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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
New p53 related genes in human tumors: significant downregulation in colon and lung carcinomas
M E LLeonart1, F Vidal, D Gallardo
1Department of Pathology, Hospital Vall d'Hebron, 08035 Barcelona, Spain. melleona@ir.vhebron.net
Abstract:
Human epithelial tumors need to accumulate multiple genetic alterations to form invasive carcinomas. These genetic alterations are related with growth factor receptors, cell signalling, the cell cycle and cell invasiveness. Importantly, cells need to avoid senescence and become immortalized for this process. Recently, five genes: RPS6KA6, HDAC4, KIAA0828, TCP1 and Tip60, which modulate p53-dependent function and avoid senescence were identified in a large-scale RNA interference screen. Twenty colon, 20 prostate and 20 lung carcinomas were studied to investigate whether these genes might be related with human tumors. RNA was extracted from both normal and tumor tissue from each patient. Real-time RT-PCR was performed using TaqMan probes corresponding to the RPS6KA6, HDAC4, KIAA0828, TCP1, Tip60 and p53 genes. In colon carcinomas, the RPS6KA6, HDAC4, KIAA0828 and Tip60 genes were downregulated in tumor tissue as compared with normal tissue (P < 0.001 for all genes). In lung carcinomas, HDAC4, KIAA0820 and Tip60 were downregulated (P < 0.01, P < 0.001 and P < 0.001 respectively). Whereas no significant differences were observed in prostate carcinomas, striking downregulation of the RPS6KA6 and KIAA0828 genes was observed in colon carcinomas and KIAA0828 in a subset of lung carcinomas. mRNA expression of these genes may control p53 function as well as the ras-MAPK pathway, methylation and transcriptional cellular programs. These results could unravel a novel set of regulatory suppressor genes involved in human colon and lung tumors.
Insights
Five genes regulating senescence and p53 function were investigated in human tumors. RPS6KA6, HDAC4, KIAA0828, and Tip60 showed downregulation in colon and lung carcinomas, suggesting their role as novel suppressor genes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Human carcinomas develop through multiple genetic alterations affecting cell growth, signaling, and invasiveness.
- Cellular senescence evasion and immortalization are critical steps in tumor progression.
- A recent screen identified five genes (RPS6KA6, HDAC4, KIAA0828, TCP1, Tip60) that modulate p53 function and senescence.
Purpose of the Study:
- To investigate the potential association of these five genes with human colon, prostate, and lung carcinomas.
- To determine if the expression levels of these genes differ between tumor and normal tissues.
Main Methods:
- RNA extraction from normal and tumor tissues of 20 patients each for colon, prostate, and lung carcinomas.
- Real-time RT-PCR using TaqMan probes to quantify mRNA expression of RPS6KA6, HDAC4, KIAA0828, TCP1, Tip60, and p53.
Main Results:
- Significant downregulation of RPS6KA6, HDAC4, KIAA0828, and Tip60 was observed in colon carcinomas compared to normal tissue (P < 0.001).
- HDAC4, KIAA0828, and Tip60 were downregulated in lung carcinomas (P < 0.01, P < 0.001, P < 0.001 respectively).
- No significant differences were found in prostate carcinomas; however, RPS6KA6 and KIAA0828 were notably downregulated in colon tumors and KIAA0828 in a subset of lung tumors.
Conclusions:
- The identified genes (RPS6KA6, HDAC4, KIAA0828, Tip60) may function as regulatory suppressor genes in human colon and lung tumors.
- Altered mRNA expression of these genes could impact p53 function, the ras-MAPK pathway, methylation, and transcriptional programs.
- These findings suggest a novel set of genes involved in the development of specific human carcinomas.
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