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The epidermal growth factor receptor responsive miR-125a represses mesenchymal morphology in ovarian cancer cells
Karen D Cowden Dahl1, Richard Dahl, Jessica N Kruichak
1Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, NM 87131-0001, USA. kcowdendahl@salud.unm.edu
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.
Insights
Epidermal growth factor receptor (EGFR) signaling represses miR-125a, a microRNA that inhibits ovarian cancer cell invasion. This pathway promotes metastasis by altering microRNA expression, offering new therapeutic targets.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Epithelial-to-mesenchymal transition (EMT) is crucial for embryonic development and tumor metastasis.
- MicroRNAs (miRNAs) are increasingly recognized as regulators of cancer progression and EMT.
- Epidermal growth factor receptor (EGFR) overexpression in ovarian cancer correlates with poor prognosis and induces EMT.
Purpose of the Study:
- To elucidate the mechanisms by which EGFR signaling influences miRNA expression in ovarian cancer.
- To investigate the role of miR-125a in regulating EMT and invasive behavior of ovarian cancer cells.
- To identify novel regulators of ovarian cancer metastasis.
Main Methods:
- Analysis of EGFR signaling pathways in ovarian cancer cells.
- Quantitative PCR to measure miRNA expression levels.
- Western blotting to assess protein expression of transcription factors and target genes.
- Cell morphology and invasion assays.
Main Results:
- EGFR signaling transcriptionally represses the miRNA miR-125a via the transcription factor PEA3.
- Overexpression of miR-125a promotes the conversion of invasive ovarian cancer cells from mesenchymal to epithelial morphology, indicating it's an EMT suppressor.
- AT-rich interactive domain 3B (ARID3B) was identified as a direct target of miR-125a and is overexpressed in human ovarian cancers.
Conclusions:
- EGFR-mediated repression of miR-125a is a novel mechanism driving ovarian cancer cell invasion and metastasis.
- miR-125a acts as a tumor suppressor by inhibiting EMT and invasive phenotypes.
- Targeting the EGFR-PEA3-miR-125a-ARID3B axis may offer therapeutic strategies for ovarian cancer.
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