Tribbles 2 mediates cisplatin sensitivity and DNA damage response in epithelial ovarian cancer |
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| Authors: | Daniel Kritsch Franziska Hoffmann Daniel Steinbach Lars Jansen Stella Mary Photini Mieczyslaw Gajda Alexander S. Mosig Jürgen Sonnemann Sven Peters Margarita Melnikova Jürgen Thomale Matthias Dürst Ingo B. Runnebaum Norman Häfner |
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| Affiliation: | 1. Department of Gynecology and Reproductive Medicine, Jena University Hospital, Friedrich‐Schiller University, Jena, Germany;2. Department of Obstetrics, Jena University Hospital, Friedrich‐Schiller University, Jena, Germany;3. Institute of Pathology, Jena University Hospital, Friedrich‐Schiller University, Jena, Germany;4. Department of Biochemistry II, Jena University Hospital, Friedrich‐Schiller University, Jena, Germany;5. Children's Clinic, Department of Pediatric Hematology and Oncology, Jena University Hospital, Friedrich‐Schiller University, Jena, Germany;6. Experimental Ophthalmology, Jena University Hospital, Friedrich‐Schiller University, Jena, Germany;7. DNA Repair Lab, Institute for Cell Biology, University Hospital Duisburg‐Essen, Essen, Germany |
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| Abstract: | Aim was to identify methylated genes with functional involvement in cisplatin‐resistance development of epithelial ovarian cancer (EOC). Genome‐wide analyses of hypermethylated CpG‐islands in resistant cell lines in combination with qRT‐PCR analyses were used to identify epigenetically silenced genes. EOC‐Type‐II tumors were analyzed for gene methylation and expression and TCGA data were interrogated in‐silico. Experiments revealed 37 commonly hypermethylated genes in resistant cells of which Tribbles 2 (TRIB2) showed the most pronounced downregulation on mRNA level and was characterized further. TRIB2 showed a reactivation after 5′‐Aza‐Cytidine treatment in resistant cells but a cisplatin‐dependent, prominent upregulation on mRNA level in sensitive cells, only. Re‐expression in resistant A2780 cells increased the sensitivity to cisplatin and other DNA‐damaging agents, but not taxanes. Contrary, knockdown of TRIB2 increased resistance to cisplatin in sensitive cells. TRIB2 was involved in the induction of a cisplatin‐dependent cell cycle arrest and apoptosis by influencing p21 and survivin expression. An increased Pt‐DNA‐adduct formation in TRIB2 re‐expressing cells did not translate in higher levels of dsDNA damage (yH2AX‐foci). Thus, TRIB2 is potentially involved in the signal transduction from nucleotide excision repair of intrastrand cross links. Importantly, patient stratification of two homogenous cohorts of EOC‐Type‐II patients from Jena (n = 38) and the TCGA (n = 149) by TRIB2 mRNA expression consistently revealed a significantly decreased PFS for patients with low TRIB2 levels (log‐rank p < 0.05). Tumors from resistant patients expressed the lowest levels of TRIB2. Downregulation of TRIB2 contributes to platin‐resistance and TRIB2 expression should be validated as prognostic and predictive marker for EOC. |
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| Keywords: | platin resistance DNA damage response ovarian cancer prognosis |
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