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Int J Cancer. 2017 Oct 15;141(8):1600-1614. doi: 10.1002/ijc.30860. Epub 2017 Jul 12.

Tribbles 2 mediates cisplatin sensitivity and DNA damage response in epithelial ovarian cancer.

Author information

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.

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.

KEYWORDS:

DNA damage response; ovarian cancer; platin resistance; prognosis

PMID:
28670762
DOI:
10.1002/ijc.30860
[Indexed for MEDLINE]

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