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Skin cancer teams up with Sonic the Hedgehog

March 08, 2016

Basal cell carcinoma (also known as basalioma or basal cell cancer -- BCC) is the most common, and the 5th expensive cancer type to cure, making about 90% of malignant skin tumors. Among risk factors there are genetic malfunctions, appearance of freckles, x-rays and radiation, burns or use of immunosuppressive medication (for organ transplantation, for instance).

'The work led by Sergey Nikolaev, University of Geneva, resulted in a finding that more than 80% of BCC cases contain gene mutations leading to tumor formation of other types, that were not associated with BCC initially. This discovery proves the existence of mechanisms helping BCC to resist anticancer therapy, which opens new range of opportunities for further clinical trials,' explains Vladimir Seplyarskiy, coauthor of the paper and junior researcher at the Bioengineering and Bioinformatics Department, Moscow State University.

Supersonic hedgehog & Co

Among genes and corresponding proteins where mutative malfunctions provoke cancer in 'the basal cell carcinoma inquiry' appear the elements of a Sonic hedgehog (Hh) signaling pathway. Hh manages task distribution among cells during the embryogenesis and further 'self-determination', as well as forming of organs' left-side and right-side orientation.

Under normal conditions the Sonic hedgehog signaling pathway is started by an eponymous signaling protein. Found first in drosophila, the Sonic hedgehog gene, which's absence made flies' embryos look like thorny balls, was actually named after Supersonic The Hedgehog, a character of comics and videogames.

85% of basalioma cover gene of the Sonic hedgehog signaling pathway, which leads to it's activation without a help of the 'regulating hedgehog'.

There belong PTCH1 receptors and SMO protein immersed in the cell membrane, which passes the hedgehogs protein's instruction to start protein synthesis to Gli transcription factor. Together with that, among 'the accused' in more than a half of tumor cells a 'broken' version of TP53 gene can be found, that under normal conditions suppresses forming of a tumor and orders the cells containing a defective DNA to 'commit suicide' by apoptosis.

Sabotaging treatment: who is behind that?

A SMO protein suppression, enabled by a medicine called Vismodegib, neutralizes breach's consequences in a chain interaction controlled by the Sonic hedgehog gene. Thanks to that medicine, the orders of the commander do not reach its subjects, and the job of the whole chain is stopped: so, pulling one of the first dominoes in a row, you can prevent falling of all other.

Though in 50% of cases the tumor tissue either does not react to medical treatment, or develop resistance. It is SMO protein mutations responsible for a half of those complications: they prevent interaction of Vismodegib and SMO, however reasons for the second half remain unknown.

That is why scientists payed attention to the fact that 85% of basal carcinoma contain genetic mutations, related to other cancer types development, including far more dangerous, such as melanoma.

After detecting those oncogenic gene mutations, scientists managed to confirm activation of corresponding cancer tracts experimentally. One of the important observations made during the research was that the detected mutations are often seen in a subtype of aggressive basaliomas.

'We researched the peculiarities of mutation process happening in basalis cellular carcinoma cells. More than 100 of cancer exomes (a part of genome consisting of protein-coding DNA sequences) allow both to find out, which genes provoke this type of cancer, and to research, which processes help storing mutations (most of which do not influence cancer development even in cancer samples). We compared mutation profile of basal cell carcinoma with other cancer type -- melanoma, also provoked by ultraviolet radiation. As the result we managed conclude that oxidative stress and UV play a more important role in basal cell carcinoma development,' tells Vladimir Seplyarskiy.

Criminogenic schemes

To catch the remaining accomplices red-handed in that nearly detective story, biologists analyzed 293 species of tumor tissues of 236 patients. 30 species belonged to Gorlin syndrome sufferers (a genetic disease, dramatically increasing the likelihood of multiple basaliomas appearance). Among them were also 23 Vismodegib-resistiant and 259 not exposed to the medicine.

Scientists compared mutations in basalioma, melanoma, Wilson disease (kidney cancer usually formed in the first-third year of life) and other cancer types, which are probably connected with Sonic hedgehog gene and its 'accomplices' of the same pathway.

The inquiry showed: of 387 genes in the 'list of suspects' several may contribute to the appearance of basalis cellular carcinoma and developing sustainability to treatment. Among them -- genes forming Hippo-YAP pathway, and not only Sonic hedgehog controlled pathways, that used to bear the whole responsibility. Also in basal carcinoma N-Myc protein content were exceeded, that was caused by point mutation (replacement of one nucleotide - a DNA 'letter') in ??1 site. In other tumor types, where N-Myc protein in a high concentration was 'caught red-handed' earlier, the reason was a mutation provoking multiple increase of MYCN gene's copies.

According to Vladimir Seplyarskiy, 'this study is a turning point in understanding molecular mechanisms of appearance and development of basalis carcinoma. The fact that basilioma cells are subject to oxidative stress may give start to an alternative anticancer therapy of basalis cellular carcinoma.'. The results also show which mutagens affect DNA damage in skin cells, the researcher says.

Lomonosov Moscow State University

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