Scientists around the globe are trying to develop effective therapies to treat cancer. Ultimate goal is to cure cancer at all or even invent such drugs that would allow preventing it in the first place. However, in order to do that it is important to understand what causes cancer, what mechanisms are behind it. Which is why an international group led by RIKEN in Japan and INSERM in France have conducted a research, which showed that retroviral long-terminal-repeat (LTR) promoters are highly activated in hepatocellular carcinomas, which is the most common type of liver cancer.
There are several very interesting facts about these results. Firstly, retroviral LTRs are a type of repetitive elements that are widely distributed in the human genome. Secondly, these areas which are particularly activated in hepatocellular carcinomas are not normally activated in the liver but are in reproductive tissues such as testis and placenta. All of this suggests that activation of LTR promoters may be involved in the development of cancer in the liver.
Many scientists believe that the retroviral LTRs are actually remnants of retroviruses (like, for example, HIV) that lost the ability to exit from cells and became parasitic elements in the genome. Piero Carninci, one of corresponding authors of the study, explained that “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.” Of course, in order to get this new data, team of scientists had to use very innovative methods and techniques to research the liver samples.
Researchers used technology called CAGE. It is a technique developed at RIKEN, which is used to analyse RNA expression in liver cancer tumours and non-tumour tissue taken from the same patients. It allowed scientists to discover 4,756 non-coding promoters that were more highly activated in the tumour tissue than the non-tumour tissue.
Moreover, 935 of these were located in retroviral LTRs, which allowed scientists to make such conclusions mentioned above. In the next step of the research, scientists examined the causes and aggressiveness of the tumours. They discovered correlation between the activation of LTR promoters with the cause of the tumour and with the progression of cancer.
Correlation of LTR promoters with the cause of the tumour differed, depending on association of the cancer with hepatitis B, hepatitis C, or alcohol use. Study showed that activation of LTR promoters can be linked directly to progression of the liver cancer – less differentiated tumours with a higher chance of recurrence, had higher levels of expression of these promoters. Such different patterns in different type of liver tumours may mean that the activation of LTR may not be random, but actually be in the centre of mechanism through which cancer arises.
To confirm the results, scientists used mouse models of hepatocellular carcinomas. Scientists found that 8.9% of the activated non-coding promoters were located in LTR elements. They also discovered that the expression of them was higher in more advanced tumours. Scientists say that this shows that similar phenomenon may be observed both in humans and mice. As this is very important research, which may uncover the mechanisms behind the cause of the liver cancer, scientists already have next steps planned.
Now team of researchers will try to reveal the function of the various LTRs, which should enable them to put together a picture of how they contribute to the emergence of cancer. They say that ultimately better understanding of the mechanism of hepatocellular carcinoma may help to identify certain biomarkers, which could help to develop new diagnostic techniques.
Scientists note that early and accurate diagnosis is very important, especially in this type of cancer, as hepatocellular carcinoma is the second largest cause of cancer deaths in the world, being responsible for the death of 700,000 people every year. However, every small step towards better treatments and diagnosis of cancer is a step to the right direction and world is still waiting for science to cure cancer for once and for all.