An international research team led by cell biologists at the University of California, Riverside has uncovered a new insight into colon cancer, the third leading cause of cancer-related deaths in the United States. The research provides potential new avenues for diagnosing and treating the disease.
Led by Frances Sladek at UC Riverside and Graham Robertson at the University of Sydney, Australia, the team analyzed about 450 human colon cancer specimens and found that in nearly 80 percent of them the variants of a gene, HNF4A, are out of balance.
Human beings express several variants of the HNF4A gene, classified as P1 and P2 variants. Some tissues, like liver, have just one type of variant but the colon has both P1 and P2 variants. The P1 variant is found in the nuclei of cells in the normal colon but in the human colon cancer samples this variant is frequently either absent or located outside of the nucleus and, presumably, no longer functional.
Using human colon cancer cell lines and in vitro assays, the researchers found that the imbalance observed in the human tumor tissues seemed to be the result of a complex, multi-step process by an enzyme, Src kinase. Src kinase has been known to be activated in colon cancer but, until now, it was not known to act on the HNF4a protein (HNF4A is the gene, a stretch of DNA; HNF4a is the protein encoded by HNF4A). The UCR group found that activated Src modifies the P1 but not the P2 variant. The net result is loss of the P1 variant in the nuclei of cells in the colon.
The study results recently appeared online in the Proceedings of the National Academy of Sciences.
"Loss of nuclear P1 HNF4a protein in the colon may be an early sign of colon cancer," explained Sladek, a professor of cell biology and toxicologist. "A healthy colon has a good but delicate balance of the two HNF4a variants. If you could prevent the loss of the P1 variant via drugs, you might be able to maintain a normal colon and prevent colon cancer."
The researchers found another factor that increases a person's susceptibility to the disease: certain "single nucleotide polymorphisms" or SNPs located in the HNF4A gene. An SNP is a DNA sequence variation -- a minor change in the genomic sequence that accounts for the variations we see between individuals. SNPs are the most common type of genetic variation among people.
"Individuals with certain SNPs may be more susceptible to colon cancer," said Karthikeyani Chellappa, a postdoctoral researcher in Sladek's lab and the first author of the research paper. "That's because these SNPs result in a greater amount of modification and a faster degradation of HNF4a by Src, at least in cell-based assays. It still needs to be investigated, though, whether individuals carrying these SNPs are indeed more susceptible to colon cancer."
Sladek noted that drugs are already available for inhibiting the activity of Src kinase.
"Some of these drugs are in clinical trials for colon cancer," she said. "It would be exciting to determine whether these drugs can maintain the P1 HNF4a protein levels, as well as inhibit the Src kinase activity."
A multifactorial disease influenced by genetics and the environment, colon cancer starts as a small polyp in the large intestine (colon) or the rectum (end of the colon). While most of the polyps are benign, some do turn cancerous. With proper screening, the disease can be detected early, when it is most curable.
Sladek, Chellappa and Robertson were joined in the research by Songqin Pan and Jake M. Schnabl at UCR; Lucy Jankova, Caroline L-S. Fung, Charles Chan, Owen F. Dent and Stephen J. Clarke at the University of Sydney, Australia; and Yann Brelivet of the Institut de G้n้tique et de Biologie Mol้culaire et Cellulaire, Illkirch, France. Robertson and the Australian members of the team performed all the analysis of the human tumor samples.
The research was supported in part by a National Institutes of Health grant to Sladek.
- K. Chellappa, L. Jankova, J. M. Schnabl, S. Pan, Y. Brelivet, C. L.-S. Fung, C. Chan, O. F. Dent, S. J. Clarke, G. R. Robertson, F. M. Sladek. Src tyrosine kinase phosphorylation of nuclear receptor HNF4 correlates with isoform-specific loss of HNF4 in human colon cancer. Proceedings of the National Academy of Sciences, 2012; DOI: 10.1073/pnas.1106799109
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