The RUNX1 transcription factor is expressed in serous epithelial ovarian carcinoma and contributes to cell proliferation, migration and invasion

Abstract

Previously, we have identified the RUNX1 gene as hypomethylated and overexpressed in post-chemotherapy (CT) primary cultures derived from epithelial ovarian cancer (EOC) patients, when compared with primary cultures derived from matched primary (prior to CT) tumors. Here we show that RUNX1 displays a trend of hypomethylation, although not significant, in omental metastases compared with primary EOC tumors. Surprisingly, RUNX1 displayed significantly higher expression not only in metastatic tissue, but also in high-grade primary tumors and even in low malignant potential tumors. The RUNX1 expression levels were almost identical in primary tumors and omental metastases, suggesting that RUNX1 hypomethylation might have a limited impact on its overexpression in advanced (metastatic) stage of the disease. Knockdown of the RUNX1 expression in EOC cells led to sharp decrease of cell proliferation and induced G 1 cell cycle arrest. Moreover, RUNX1 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon RUNX1 suppression, while a number of pro-apoptotic genes and some EOC tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the RUNX1 gene in EOC progression and suggest that RUNX1 might be a novel EOC therapeutic target. Further studies are needed to more completely elucidate the functional implications of RUNX1 and other members of the RUNX gene family in ovarian tumorigenesis.

Transient RUNX1 Expression during Early Mesendodermal Differentiation of hESCs Promotes Epithelial to Mesenchymal Transition through TGFB2 Signaling

“…These findings are consistent with the emerging role of RUNX1 in controlling cell motility and migration in other biological systems. Our laboratory has previously shown that Runx1 depletion in breast cancer cells results in a decreased migration and invasion phenotype (Browne et al., 2015); similar results were found in ovarian cancer cells (Keita et al., 2013). Likewise, Runx1b is responsible for inducing a cell adhesion and migration program prior to release of mouse hematopoietic stem cells from hemogenic endothelium (Lie-A-Ling et al., 2014).…”

MicroRNA-378-mediated suppression of Runx1 alleviates the aggressive phenotype of triple-negative MDA-MB-231 human breast cancer cells

“…Our study describes, for the first time, a clinically relevant mechanism for control of Runx1 in breast cancer through miRNA regulation. These studies showing that miR-378 expression inhibits breast cancer cell activities are relevant to other cancers where Runx1 is associated with tumorigenesis [6–8]; also, loss of miR-378 is associated with cancers [42–44], thereby becoming a viable therapeutic strategy. MicroRNAs are emerging as therapeutic molecules [23, 75] and a replacement therapy using a miR-34 mimic (called MRX34), a master tumor suppressor, was first administered to cancer patients in a multicenter, open-label phase I clinical trial, due to be completed later this year.…”

Thyroid Hormone Receptor-β (TRβ) Mediates Runt-Related Transcription Factor 2 (Runx2) Expression in Thyroid Cancer Cells: A Novel Signaling Pathway in Thyroid Cancer

“…The difference in expression corresponded to the degree of differentiation in PTC, FTC, and ATC with the greatest differences observed between normal and ATC cells. Since Runx1, another member of the Runx family, has also been implicated in breast (48), ovarian (49), prostate (50) and solid tumors, we also determined its relative expression. Runx 1 protein levels were not correlated with thyroid cancer cell types ( Figure 1A).…”