The Epidermal Growth Factor Receptor Responsive miR-125a Represses Mesenchymal Morphology in Ovarian Cancer Cells

Abstract

The epithelial-to-mesenchymal transition (EMT) that occurs during embryonic development is recapitulated during tumor metastasis. Important regulators of this process include growth factors, transcription factors, and adhesion molecules. New evidence suggests that microRNA (miRNA) activity contributes to metastatic progression and EMT; however, the mechanisms leading to altered miRNA expression during cancer progression remain poorly understood. Importantly, overexpression of the epidermal growth factor receptor (EGFR) in ovarian cancer correlates with poor disease outcome and induces EMT in ovarian cancer cells. We report that EGFR signaling leads to transcriptional repression of the miRNA miR-125a through the ETS family transcription factor PEA3. Overexpression of miR-125a induces conversion of highly invasive ovarian cancer cells from a mesenchymal to an epithelial morphology, suggesting miR-125a is a negative regulator of EMT. We identify AT-rich interactive domain 3B (ARID3B) as a target of miR-125a and demonstrate that ARID3B is overexpressed in human ovarian cancer. Repression of miR-125a through growth factor signaling represents a novel mechanism for regulating ovarian cancer invasive behavior.

Upregulation of Proapoptotic MicroRNA mir-125a After Massive Small Bowel Resection in Rats

“…Of relevance to our studies, previous publications have documented interactions between EGF and mir-125a in several malignancies. 43,44,58 For example, EGF has been shown to repress mir-125a transcription in ovarian cells. 58 Further studies are necessary to investigate the relationship between activation of this signaling pathway and the apoptosis-inducing effects of mir-125a in the intestine.…”

miR-125a inhibits the migration and invasion of liver cancer cells via suppression of the PI3K/AKT/mTOR signaling pathway

“…MicroRNAs (miRs) are single-stranded noncoding RNAs, containing 17-19 nucleotides, which are associated with the development and progression of tumors (8)(9)(10)(11)(12) such as oropharyngeal squamous cell carcinoma (8), non-small cell lung cancer (9), thyroid cancer (10). miR-125a has previously been reported to block the proliferation, invasion and migration of breast cancer cells (13), and was also found to be effective in preventing the invasion of ovarian cancer (14), glioma (15), lung cancer (16)(17)(18) and gastric cancer (19). miR-125a has been demonstrated to be implicated in hepatitis B virus duplication and the progression of hepatitis B (20,21).…”

ARID3B increases ovarian tumor burden and is associated with a cancer stem cell gene signature

“…Recently we demonstrated that ARID3B is significantly overexpressed in ovarian cancer compared to normal ovarian surface epithelium and benign ovarian tumors [19]. We wanted to establish a xenograft model of ovarian cancer in mice where ARID3B is expressed at comparable levels to what is observed in human tumors.…”

“…We previously demonstrated that ARID3B is overexpressed in human serous ovarian cancer [19]. However, it was not known if ARID3B expression might enhance ovarian cancer tumorgenicity as it does for neuroblastoma [16].…”