They describe a new molecular mechanism involved in the formation of colorectal tumors

Colorectal cancer – colon or rectum – is the third type of cancer most diagnosed worldwide. Up to 80 % of cases are related to environmental and lifestyle factors, such as an unhealthy diet, sedentary lifestyle, obesity, smoking or excessive alcohol consumption. Most colorectal cancers originate from adenomatous polyps, a precaceral lesion that, if not detected and removed in time, can evolve towards a malignant tumor.

A recent study published in Nature Communications It describes a new molecular mechanism involved in the formation of colorectal tumors and that favors its progression towards more aggressive forms. The investigation has been led by Nabil DjouderHead of the group of Growth Factors, Nutrients and Cancer, of the National Oncological Research Center (CNIO). This discovery opens new paths for the development of colorectal cancer prevention strategies.

P53 shortage, the vigilante of the cell division

In research with mouse models, the authors observed that a protein, called P53, began to degrade – to reduce its presence – in the initial stages of tumors formation. This allowed the appearance and development of cancer.

The antitumor function of P53 is known. This protein blocks the division of cells and contributes to the destroying when they have some dysfunction, so P53 is considered a tumor suppressor. When P53 loses its function, cells acquire the ability to grow out of control. However, the finding that the degradation of P53 begins the tumor process in colon cancer is completely new.

This study, with Irene Herranz-Montoya as first authorfind that The shortage of P53 favors tumor formation due to lack of control in cell proliferationand also facilitates that tumor cells accumulate other mutations that, together, drive the progression to more aggressive tumors.

In addition, the CNIO group has identified an unprecedented mechanism in the regulation of P53 levels. It is a protein called URI, known for its expression in other types of cancer. This study shows that when URI levels increase in cells, it decreases P53.

New way for prevention

Previous works, especially the Nabil Djouder team, had already related URI protein with other types of cancer, especially with the liver. But this is the first time that URI is associated with colorectal tumors. “URI levels begin to rise very at the beginning, which leads to adenoma formation, an aberrant growth that still does not constitute cancer, but it is at that stage where P53 begins to degrade” “explains Herranz.

In their experiments in mice they saw that, If they eliminated URI or raised the P53 levels in the polyps, they did not transform into tumors and mice with colorectal cancer lived longer.

“Our results provide more detailed compression of how colorectal cancer evolves. If we focus on investigating the molecular mechanisms that cause the degradation of P53, including the increase of URI, we could in the future intervene in the initial stages of cancer and prevent its progression to more aggressive forms of the disease”says Herranz. With this objective, the team now focuses its work on the development of URI protein inhibitors.

“The future lies in the inhibition of URI, a strategy that we are developing in the laboratory. We look tumor progression and improving the treatment of patients “, Djouder explains.

The published work demonstrates that URI’s expression is regulated by MyC, an oncogen that plays a crucial role at the beginning of colon cancer due to its involvement in cell proliferation and in the regulation of other key genes for cancer. MyC activates Uri’s expression, which degrades P53 and thus favors the beginning of the tumor process.

Lifestyle and diet relationship

Djouder points out that this new mechanism could shed light on recent studies that investigate the possible causes of the increase in the incidence of colorectal cancer in young adults, in relation to environmental factors and lifestyles.

“Previously, my team has also shown that URI’s expression is related to certain environmental factors, such as a bad diet, both in other types of cancer and in the intestine. This suggests that URI and the degradation of P53 at the beginning of colorectal cancer could be associated with these factors”explains Djouder.

On the other hand, the progressive decrease in P53 protein seems to happen independently to another process that was already known: the loss of the gene TP53 –The who encodes the P53 protein– in late stages of colorectal cancer. Both processes can occur and influence parallel cancer: protein degradation in the initial phases, and the loss of gene in more advanced stages and in the context of greater aggressiveness and the propagation of metastasis.

The study has been validated using human samples, donated by the biobanco of the Ramon and Cajal hospital and in collaboration with Cristian Perna, from patients with adenomas and colon cancer in advanced stages. In addition, it has been complemented with analyzed data with bioinformatic methods.

Financing

CNIO is a public research center dependent on the Ministry of Science, Innovation and Universities.

This study has been financed with funds from the Ministry of Science, Innovation and Universities, the Spanish Association against Cancer (AECC), the BBVA Foundation, and the public system of Spanish science.