A new method in the treatment of colon cancer! HNF4A gene variant
In a study just published in the Proceedings of the National Academy of Sciences, an international research team led by the University of California, Colon cancerintroduced a new perspective on Researchers who analyzed 450 colon cancer samples in the study found that 80% of them had unbalanced HNF4A gene variants. The research could provide potential new avenues in the diagnosis and treatment of the disease. Professor at UC Riverside Dr. The team, led by Frances Sladek, analyzed approximately 450 human colon cancer samples and found that approximately 80% of them had unstable HNF4A gene variants.
Humans produce several variants of the HNF4A gene classified as P1 and P2 variants. Some tissues, such as the liver, have only one variant, but the colon has both the P1 and P2 variants. The P1 variant is found in the nuclei of cells in the normal colon, but in human colon cancer samples this variant is often either absent or located outside the nucleus and is usually non-functional.
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Using a human colon cancer cell line and in vitro samples, the researchers determined that the instability observed in human tumor tissues appears to be the result of a complex formed in a multistep process by an enzyme called Src kinase. Src kinase was known to be activated in colon cancer, but its effect on the HNF4a protein was not known to date (a gene, HNF4A, part of DNA; HNF4a, a protein encoded by HNF4A). The UCR group found that activated Src changed the P1 variant but not the P2 variant. The result is that nuclei in colon cells lose the P1 variant.
prof. Dr. Sladek says, “Destruction of the nuclear P1 HNF4a protein in the colon may be an early sign of colon cancer. A healthy colon has a good but delicate balance of both HNF4a variants. “If the loss of the P1 variant can be prevented with drugs, you can have a normal colon and prevent colon cancer,” he said.
Researchers have found another factor that increases a person’s susceptibility to this disease: a “single nucleotide polymorphism,” or SNPs detected in the HNF4A gene. A SNP is DNA sequence variation – a minor variation in genome sequence that explains the variation we see between individuals. SNPs are the most common type of genetic variation among humans. Co-author of the published article, Dr. Karthikeyani Chellappa said, “Individuals with certain SNPs may be more prone to colon cancer. These SNPs therefore result in a large exchange and rapid degradation of HNF4a by Src, at least in cell-based experiments. “While these data still need to be investigated, individuals carrying these SNPs are indeed more prone to colon cancer.”
prof. Dr. Sladek stated that there are already drugs available to inhibit the activity of Src kinase, “Clinical studies of some of these drugs for colon cancer continue. These drugs maintain P1 at the level of HNF4a protein and inhibit Src kinase activity as well. This is exciting,” he said.
Colon cancer, which starts as a small polyp in the large intestine or rectum, is a multifactorial disease influenced by genetics and environment. While most polyps are benign, some can turn into cancer. With regular follow-up, the disease can be detected early, when it can be best treated.
Sladek, Chellappa, and Robertson participated in the research from UCR Songqin Pan and Jake M. Schnabl; Lucy Jankova, Caroline LS. Fung, Charles Chan, Owen F. Dent, and Stephen J. Clarke the University of Sydney, Australia; and Yann Brelivet from the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France. Robertson and Australian members of the team performed all analyzes on human tumor samples. He supported the National Institutes of Health Sladek in some parts of the research.
SOURCE: Src tyrosine kinase phosphorylation of nuclear receptor HNF4 correlates with isoform-specific loss of HNF4 in human colon cancer. K. Chellappa, L. Jankova, JM Schnabl, S. Pan, Y. Brelivet, CL-S. Fung, C. Chan, OF Dent, SJ Clarke, GR Robertson, FM Sladek. Proceedings of the National Academy of Sciences, 2012; DOI: 10.1073/pnas.1106799109