Growth and Spread of Ovarian Cancer Mediated by a Specific MicroRNA

Cancer researchers have linked the gene silencing activity of a specific microRNA (miRNA) to TGF-beta (transforming growth factor beta)-mediated molecular pathways that support the growth and spread of ovarian cancer.

MicroRNAs (miRNAs) are a small noncoding family of 19- to 25-nucleotide RNAs that regulate gene expression by targeting mRNAs in a sequence specific manner, inducing translational repression or mRNA degradation, depending on the degree of complementarity between miRNAs and their targets. Many miRNAs are conserved in sequence between distantly related organisms, suggesting that these molecules participate in essential processes. In fact, miRNAs have been shown to be involved in the regulation of gene expression during development, cell proliferation, apoptosis, glucose metabolism, stress resistance, and cancer.

Investigators at Case Western Reserve University (Cleveland, OH, USA) reported in a study published in the January 7, 2014, online edition of the journal Nature Communications that the microRNA miR-181a promoted TGF-beta-mediated epithelial-to-mesenchymal transition (a step critical to cancer spread) via repression of its functional target, the gene SMAD7.

TGF-beta acts as an antiproliferative factor in normal epithelial cells and at early stages of cancer development. When a cell is transformed into a cancer cell, parts of the TGF-beta signaling pathway are mutated, and TGF-beta no longer controls the cell. These cancer cells and surrounding stromal cells begin to proliferate. Both types of cell increase their production of TGF-beta. This TGF-beta acts on the surrounding stromal cells, immune cells, endothelial and smooth muscle cells. It causes immunosuppression and angiogenesis, which makes the cancer more invasive.

The SMAD7 gene product generally shuts down the TGF-beta signaling pathway. However, when miR-181a silences the expression of SMAD7, TGF-beta is not suppressed and metastasis is promoted.

"We found that this (miR-181a) was one of the top expressing microRNAs in tumors from patients who recurred within the first six months after treatment," said senior author Dr. Analisa DiFeo, assistant professor of general medical science-oncology at Case Western Reserve University. "We also found higher levels in recurrent tumors compared to primary tumors in the women we tested. By looking at the expression of this microRNA in tumor samples, we get an idea of which women may respond to standard chemotherapy and which are at a high risk for recurrence. This helps guide treatment decisions and improve survival rates."

"We are now looking for small molecules that can block the interaction between miR-181a and SMAD 7, stop TGF-beta activation and prevent this micro-RNA from spreading and disseminating ovarian cancer," said Dr. DiFeo.

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