Scientists from Far Eastern Federal University (FEFU, Russia), University of Geneva (Switzerland), Minjiang University, and Fuzhou University (China) pointed out WDR74 protein playing an important role in lung cancer and melanoma primary tumours/metastases progression.

During the research, the artificially gained WDR74 function brought about a high activity in cancer cells. However, when the function had been dropped cells failed to metastasise becoming more vulnerable to chemotherapy.

Related articles are published in Cancer Letters and Oncogene.

Except for brain cancer and some forms of blood cancer, not the main tumour but its metastases kill the patient taking over vital organs.

Metastases form at a certain stage of the primary tumour progression when its cells start separating and entering the bloodstream.

Such cells are called circulating tumour cells, and they give rise to metastases which are secondary tumours appearing in different parts of the human body.

Fortunately, just subtle minority, tenths or even hundredths of a percent, of circulating tumour cells is capable of metastasising.

A few years ago, Chinese scientists from the laboratory of Dr. Lee Jia (Fuzhou University) wondered what discriminates "successful" circulating tumour cells from "unsuccessful" ones.

Searching for a possible answer, they analysed tumour cells (proteomic analysis) and spotted proteins highly expressed in active metastatic cells and lost in passive ones.

One of these proteins was WDR74; its expression level in "successful" circulating tumour cells was two times higher than in the initial tumour.

Scientists set up hypotheses stated this protein is a trigger helping a circulating tumour cell turn into a secondary tumour.

"Within this discovery, two of our scientific publications were being built, one devoted to lung cancer, and the other to melanoma.

To test the oncogenic activity of WDR74 in circulating tumour cells of lung cancer and melanoma, we "turned off" this protein by the method of gene correction CRISPR / Cas9 and interfering RNAs to remove/reduce the amount of protein.

After that, we monitored what happens to the cells in the context of their proliferation, colony formation, cell cycle, ability to migrate and grasp in body tissues.

We have also conducted the opposite experiment increasing the amount of WDR74 protein in cancer cells.

Both types of experiment confirmed that WDR74 plays a crucial role in the progression of the tumour and its metastases.

Protein absence decreases, and the presence increases the oncogenic properties of circulating tumour cells.

In vivo this confirmed during the experiments conducted on mice." said prof. Vladimir Katanaev, one of the research authors, Head of the Laboratory of Pharmacology of Natural Compounds, Department of Pharmacology and Pharmacy of the FEFU School of Biomedicine.

The scientist explained that WDR74 has at least two mechanisms of action.

In different tumours, they have different priorities.

In lung cancer cells, the protein primarily regulates WNT signalling pathways, which are active in tumour cells and passive in healthy cells of our body.

In melanoma, WDR74 indirectly affects the expression of a number of other proteins, including the famous p53.

The sequence is as follows: WDR74 regulates the amount of ribosomal protein RLP5, which has additional, extraribosomal properties; RLP5 regulates MDM2 protein ligase, and MDM2, in turn, leads to the degradation of p53 protein.

The question of which mechanism is responsible for the expression of WDR74 itself remains unsolved.

Lung cancer is notorious for the lack of effective therapy methods.

The same is melanoma: the mechanisms of its progression understood poorly.

The published studies open up new paths to the development of effective curing methods for metastases of these two cancer types with targeted drugs. Such remedies should hit specific protein targets in the circulating tumour cells.

The drugs development is the task of the next stage of the work of scientists from Russia, China, and Switzerland or other research groups.

Source: Far Eastern Federal University

Image: FEFU Press Office