A research team made up of staff from the Institute for Biomedical Research of Lleida (IRBLleida), the Bellvitge Biomedical Research Institute (IDIBELL) and the Center for Biomedical Research in Cancer Network (CIBERONC), among others, has identified a group of regulatory molecules that can decisively influence the progression of endometrial cancer. In the study, which they have recently published in the journal Cell Death & Disease, reveal the role of a cluster of miRNAs (called miR-424(322)~503) in endometrial cancer.

MicroRNAs (miRNAs) are small molecules that regulate gene activation and play a fundamental role in many biological processes, including cancer. In this context, they play an important role in several stages, from the onset of the disease to its progression and metastasis, but their contribution varies greatly depending on the specific type of miRNA and the specific type of cancer. In endometrial cancer, although several miRNAs involved have been identified so far, there is still much to be discovered about how they act in vivo in the body. And this research is a big step forward in this direction.

Endometrial cancer is a complex cancer, in which several molecular pathways involved in the normal maintenance of the endometrium are altered, contributing significantly to the onset and progression of cancer. Mutations in the PTEN gene, which is often mutated in patients, are among the most common.

A group of miRNAs with a different role depending on the type of cancer

When the PTEN gene loses its function, a molecular pathway called PI3K/AKT is overactivated, which promotes cell proliferation while preventing programmed cell death (apoptosis), an essential mechanism for maintaining tissue balance. Excessive proliferation and lack of cell death are two key ingredients to confer a malignant profile on endometrial cells, which become cancerous.

The researchers’ work wanted to delve into the relationship between PTEN loss and PI3K/AKT activation to see what other biological actors are involved. Focusing on the study of miRNAs, they have managed to identify a specific group, the miR-424(322)~503 cluster, which appears overexpressed when PTEN is lost.

This cluster, made up of two miRNAs (miRNA-424 and miRNA-503), is critical in the regulation of various cellular processes related to cancer. “Functionally, the role of this group of miRNAs in cancer is paradoxical, since they can be overexpressed or inhibited depending on the type of cancer, and act as oncogenes or tumour suppressors depending on the type of cell and its microenvironment,” explains Dr Maria Vidal, first author of the study and researcher at IRBLleida. Until now, its specific role in endometrial cancer had been minimally explored, so it was not very well known how it acted in this context,” she adds.

A decisive role in endometrial cancer, on the rise in recent years

Now, thanks to the new study, we have a more concrete idea of the role of these molecules in endometrial cancer. To do this, genetically modified mice have been created that have neither the PTEN gene nor the miRNA cluster. The results show how the double absence reduces the proliferation of cancer cells and restores the cells’ ability to die naturally, which slows tumor development. In other words, “in the context of the loss of the PTEN gene, which often occurs in patients with endometrial cancer, this cluster becomes a critical regulator of carcinogenesis: it triggers molecular changes that contribute to the development of cancer,” explains Dr. David Llobet, co-director of the work, principal investigator of the Gynecological Cancer group at IDIBELL and also a CIBERONC researcher.

The research team has proven this by going a step further: without the cluster, the aggressiveness of the tumour is significantly reduced and, in some cases, even prevents its formation. This is a very relevant discovery, considering that endometrial cancer affects about 420,000 women worldwide and registers more than 5,000 new cases in Spain each year. It is the most common cancer of the female sexual system and the 6th most common in women. Its incidence has increased globally in recent years constantly, partly due to the aging of the population, since it mainly affects post-menopausal women of 60 years of age on average.

An Important Discovery in Endometrial Cancer, and Beyond

In addition, the researchers have observed that this cluster also affects normal endometrial cells, suggesting that it could be involved in other diseases. “Apart from cancer, we have seen that this cluster can regulate broader aspects of endometrial biology and, therefore, it could participate in other endometrial pathologies such as endometriosis,” says Dr. Xavier Dolcet, co-director of the study, researcher at IRBLleida and also at CIBERONC.

In short, this discovery opens the door to new therapeutic strategies that could improve the treatment of endometrial cancer in the future, focusing on the regulation of microRNAs to recover lost cellular control mechanisms. It also expands the knowledge of the role of these molecules in the biology of the endometrium, and may open new avenues of research into their specific role in diseases with a high incidence but still quite unknown, such as endometriosis.

About this research

This research has been possible thanks to funding from the Institute for Biomedical Research of Lleida, the Ministry of Science, Innovation and Universities, the Carlos III Health Institute (co-financed with the European Regional Development Fund. ERDF, a way to build Europe) and the CIBERONC network (CB16/1200231). 

About IDIBELL

The Bellvitge Biomedical Research Institute (IDIBELL) is a research centre created in 2004 and specialising in cancer, neuroscience, translational medicine and regenerative medicine. It has a team of more than 1,500 professionals who, from 73 research groups, publish more than 1,400 scientific articles a year. L’IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Health Institute, the Catalan Institute of Oncology, the University of Barcelona and the City Council of L’Hospitalet de Llobregat.

IDIBELL is a member of the Campus d’Excelencia Internacional of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centres accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the HR Excellence in Research program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Centre of the AECC Scientific Foundation (FCAECC).