncogene, but it does seem to serve as an important facilitator of pro-oncogenic functions in tumor cells. In these cancer cells, post-transcriptional regulation of different mRNA subpopulations serves as an important component in gene expression relative to normal cells. Since the CPE elements which CPEB4 binds to are present in hundreds of specific mRNAs related to proliferation, differentiation and chromosome segregation, it will be interesting to see how this new information will influence future research aimed at preventing the formation of glioblastomas, PDAs, and other carcinomas.

Original Research Paper: http://www.nature.com/nm/journal/vaop/ncurrent/abs/nm.2540.html

Original Press Release: http://www.irbbarcelona.org/index.php/en/news/irb-news/scientific/discov...