Starting with 2,942 genes that TCGA identified as overexpressed in the mesenchymal group, they narrowed that list to 253 genes, 219 of which were associated with miRNA.
They found that the 219 miRNA-associated mesenchymal genes divided 455 ovarian cancer patients into two clusters:
The team confirmed these results in three independent data sets totaling 560 ovarian cancer patients.
Nineteen miRNAs were identified, eight of which were predicted to control 89 percent of the 219 miRNA-associated genes. Of the eight, the least was known about miR-506, and it was least expressed in the mesencyhmal cases. "We decided to focus on miR-506," Zhang said.
miR-506 blocks mesenchymal, helps epithelial proteins
In a series of cell line experiments, the scientists forced overexpression of miR-506 and a control miRNA in ovarian cancer cells. Treated cells had much lower levels of two important mesenchymal markers and higher levels of E-cadherin, a protein vital to epithelial cells.
Additional experiments showed miR-506 specifically inhibited SNAI2, a mesenchymal-cell-promoting protein, by binding to the promoter region of its gene, blocking activation.
Transforming growth factor beta (TGF) induces epithelial-to-mesenchymal cell transition, and the team found that it was prominent in the mesenchymal type of ovarian cancer. In cancer cells treated with miR-506 and then treated with TGF, the miRNA completely abolished TGF's effects.
In human tumors, more miR-506 tied to improved survival
Analysis of 92 ovarian cancer tumors from Tianjin Hospital in Tianjin, China, showed:
|Contact: Scott Merville|
University of Texas M. D. Anderson Cancer Center