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PNAS-4 expression and its relationship to p53 in colorectal cancer
1Laboratory of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan Province, China.
Abstract:
PNAS-4 is a novel pro-apoptotic protein activated during the early response to DNA damage; however, the molecular mechanisms and pathways regulating PNAS-4 expression in tumors are not well understood. We hypothesized that PNAS-4 is a p53 down-stream target gene and designed this study. We searched online for putative p53-binding sites in the entire PNAS-4 gene and did not find any corresponding information. In HCT116 colon cancer cells, after being transfected with small interfering RNA to silence p53, the expressions of PNAS-4 and other known p53 target gene (Apaf1, Bax, Fas and Dr5) were determined by real-time PCR. We found that PNAS-4 was up-regulated while Apaf1, Bax, Fas and Dr5 were down-regulated. We then examined the expression of PNAS-4 and p53 mutation in colorectal cancer patients. PNAS-4 expressed both in colorectal cancers and normal tissues, but compared with paired control, PNAS-4 was up-regulated in cancers (P=0.018). PNAS-4 overexpression ratios were correlated to the p53 mutant status (P=0.001). The mean PNAS-4 expression levels of p53 mutant homozygote group and heterozygote group were higher than that of p53 wild type group (P=0.013). The expression ratios of PNAS-4 (every sample in relative to its paired normal mucosa) were different between negative lymph node metastasis (66% up-regulated, 34% down-regulated) and positive metastasis (42% up-regulated, 58% down-regulated). Taken together, these findings suggested that PNAS-4 was not a p53 target, but overexpression of PNAS-4 was correlated to p53 inactivity in colorectal cancer.
Insights
PNAS-4 is a novel pro-apoptotic protein. This study found PNAS-4 is not a p53 target gene, but its overexpression correlates with p53 inactivity in colorectal cancer, impacting tumor progression.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- PNAS-4 is a novel pro-apoptotic protein involved in DNA damage response.
- Mechanisms regulating PNAS-4 expression in tumors are not well understood.
- The study investigated the relationship between PNAS-4 and p53 in colorectal cancer.
Purpose of the Study:
- To determine if PNAS-4 is a downstream target of p53.
- To investigate the correlation between PNAS-4 expression and p53 mutation status in colorectal cancer.
- To explore the role of PNAS-4 in colorectal cancer progression and metastasis.
Main Methods:
- Searched for p53-binding sites in the PNAS-4 gene.
- Used real-time PCR to analyze PNAS-4 and known p53 target gene expression in p53-silenced HCT116 cells.
- Examined PNAS-4 expression and p53 mutation status in colorectal cancer patient samples.
Main Results:
- No p53-binding sites were found in the PNAS-4 gene.
- PNAS-4 was upregulated, while known p53 targets were downregulated, after p53 silencing.
- PNAS-4 was upregulated in colorectal cancers compared to normal tissues and correlated with p53 mutant status.
- PNAS-4 overexpression was associated with lymph node metastasis.
Conclusions:
- PNAS-4 is not a p53 target gene.
- PNAS-4 overexpression is linked to p53 inactivity in colorectal cancer.
- PNAS-4 may play a role in colorectal cancer progression and metastasis.
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