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Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
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Tribbles 2 mediates cisplatin sensitivity and DNA damage response in epithelial ovarian cancer

Daniel Kritsch1, Franziska Hoffmann1, Daniel Steinbach1

  • 1Department of Gynecology and Reproductive Medicine, Jena University Hospital, Friedrich-Schiller University, Jena, Germany.

International Journal of Cancer
|July 4, 2017
PubMed

Insights

Tribbles 2 (TRIB2) gene silencing contributes to cisplatin resistance in epithelial ovarian cancer (EOC). Restoring TRIB2 expression can re-sensitize EOC cells to chemotherapy, suggesting its potential as a prognostic marker.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Epithelial ovarian cancer (EOC) frequently develops resistance to cisplatin, a cornerstone chemotherapy.
  • Epigenetic modifications, particularly gene hypermethylation, are implicated in treatment resistance.
  • Identifying genes involved in cisplatin resistance is crucial for developing novel therapeutic strategies.

Purpose of the Study:

  • To identify epigenetically silenced genes functionally involved in cisplatin resistance in EOC.
  • To investigate the role of Tribbles 2 (TRIB2) in mediating cisplatin sensitivity and resistance.
  • To evaluate TRIB2 as a potential prognostic and predictive biomarker in EOC patients.

Main Methods:

  • Genome-wide methylation analysis of CpG islands in cisplatin-resistant EOC cell lines.
  • Quantitative reverse transcription PCR (qRT-PCR) to assess gene expression.
  • In silico analysis of The Cancer Genome Atlas (TCGA) data.
  • Functional studies involving gene re-expression and knockdown in EOC cells.
  • Analysis of patient cohorts for correlation between TRIB2 expression and progression-free survival (PFS).

Main Results:

  • 37 genes were commonly hypermethylated in resistant cells; TRIB2 exhibited significant downregulation.
  • TRIB2 re-expression in resistant cells increased sensitivity to cisplatin and other DNA-damaging agents.
  • TRIB2 knockdown in sensitive cells conferred cisplatin resistance.
  • TRIB2 influences cisplatin-induced cell cycle arrest and apoptosis via p21 and survivin.
  • Low TRIB2 mRNA expression in EOC tumors correlated with significantly decreased PFS in two independent patient cohorts.

Conclusions:

  • Downregulation of TRIB2, driven by hypermethylation, contributes to cisplatin resistance in EOC.
  • TRIB2 plays a role in DNA damage response pathways, potentially involving nucleotide excision repair.
  • TRIB2 expression levels may serve as a valuable prognostic and predictive biomarker for EOC treatment outcomes.
Keywords:
DNA damage responseovarian cancerplatin resistanceprognosis

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