Viral Hepatitis and Liver Cancer Development

Researchers are zeroing in on a mechanism behind the development of liver cancer, which could have treatment implications for individuals infected with hepatitis C.

In a recent study published in Genome Research, retroviral long-terminal-repeat (LTR) promoters were found to be highly active in hepatocellular carcinomas (HCC), which is the most common form of liver cancer.

The researchers found that these areas, which are particularly activated in HCC associated with viral hepatitis, are normally activated in reproductive tissues, such as the testis and placenta.

These findings indicate that the activation of LTR promoters may contribute to cancer development in the liver.

"Since these viral elements contain elements that are capable of functions such as transcription, it seems that organisms have sometimes made use of these LTRs for their own purposes, and in fact they are highly activated in reproductive tissues and, as we discovered earlier, in ES and iPS cells,” said corresponding author Piero Carninci, of the RIKEN Center for Life Science Technologies.

The researchers utilized a technique developed at RIKEN called CAGE technology to analyze RNA expression in non-tumor tissue and liver cancer tumor tissue from the same patients. The findings showed 4756 non-coding promoters that are more highly activated in tumor tissue than in non-tumor tissue. Of this total, 935 were found in retroviral LTRs.

The activation of LTR promoters correlated with the cause of the tumor, which was different among patients with cancer associated with hepatitis B, hepatitis C, or alcohol use, and with cancer progression.

Specifically, less differentiated tumors associated with a higher chance of recurrence showed higher levels of expression.

"The fact that different patterns were found in tumors of different etiologies suggests that these are not simply random activations but may be part of the mechanism through which the cancer arose," said first author Kosuke Hashimoto.

In a mouse model of HCC, 18.9% of upregulated non-coding promoters were found in LTR elements, with expression greater in more advanced tumors.

"It appears that we are seeing a similar phenomenon in both the mouse and humans,” Hashimoto said.

Researchers plan to continue evaluating the function of different LTRs to better decipher how it contributes to cancer development.

"We hope that this work could lead to a better understanding of the mechanism of hepatocellular carcinoma and to the identification of biomarkers that could be used as diagnostic tests,” Carninci said. “This is very important considering that liver cancer is the second largest cause of cancer deaths in the world, killing more than 700,000 people every year."