2018-06-11 10:42:14
Confirmation of the existence of oncogenes, that is, genes that favor the development of cancer, has perhaps been one of the scientific advances that have helped the most to fight this disease. The existence of oncogenes was proposed in 1914 by the German biologist Theodor Boveri. However, the first oncogene was discovered only in 1970. This oncogene was identified in tumors called sarcomas, hence it was named Src. Shortly thereafter, the Src oncogene was found to be a viral form of a gene involved in cell growth. Thus, the oncogene was revealed as a gene “stolen” from the cells by a virus, a virus in which the gene had mutated in such a way that it now produced an always-active protein, capable of continuously stimulating cell reproduction, which favored its generation. viral reproduction inside infected cells.
After this first oncogene, dozens of other oncogenes have been discovered, not all of which have been “stolen” by viruses. Since oncogenes produce activated oncoproteins that stimulate cell growth, many antitumor drugs act by inhibiting the action of these oncoproteins, particularly when these are enzymes that activate some molecular mechanism that stimulates cell division.
Cells during their reproduction follow an ordered set of steps leading to the generation of two identical daughter cells from an original cell. This ordered process is called the cell cycle. All oncogenes stimulate in one way or another the entry of cells into this cycle of cell reproduction.
However, for a cell to reproduce successfully, it is not enough just for it to receive growth signals, internal or external to itself, that activate the cell cycle. It is also necessary that the cell that is going to reproduce has the necessary matter and energy to reproduce. Without them, even one or more activated oncogenes would be unable to get the cell to reproduce. For this reason, normal genes that, when functioning in a high way, facilitate the obtaining of more energy or more raw material for cell reproduction, could indirectly act as oncogenes, promoting this process and allowing the generation of tumors more easily.
fatty liver disease and liver cancer.
Although today it is abundantly clear that the activity of one or another gene that stimulates cell reproduction is necessary for the appearance of tumors, some types of cancer still lack mutated genes that explain their appearance and growth. This is the case of liver carcinoma associated with non-alcoholic fatty liver disease. This disease and the associated cancer have seen their incidence increase in the developed world, especially because fatty liver is more frequent in the case of obesity. Between 30 and 40% of the adult population suffers from fatty liver, a percentage that rises to more than 75% among the obese. A percentage of those affected by fatty liver will develop liver carcinoma, a type of cancer that lacks a mutated gene that explains it and, therefore, also lacks a specific therapeutic strategy against it.
In order to try to find out which genes could be involved in the development of fatty liver disease and liver carcinoma, a large and better funded group of Chinese researchers (probably better funded than the vast majority of Spanish groups) have studied in depth the genomes of Cancer cells isolated from biopsies of fatty liver-associated liver carcinoma. In their studies, an apparently nondescript gene appears to be highly functioning in many tumors. This is the gene called squalene epoxidase (SQLE). This gene produces a very important enzyme for the synthesis of cholesterol.
Cholesterol is a fundamental molecule for the formation of cell membranes, and its synthesis can be a limiting step in cell reproduction, since if a sufficient amount of cell membrane cannot be generated, two daughter cells cannot be formed from an original one. . For this reason, the researchers decided to study the function of the gene in more detail. SQLE.
The researchers generate transgenic mice with higher levels of functioning of this gene and verify in them that the gene induces fatty liver and a higher incidence of liver tumors. The studies with these animals also allow them to conclude that the accelerated metabolism of cholesterol decreases the functioning of other genes that slow down cell reproduction, which is why it is accelerated.
The follow-up of patients with liver carcinoma also allows them to find out that the prognosis of the disease is much worse in those who have higher levels of gene function SQLE. This indicates that the gene may function as a novel marker of disease progression.
However, the most interesting thing is that there is already a drug in use capable of stopping the functioning of the squalene epoxidase enzyme. This is terbinafine, a drug used until now as an antifungal to treat, among other things, athlete’s foot. Scientists study the effect of terbinafine on the growth of liver carcinoma cells and find that it is greatly reduced both in cells grown in the laboratory and in tumors grown in mice. This antitumor effect is associated with the restoration to normal levels of the functioning of the genes that stop cell reproduction.
This is good news for the fight against cancer, as it is likely that not only liver tumors, but many other types as well, could benefit from terbinafine treatment. It will be necessary, however, to wait for clinical trials with patients to be carried out before terbinafine is available as an approved drug for antitumor use.
Reference: Dabin Liu et al. Squalene epoxidase drives NAFLD-induced hepatocellular carcinoma and is a pharmaceutical target. Sci. Transl. Med. 10, eaap9840 (2018).
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