Journal article
The O-glycan pathway is associated with in vitro sensitivity to gemcitabine and overall survival from ovarian cancer
International journal of oncology, Vol.41(1), pp.179-188
07/2012
DOI: 10.3892/ijo.2012.1451
PMCID: PMC4017641
PMID: 22552627
Abstract
Ovarian cancer (OVCA) is the most lethal gynecological malignancy. The high mortality rate associated with this disease is due in large part to the development of resistance to chemotherapy; however, the biological basis of this remains unclear. Gemcitabine is frequently used for the treatment of patients with platinum-resistant OVCA. We report molecular signaling pathways associated with OVCA response to gemcitabine. Forty-one OVCA cell lines were subjected to gene expression analysis; in parallel, IC50 values for gemcitabine were quantified using CellTiter-Blue viability assays. Pearson's correlation coefficients were calculated for gene expression and gemcitabine IC50 values. The genes associated with gemcitabine sensitivity were subjected to pathway analysis. For the identified pathways, principal component analysis was used to derive pathway signatures and corresponding scores, which represent overall measures of pathway expression. Expression levels of the identified pathways were then evaluated in a series of clinico-genomic datasets from 142 patients with stage III/IV serous OVCA. We found that in vitro gemcitabine sensitivity was associated with expression of 131 genes (p<0.001). These genes include significant representation of three molecular signaling pathways (p<0.02): O-glycan biosynthesis, Role of Nek in cell cycle regulation and Antiviral actions of Interferons. In an external clinico-genomic OVCA dataset (n=142), expression of the O-glycan pathway was associated with overall survival, independent of surgical cytoreductive status, grade and age (p<0.001). Expression levels of Role of Nek in cell cycle regulation and Antiviral actions of Interferons were not associated with survival (p=0.31 and p=0.54, respectively). Collectively, expression of the O-glycan biosynthesis pathway, which modifies protein function via post-translational carbohydrate binding, is independently associated with overall survival from OVCA. Our findings shed light on the molecular basis of OVCA responsiveness to gemcitabine and also identify a signaling pathway that may influence patient survival.
Details
- Title: Subtitle
- The O-glycan pathway is associated with in vitro sensitivity to gemcitabine and overall survival from ovarian cancer
- Creators
- Nadim Bou Zgheib - Department of Women's Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USAYin XiongDouglas C MarchionElona BicakuHye Sook ChonXiaomang Ba SticklesEntidhar Al SawahPatricia L JudsonArdeshir HakamJesus Gonzalez-BosquetRobert M WenhamSachin M ApteChristopher L CubittDung Tsa ChenJohnathan M Lancaster
- Resource Type
- Journal article
- Publication Details
- International journal of oncology, Vol.41(1), pp.179-188
- Publisher
- Greece
- DOI
- 10.3892/ijo.2012.1451
- PMID
- 22552627
- PMCID
- PMC4017641
- ISSN
- 1019-6439
- eISSN
- 1791-2423
- Grant note
- R21 CA110499 / NCI NIH HHS R21 CA-110499-01A2 / NCI NIH HHS P30 CA076292 / NCI NIH HHS
- Language
- English
- Date published
- 07/2012
- Academic Unit
- Obstetrics and Gynecology
- Record Identifier
- 9983931818702771
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