New UP paper shows how tiny RNAs fine-tune switch critical in cancer development

Aguda has held teaching and research positions in various institutions in the US and Canada (Photo from his LinkedIn page)

The restriction point (R) marks a switch in G1 from growth factor-dependent to growth factor-independent progression of the cell cycle. This switch must be properly regulated, otherwise it can upset normal cell processes and result in diseases such cancer, neurodegenerative disorders, stroke and myocardial infarction. 

In the paper “MicroRNA inhibition fine-tunes and provides robustness to the restriction point switch of the cell cycle,” Dr. Ricardo del Rosario of the Stanley Center for Psychiatric Research at Broad Institute of MIT and Harvard, Joseph Ray Clarence Damasco of the Institute of Mathematics at UP Diliman and Dr. Baltazar Aguda of the UP Philippine Genome Center looked at the role of microRNAs in the regulation of this switch and the development and progression of cancer.

Damasco is a summa cum laude graduate of mathematics (Photo from the Science Education Institute, DOST)

Damasco is a summa cum laude graduate of mathematics from UP (Photo from the website of the Science Education Institute, DOST)

Aguda and his co-researchers, in an earlier study, came up with the ‘A model’ that predicated how RNAs tune the sequence of cellular states from quiescence (the resting phase) to proliferation (a result of cell growth and cell division) and then to apoptosis (or programmed cell death). They also suggested that between normal cell proliferation and the onset of apoptosis is a ‘cancer zone’, a range of oncogenic (mutation) activity that makes cancer more probable. 

But the latest paper, published in Scientific Reports in September 2016, relied on an analysis of what they called the R model, a framework for examining the influence of the microRNA cluster miR-17-92 on the properties of the restriction point switch. They included the miR-17-92 to extend the Yao model, the first in-vitro demonstration of how R serves as a bistable switch. 

A cancer network commonly described as the Rb-E2F network.

From the paper: A cancer network commonly described as the Rb-E2F network.

They found that “as the microRNA inhibition efficiency is varied, the influence of miR-17-92 on the characteristics of the bistable switch of the R model match those of the A model.” Moreover, since the R model makes it possible to conduct a comparative analysis of microRNA regulation of c-Myc and E2F, the “R model offers predictions beyond those made by the A model.”

The paper proves through mathematical analysis that microRNAs play an essential role in fine-tuning and providing robustness to the switch, and that microRNA regulation can steer cells in or out of cancer states.

Aguda, a Balik-PhD grantee, is the newly-appointed executive director of the Philippine Genome Center while Damasco is an instructor at the Institute of Mathematics, UP Diliman.