A potential role of microRNAs in protein accumulation in cellular senescence analyzed by bioinformatics
June
A potential role of microRNAs in protein accumulation in cellular senescence analyzed by bioinformatics
Yuequan Zhu 0 1
Kai Xiong 0 1
Jiangcheng Shi 1
Qinghua Cui 1
Lixiang Xue 0 1
☯ These authors contributed equally to this work. 1
1
1
0 Medical Research Center, Department of Radiation Oncology, Peking University Third Hospital , Beijing , China , 2 Department of Biomedical Informatics, School of Basic Medical Sciences, Peking University , Beijing , China
1 Editor: Yu Xue, Huazhong University of Science and Technology , CHINA
Cellular senescence is an important protective mechanism against cell proliferation and has critical roles in aging and aging-related disease. Recently, one interesting observation is that the protein abundance is higher in senescent cells than that in young cells. So far, some factors were presented to interpret this observation, such as active protein synthesis linked with autophagy, mTOR, and oxidative stress. Here, applying bioinformatic analysis of microRNA profiles in young cells and aging cells, we revealed that globally senescent cells show lower miRNA abundance than that in young cells, suggesting that the repression of protein synthesis by miRNA in senescent cells could be largely attenuated. This finding provides clues that protein accumulation in cellular senescence could be associated with lower miRNA abundance in aging cells.
Introduction
Cellular senescence is the process of accumulative changes in both cellular structure and
function that disrupts metabolism, resulting in deterioration and irreversible cell cycle arrest. Cells
undergo senesce normally after a certain times divisions in vitro and can also be induced to
senesce by toxins, irradiation, and oncogenes, etc. [
1
]. Cellular senescence represents a robust
and important tumor-suppressive barrier that inhibits cell proliferation and malignancy[
2
].
Because cells are the basic blocks of organisms, cellular senescence is account for the whole
aging process. So far, it has been well documented that senescence plays critical roles in aging
and aging-related disease, such as cancer[
2
], cardiovascular disease[
3
], and diabetes[
4
].
Therefore, cellular senescence is becoming one important mechanism for understanding a number
of physiological and pathological processes.
Recently, one amazing observation is that the total amount of proteins in senescent cells
increased compared with that in young cells, suggesting that protein synthesis seems to be
activated in senescent cells [5±7]. So far, a number of studies on the mechanism were presented to
explain the above phenomenon. For example, oxidative stress resulted from aging may result
in the accumulation of damaged proteins[
5
]. Although how protein synthesis and autophagy
are activated in senescence remains largely unknown, it is accepted that oncogene, such as Ras
could activate autophagy, which further facilitates protein synthesis and results in the cellular
senescence [
6
]. These mechanisms greatly improved our understanding to cellular senescence;
however, more evidences are needed to provide a comprehensive understanding of
senescence. Given that protein-coding genes are negatively regulated by miRNAs, it remains
unknown whether miRNAs accumulated or decreased in aging cells. Here, by analyzing
miRNA expression profiles of senescent cells and young cells, we raised our hypothesis that
repressed miRNA expression might partly explain the accumulated proteins in senescent cells.
miRNAs mainly function as negative gene regulators to repress mRNA translation or
degrade mRNAs through binding the 3'UTR of targets [
8
]. As one class of small noncoding
RNAs, miRNA plays critical roles in many biological processes. It has been revealed that
miRNA-related dysfunctions are associated with a wide spectrum of diseases, including aging
and aging-related disease[
9
]. Recently, emerging studies have also shown that miRNAs are
involved in the regulation during cellular senescence as well [
10, 11
]. Thus, miRNAs might
serve as a new indicating molecules during senescence transition and may shed light on the
understanding cellular senescence and aging. However, crucial questions need to be urgently
addressed: Is miRNA synthesis also activated like protein synthesis in senescent cells? Do
miRNAs contribute to the accumulated proteins in senescent cells?
Here by an integrative analysis of miRNA profiles in young and aging cells, we revealed
that globally senescent cells show lower miRNA abundance than young cells, suggesting that
the repression on protein synthesis by miRNAs in senescent cells could be largely released.
This finding suggests that lower miRNA abundance in aging cells could be another factor in
interpreting the phenomenon of protein accumulation in cellular senescence.
Materials and methods
miRNA expression datasets
We obtained the miRNA expression profiles of young and replicative senescent human
umbilical vein endothelial (...truncated)