Researchers report discoveries regarding a molecule with the potential to treat ovarian cancer

The FAPESP-funded Center for Cell-Based Therapy explored the action mechanism of a microRNA that reduces tumor size and blocks metastasis when overexpressed.

By Maria Fernanda Ziegler  |  Agência FAPESP – Scientists in Brazil and the United States have reported discoveries regarding a molecule with the potential to combat ovarian cancer and prevent it from spreading to other parts of the body (metastasis). The article is published in the journal Cancer Research.

The molecule miR-450a is usually underexpressed in tumors, but experiments in cultured cells and mice showed that when overexpressed, it can have positive effects on the treatment of cancer by silencing genes involved in cell migration and tumor energy metabolism.

The study was conducted at the Center for Cell-Based Therapy (CTC). CTC is a Research, Innovation and Dissemination Center (RIDC) funded by FAPESP and hosted by the University of São Paulo (USP) at Ribeirão Preto, São Paulo State.

Markus Hafner, a researcher at the Laboratory of Muscle Stem Cells and Gene Regulation, also contributed to the study. The laboratory is a part of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, one of the National Institutes of Health (NIH) in the United States.

“It’s a promising molecule that can be the basis for future therapeutic strategies against ovarian cancer using nanotechnology,” Wilson Araújo da Silva Junior, a researcher affiliated with CTC and principal investigator for the study, told Agência FAPESP.

Ovarian cancer is initially asymptomatic and often goes undetected until it is already at an advanced stage. Surgery is currently the main component of treatment. “Administration of miR-450a, with or without chemotherapy, can contribute as neoadjuvant therapy [to shrink the tumor before surgery], improving the preoperative response rate. In more advanced cases, it could reduce the risk of progression or death, possibly with less severe side effects than chemotherapy. Another interesting point is the molecule’s capacity to block the process of metastasis,” Silva Junior said.

Cell energy reduction

MicroRNAs like miR-450a are small RNAs that do not encode proteins but perform a regulatory role in the genome and hence in several intracellular processes. They bind to messenger RNAs expressed by genes and break them down or prevent them from being translated into proteins. An increase in a cell’s microRNA expression, therefore, means that a process is being inhibited.

In vitro and in vivo trials performed at CTC as part of the PhD research of Bruna Muys, who is supported by a scholarship from FAPESP, showed that when miR-450a was overexpressed, it not only reduced the tumor but also blocked the process of metastasis. However, it was still necessary to identify the proliferation and cell invasion genes that were inhibited by the molecule.

In this stage of the study, the researchers collaborated with the NIH group via a research internship abroad (BEPE) with support from FAPESP.

“After the characterization stage, we had to find out which cellular migration and invasion genes were regulated by miR-450a,” Silva Junior said. “With the technology available at the NIH lab to look for noncoding RNA targets, we discovered that this microRNA also caused cell death by reducing cell energy.”

The researchers found that miR-450a blocked genes associated with vimentin, a protein in the cell invasion pathway. It also dysregulated genes involved in the epithelial-to-mesenchymal transition pathway – essential for cell migration, invasion and resistance to apoptosis (programmed cell death) – thereby inhibiting the process of metastasis.

The molecule also decreased tumor growth by inhibiting one mitochondrial gene (MT-ND2) and three nuclear genes (ACO2, ATP5B and TIMMDC1) involved in one of the stages of cell respiration and in energy production (oxidative phosphorylation).

As a result of the changes in energy metabolism, glutaminolysis decreased and glycolysis increased in cells that overexpressed miR-450a. According to researchers, this energy imbalance may lead to inefficient production of lipids, amino acids and nucleic acids by tumor cells, inhibiting the signaling pathways associated with tumor cell migration and invasion

Information from placenta

The details of this molecule’s action mechanism were discovered as a result of Muys’s master’s research, which was also supported by FAPESP and was linked to CTC. The study, published in PLOS ONE in 2016, showed that expression of miR-450a was high in placenta and low in tumors, including ovarian tumors. The group concluded that in the placenta, this and other microRNAs regulate mechanisms that are analogous to tumor development.

Although placenta and tumor formation are entirely different processes, their genetic programming is similar to a certain extent. “The placenta grows, invades the womb, proliferates, and undergoes vascularization in a process called angiogenesis. This is all tumors need, but genetic programming acts in a controlled manner in the placenta and not in tumors,” Silva Junior said.

The group then decided to look for novel therapeutic targets by studying genes that are highly expressed in the placenta and are inactive in tumors. “This correlation means molecules like miR-450a cease to regulate biological processes that are important to tumor development. Based on our findings, if a gene appears with these characteristics, we can assume it could be a good therapeutic target,” Silva Junior explained.

The article “miR-450a acts as a tumor suppressor in ovarian cancer by regulating energy metabolism” (doi: 10.1158/0008-5472 CAN-19-0490) by Bruna Rodrigues Muys, Joanne F. Sousa, Jessica Rodrigues Place, Luiz Ferreira de Araújo, Aisha A. Arshad, Dimitris G. Anastasias, Xian Tao Wang, Xiao Ling Li, Greece Andreotti de Molfetta, Annalisa Rambo, Ashish Lal, Daniel Notre Vidal, Markus Hafner and Wilson A. Silva can be retrieved from: cancerres.aacrjournals.org/content/79/13/3294.