A new press release from the Baylor College of Medicine newsroom reports that BCM researchers have determined that the toxic, chronic build-up of bile acids may may lead to the onset of liver cancer, as these bile acids function as promoters of spontaneous tumor growth.
The BCM study, which was recently published in the journal Cell Reports, demonstrates that this build-up is the start of a chain-reaction within the body that leads to the over expression of the IQGAP1 protein, which in turn activates the Yes-associated protein (YAP). Dr. David Moore, professor of molecular and cellular biology at BCM and the corresponding author of the report, explains that “Activation of YAP is associated with human liver cancer and a form of that disease that is associated with particularly poor prognosis,” and that in the study, in which normal mice were fed a diet that increases bile acid levels that in turn activated YAP in the liver, it was found that, “toxic levels of bile acids activate YAP, and the mice develop cancer spontaneously.”
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The BCM press release goes on to explain that, “Normally, levels of bile acids components of bile, which is essential to digestion are tightly controlled because they are potentially toxic to the liver,” according to Dr. Moore. In studies with a mouse model that lacks two key components (nuclear receptors FXR and SHP) of this regulatory pathway, he and his colleagues found that the animals have enlarged livers, proliferation of liver progenitor cells and YAP activation and eventually develop spontaneous liver tumors.”
The results of Dr. Moore’s study are promising, since they reveal a clear cause-effect pattern that leads to increased, toxic levels of bile and tumors associated with liver cancer: “IQGAP1 is not originally present in the liver. It only appears in the presence of toxic levels of bile acids,” he noted. Thus if researchers are able to either decrease levels of IQGAP1 or toxic levels of bile in the system, they could in turn dramatically decrease the prevalence of spontaneous tumor development associated with liver cancer.
Others who took part in this work include: Sayeepriyadarshini Anakk and Milton J. Finegold, both of BCM; Manoj Bhosale of University of Illinois at Urbana-Champaign; Valentina A. Schmidt of Stony Brook University in New York; and Randy L. Johnson of the University of Texas MD Anderson Cancer Center in Houston. Anakk is now at the University of Illinois at Urbana-Champaign. Moore holds the The R. P. Doherty, Jr. Welch Chair in Science.
Funding for this work came from the National Institute Diabetes and Digestive and Kidney Diseases, Digestive Disease Center Morphology Core (Grant DK56338, DK068804, DK62434), the National Cancer Institute MD Anderson Cancer Center proteomics core (Grant CA16672) and Cancer Prevention and Research Institute of Texas (Grant RP120138), the R.P.Doherty, Jr. Welch Chair in Science , National Institutes of Health (Grant R01HD060579), American Cancer Society Research Scholar (Grant RSG-09-033-01-CSM ) and start-up funds from the University of Illinois at Urbana-Champaign.
Photo of Dr. Moore from bcm.edu