Balancing imports and exports can be a tough task for any entity. It turns out cancer cells have a major issues when it comes to exporting pre-miRNA between the nucleus and cytoplasm that can have a pretty nasty impact on cellular homeostasis. miRNA expression profiles in tumors typically show a down regulation of miRNA expression.
A number of research teams have presented solid evidence suggesting possible explanations for this including epigenetic silencing of miRNA genes and mutations in key processing factors like exportin-5, the official miRNA shuttle service.
Prompted by some recent intriguing evidence, Dr. Manel Esteller and a band of talented researchers took a closer look at exportin-5 and Ras related nuclear protein (RAN). After screening six colorectal, four endometrial, and two gastric cell lines, here’s what they found:
- A frame shift mutation in exportin-5 causing it to come up a bit short
- This truncated exportin-5 showed up exclusively in nuclear fractions of exportin-5 mutated lines, unlike the wild type cell lines
- In the exportin-5 mutant lines, pre-miRNAs were accumulating in the nucleus as well compared to a bias to the cytoplasm in wild type cells
- Transfection of wild type exportin-5 rescued pre-miRNA traffic
“The identified tumors are unable to export them (pre-miRNAs) out of the nucleus so they lose their antitumoral protective capacity” shared Dr. Esteller. “These results have implications for a better understanding of the causes of cancer, but also for possible new treatments: in the first case because this is a new pathway to cancer completely unknown, and the second because it should stimulate the search for drugs that improve the transport of molecules from the nucleus, providing new targets in the arsenal of antitumoral compounds.”
Check out the remaining balance of details in Cancer Cell October 2010