Abstract
Cellular senescence is a stress response of human cells that removes potentially harmful cells by initiating cell cycle arrest. Inducing senescence of tumor cells may be an effective tumor-inhibiting strategy. In this study we found that PIK3R3 could inhibit the cell senescence of colorectal cancer cells and promote cell proliferation through the p53/p21 signal pathway. PIK3R3 could bind to p53 and inhibit the binding of p53 to the p21 gene promoter region, and thus affecting the transcriptional activity of p21 gene. Our study has provided new evidence of the role of PIK3R3 in p53 regulation and inhibition of PIK3R3 may be one of the potential targets of tumor therapy.
Highlights
Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract, with its mortality rate ranking the third of all types of cancer around the world[1]
PIK3R3 is overexpressed and p21 is underexpressed in CRC We first retrieved the Gene Expression Omnibus (GEO)
We found that the expression of PIK3R3 in human normal intestinal tissues is significantly lower than that in CRC tissues (Fig. 1a)
Summary
Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract, with its mortality rate ranking the third of all types of cancer around the world[1]. With the development of human societies and the changes in dietary habit, both the incidence and the mortality rate of CRC are increasing year by year[2]. Xia et al found that PIK3R3 can directly bind to p53 known as Gene Guard is an important tumor suppressor gene in the human body. Wild-type p53 maintains normal cell growth and inhibits tumor proliferation. P21, first discovered and named by Harper et al, can inhibit the activity of cyclin-dependent kinase (CDK), known as CDKN1A (cyclin-dependent kinase inhibitor 1)[11]. P21 protein binds to the CDK/cyclin complex and inhibits its activity, thereby inhibiting Rb phosphorylation and arresting the cell cycle[11,14] There are binding sites for interaction with other proteins on two conserved domains of p21 protein, including N-terminal and C-terminal cyclin-binding sites, C-terminal PCNA-binding sites, etc.13. p21 protein binds to the CDK/cyclin complex and inhibits its activity, thereby inhibiting Rb phosphorylation and arresting the cell cycle[11,14]
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