Li, Y. F. | bioRxiv Science

bioRxiv2018

Mutation Vulnerability Characterizes Human Cancer Genes

Recent studies by Tomasetti et al. revealed that the risk disparity among different types of cancer is mainly determined by inherent patterns in DNA replication errors rather than environmental factors. In this study we reveal that inherent patterns of DNA mutations plays a similar role in cancer at the molecular level. Cancer results from stochastic DNA mutations, yet non-random patterns of cancer mutations emerge when we look across hundreds of cancer genomes. Over 500 cancer genes have been identified to date as the hot spot genes of cancer mutations. It is generally believed that these gene are mutated more frequently because they reside in functionally important pathways and are hence selected during the somatic evolution process of tumor progression. This theory however does not explain why many genes in the same pathways of cancer genes are not mutated in cancer. In this study, we challenge this view by showing that the inherent patterns of spontaneous mutations of human genes not only distinguish cancer causing genes and non-cancer genes but also shapes the mutation profile of cancer genes at the sub-gene level.

bioinformatics↗

bioRxiv2017

Type 2 diabetes promotes cell centrosome amplification and the role of AKT-ROS-dependent signalling of ROCK1 and 14-3-3σ

Type2 diabetes is associated with oxidative stress which can cause cell centrosome amplification. The study investigated centrosome amplification in type 2 diabetes and the underlying mechanisms. We found that centrosome amplification was increased in the peripheral blood mononuclear cells (PBMC) from the type 2 diabetic patients, which correlated with the levels of fasting blood glucose and HbA1c. High glucose, insulin and palmitic acid, alone or in combinations, induced ROS production and centrosome amplification. Together, they increased AKT activation as well as the expression, binding and centrosome translation of ROCK1 and 14-3-3{sigma}. Results from further analyses showed that AKT-ROS-dependent upregulations of expression, binding and centrosome translocation of ROCK1 and 14-3-3{sigma} was the molecular pathway underlying the centrosome amplification induced by high glucose, insulin and palmitic acid. Moreover, the increases in AKT activation and ROS production as well as expression, binding and centrosome distribution of ROCK1 and 14-3-3{sigma} were confirmed in the PBMC from the patients with type 2 diabetes. In conclusion, our results show that type 2 diabetes promotes cell centrosome amplification, and suggest that the diabetic pathophysiological factors-activated AKT-ROS-dependent signalling of ROCK1 and 14-3-3{sigma} is the underlying molecular mechanism.

cell biology↗