Abstract
Chemoresistance to anticancer drugs substantially reduces survival in epithelial ovarian carcinoma (EOC). Here, microarray analysis showed that collagen type XI alpha 1 (COL11A1) is a chemotherapy response-associated gene. Chemoresistant cells expressed higher COL11A1 and c/EBPβ than chemosensitive cells. COL11A1 or c/EBPβ downregulation suppressed chemoresistance, whereas COL11A1 overexpression attenuated sensitivity to cisplatin and paclitaxel.The c/EBPβ binding site in the COL11A1 promoter was identified as the major determinant of cisplatin- and paclitaxel-induced COL11A1 expression. Immunoprecipitation and immunofluorescence showed that in resistant cells, Akt and PDK1 were highly expressed and that anticancer drugs enhanced binding activity between COL11A1 and PDK1 binding and attenuated PDK1 ubiquitination and degradation. Conversely, chemosensitive cells showed decreased activity of COL11A1 binding to PDK1 and increased PDK1 ubiquitination, which were reversed by COL11A1 overexpression. Analysis of 104 EOC patients showed that high COL11A1 mRNA levels are significantly associated with poor chemoresponse and clinical outcome.
Highlights
Epithelial ovarian carcinoma (EOC) is the most lethal gynaecologic malignancy [1]
The five most differentially expressed genes (POSTN, COL11A1, INHBA, TWIST1, and THBS2) were selected and real-time RT-polymerase chain reaction (PCR) data both confirmed the reliability of www.impactjournals.com/oncotarget our expression data and identified COL11A1 as the most highly elevated transcript linked to chemoresistance, with an 8-fold increase compared to that of the control
The principal finding of our study is that EOC patients with COL11A1 overexpression had a higher rate of resistance to chemotherapy and shorter survival after first-line platinum-based regimens, indicating that elevated COL11A1 expression is an important chemoresistance marker of poor long-term survival
Summary
Despite cytoreductive surgery followed by combination cisplatin and paclitaxel chemotherapy, many EOC patients eventually relapse, develop chemoresistant tumours, and die from the disease [2]. Several studies have used gene microarrays to identify distinct genes expressed in chemoresistant EOC patients [3,4,5,6]. We analysed the expression profiles of 60 epithelial ovarian cancer tissue samples obtained at first cytoreductive surgery to identify genes associated with response to chemotherapy. Our previous findings identified COL11A1 as a disease progression-associated gene that is linked to EOC recurrence and poor survival [7]. The molecular mechanisms underlying COL11A1-increased cancer drug resistance were elucidated, providing an understanding of the mode of action
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