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JCI online early table of contents: Feb. 16, 2009

EDITOR'S PICK: Targeting the protein AEG1 impairs human liver cancer growth in mice

Hepatocellular carcinoma (HCC) is a highly aggressive form of liver cancer and one of the 5 most common cancers worldwide. Devanand Sarkar and colleagues, at Virginia Commonwealth University School of Medicine, Richmond, have now identified a gene that is expressed at high levels in human HCC tumor samples and generates a protein important for HCC progression. They therefore suggest that targeting this gene (AEG1), or the protein that it generates, might provide a new therapeutic strategy for the treatment of HCC.

In the study, human liver cells were found to express only low levels of the protein AEG1, whereas human HCC tumor samples expressed very high levels. This was associated with an increase in the number of copies of the AEG1 gene in human HCC tumor samples. Functionally, human liver cell lines engineered to overexpress AEG1 grew faster than nonengineered cells and developed into highly aggressive tumors when transplanted into mice. In addition, knocking down levels of AEG1 in human HCC cell lines after they had been allowed to form a tumor in mice limited further growth. Further analysis revealed that the effects of AEG1 were mediated, in part, via its ability to activate the Wnt signaling pathway.

TITLE: Astrocyte elevated gene-1 regulates hepatocellular carcinoma development and progression

Devanand Sarkar
Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
Phone: (804) 827-2339; Fax: (804) 628-1176; E-mail:

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METABOLIC DISEASE: Adenosine signaling links alcohol and liver disease

Heavy alcohol consumption and abuse can lead to fatty liver, a condition that may result in serious liver diseases such as hepatitis. Although the molecular events that lead to fatty liver have been determined, exactly how alcohol stimulates these has not yet been established. However, Bruce Cronstein and colleagues, at New York University School of Medicine, New York, have now established that adenosine, which is a product of the breakdown of ethanol (the alcoholic component of alcoholic beverages), has a central role in alcohol-induced fatty liver in mice. Further analysis revealed that adenosine mediated its effects in mice via two proteins, the adenosine A1 and A2B receptors. The authors therefore suggest that targeting these adenosine receptors may prove to be an effective therapy for the treatment and prevention of alcohol-induced fatty liver disease.

TITLE: Adenosine signaling contributes to ethanol-induced fatty liver in mice

Bruce N. Cronstein
New York University School of Medicine, New York, New York, USA.
Phone: (212) 263-6404; Fax: (212) 263-1048; E-mail:

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GASTROENTEROLOGY: Modulating the function of CFTR, the protein defective in cystic fibrosis

Ursula Seidler and colleagues, at Hannover Medical School, Germany, have provided new insight into the in vivo function of three proteins that interact with CFTR, the protein that is nonfunctional in individuals with cystic fibrosis, by analyzing the functional status of CFTR in the small intestine of mice lacking these proteins.

In the study, changes in CFTR-dependent secretion of HCO3 in the small intestine were analyzed in mice lacking NHERF1, NHERF2, or PDZK1. In the absence of the protein NHERF1, basal levels of secretion of HCO3 were reduced, as were levels of secretion induced by the drug forskolin. By contrast, in the absence of the protein NHERF2, forskolin-stimulated secretion of HCO3 was enhanced, and in the absence of the protein PDZK1, basal levels of secretion of HCO3 were reduced but forskolin-stimulated secretion was normal. The authors therefore conclude that the three proteins differentially modulate CFTR-dependent secretion of HCO3 in the small intestine and suggest that therapeutically targeting these proteins might provide an effective way to modulate CFTR function.

TITLE: Differential roles of NHERF1, NHERF2, and PDZK1 in regulating CFTR-mediated intestinal anion secretion in mice

Ursula Seidler
Hannover Medical School, Hannover, Germany.
Phone: 49-0-511-532-9427; Fax: 49-0-511-532-8428; E-mail:

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NEUROBIOLOGY: Antibodies hidden potential to damage nerves unmasked

Damage to nerves in the tissues, a medical condition known as neuropathy, can cause extremely debilitating pain. In some individuals, nerve damage is associated with the presence of specific immune factors: antibodies that recognize molecules known as GM1 gangliosides. Whether these antibodies actually cause disease has been hotly debated. However, Hugh J. Willison and colleagues, at the University of Glasgow, United Kingdom, have now shown that both mouse and human GM1-specific antibodies can damage live mouse nerve cells.

In the study, initial analysis indicated that only some mouse GM1-specific antibodies could bind and damage live mouse nerve cells. However, further experiments revealed that the other antibodies were unable to bind and damage liver mouse cells because the part of GM1 to which they bind was blocked by other ganglioside molecules on the nerve cell surface. If the cells were treated to remove the blocking ganglioside molecules the antibodies bound GM1 and damaged the live mouse nerve cells. Similar hidden binding sites on GM1 were identified for human GM1-specific antibodies providing a potential explanation as to why the ability of GM1-specific antibodies to cause neuropathy has been so hotly debated.

TITLE: The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice

Hugh J. Willison
University of Glasgow, Glasgow, United Kingdom.
Phone: 44-141-330-8384; Fax: 44-141-201-2993; E-mail:

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Contact: Karen Honey
Journal of Clinical Investigation

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