Colorectal cancer – colon or rectum – is the third type of cancer most diagnosed worldwide, according to the report ‘The cancer figures in Spain 2025’. Environmental and lifestyle factors, such as inadequate food, lack of physical activity, obesity or consumption of toxic such as tobacco and alcohol are associated with up to 80% of cases.
Most colorectal cancers are developed from adenomatous polyps, which are a precaceral lesion that is not detected and removed in time can evolve towards a malignant tumor. Now, a study by Spanish scientists has discovered a new molecular mechanism that plays a key role in the formation of colorectal tumors and favors its progression towards more aggressive forms.
The research has been led by Nabil Djouder, head of the Group of Growth, Nutrient and Cancer Factors, of the National Oncological Research Center (CNIO). The team carried out research with mouse models in which they observed that a protein called P53 began to degrade – to reduce its presence – in the initial stages of the formation of tumors and that this allowed the appearance and development of cancer. The study results have been published in Nature Communications and offer new options for the development of colorectal cancer prevention strategies.
An innovative therapeutic approach to stop tumor progression
The antitumor function of P53 is known. This protein blocks the division of the cells and contributes to the destroying when they have a dysfunction, so it is considered that P53 is a tumor suppressor and that, by losing their function, the cells acquire the ability to grow in a uncontrolled way. However, the finding that the degradation of P53 begins the tumor process in colon cancer is completely new.
This study has revealed that the shortage of P53 favors tumor formation due to lack of control in cell proliferation, and 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.
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,” said Irene Herranz-Montoya, first author. With this objective, the team now focuses its work on the development of URI protein inhibitors.
“If we focus on investigating the molecular mechanisms that cause P53 degradation we could intervene in the initial stages of cancer and prevent their progression to more aggressive forms of the disease”
“The future lies in the inhibition of URI, a strategy that we are developing in the laboratory. We look Tumor progression and improve the treatment of patients, ”explains Djouder.
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.
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 adultsin 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 the P53 protein seems to happen independently to another process that was already known: the loss of the TP53 gene – that 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 a greater aggressiveness and propagation of metastasis.
Source: National Oncological Research Center (CNIO)
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