Patients with advanced hepatocellular cancer have high mortality rates, and existing drugs offer only a small, though significant, survival advantage. By combining a zebrafish model of liver cancer with data from human tumors, researchers hope to identify potential genes of interest that can be targeted for new treatments for hepatocellular carcinoma, the most common form of liver cancer to develop from liver cells.
Using transgenic zebrafish as an emerging, powerful whole animal model for cancer gene discovery, in combination with cultured cells and data from human tumors, they found that a gene called UHRF1, which is highly expressed in many types of cancers, can cause liver cancer at an unprecedented rate and incidence—with tumors forming in 75% of fish within 20 days. Results from the study, conducted at the Icahn School of Medicine at Mount Sinai in New York, New York, have been published online in the journal Cancer Cell (2014; doi:10.1016/j.ccr.2014.01.003).
“This is the first time that UHRF1 has been shown to be sufficient on its own to cause any kind of cancer when it is highly expressed,” said the study’s senior investigator, Kirsten C. Sadler, PhD, of the Icahn School of Medicine at Mount Sinai.
UHRF1 has generated a lot of interest because it is a central regulator of epigenome—which is a collection of reversible modifications to DNA and the DNA packaging proteins—that are important for deciding which genes are expressed and how the DNA is transmitted during cell division. The cancer cell epigenome is dramatically different from normal cells, and the field of cancer epigenetics is exploding because of the hope that these changes could be reversed, thereby reversing the aggressive nature of cancer cells. Sadler added, “Down the road, we hope to develop drugs to target UHRF1 and thereby reset the cancer epigenome to activate antitumor mechanisms and halt liver cancer.”
When the team analyzed patient-derived liver tumors, they found that high levels of the UHRF1 were also found there as well. Most strikingly, the changes in gene expression caused by high UHRF1 levels in zebrafish were reflected in the human tumors expressing high UHRF1 levels. This finding suggests that similar mechanisms underlie UHRF1-driven liver tumor formation in both species. One of these is the ability of the cancer-prone cells to bypass the tumor-suppressive mechanisms that are activated in most cells when they receive a cancer-causing stimulus.
UHRF1 is overexpressed in around 40% to 50% of hepatocellular cancers in humans and predicts poor outcome. This overexpression is associated with poorer prognosis in terms of high recurrence rate and low term overall survival. “We have little to offer people in the setting of advanced disease—and this points to an entirely new direction,” Sadler said. “It raises the hope that epigenetic drugs could be applied to liver cancer in the future.”