RFWD3 modulates response to platinum chemotherapy and promotes cancer associated phenotypes in high grade serous...

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• High-grade serous ovarian cancer (HGSOC) frequently exhibits dysregulated DNA damage repair pathways.
• RFWD3 is a critical protein involved in DNA repair and maintenance, with its role in HGSOC being largely unexplored.

Purpose of the Study:

• To investigate the impact of RFWD3 expression on HGSOC characteristics and chemosensitivity.
• To explore RFWD3's functional roles beyond DNA repair in HGSOC.

Main Methods:

• In silico analysis of TCGA HGSOC dataset and immunohistochemistry on patient tumors.
• In vitro studies using siRNA and CRISPR/cas9 to modulate RFWD3 expression in cell lines.
• Characterization of cell lines via cytotoxicity, proliferation assays, flow cytometry, and live cell microscopy.

Main Results:

• RFWD3 expression levels varied significantly in HGSOC tumors and cell lines.
• Reduced RFWD3 expression enhanced sensitivity to DNA crosslinking agents (mitomycin C, carboplatin).
• RFWD3 deficiency led to cell cycle dysregulation, decreased proliferation, reduced migration, increased tumor mutational burden, and complete response to platinum chemotherapy.

Conclusions:

• RFWD3 expression is variable in HGSOC and influences cellular and tumor-level functions.
• RFWD3's role extends beyond DNA repair, impacting HGSOC cell behavior and treatment outcomes.