The imbalance observed in the human tumor tissues appears to be the result of a complex, multistep process by the enzyme sarcoma tyrosine kinase (SRC).
Some tissues, like liver, have just one type of variant of the nuclear receptor hepatocyte nuclear factor 4α (HNF4α), 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.
An international team led by cell biologists at the University of California, (Riverside, CA, USA) has uncovered a new insight into colon cancer. The team analyzed about 450 human colon cancer specimens and found that in nearly 80% of them, the variants of the HNF4A gene are out of balance. The team used both SRC kinase assays and human colonic adenocarcinoma tissue staining. Tissue microarrays (TMAs) were constructed with 1.0 mm cores from morphologically representative areas of the original archived paraffin blocks, the central region of the tumor, deep advancing tumor front, and adjacent non-neoplastic mucosa using an Advanced Tissue Arrayer, ATA-100.
SRC kinase has been known to be activated in colon cancer but, until now, it was not known to act on the HNF4α protein. The cell biologists 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. Another factor that increased a person's susceptibility to the disease was specific 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 seen between individuals. SNPs are the most common type of genetic variation among people. The SRC kinase assays and the ATA-100 used are manufactured by Millipore (Billerica, MA, USA).
The authors concluded that that increased staining for active SRC is associated with a loss of nuclear P1-HNF4α in a sizeable cohort of human colorectal tumors. Their findings suggest a unique link between an oncogenic kinase, a potent differentiation factor, and human colon cancer. Frances M. Sladek, PhD, a professor of cell biology and toxicologist, who was the lead author of the study said, "Loss of nuclear P1 HNF4α protein in the colon may be an early sign of colon cancer. 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 study was published on Febraury 14, 2012, in the Proceedings of the National Academy of Science of the United States (PNAS).
University of California, Riverside