Functional characterization of a novel transcript of ERCC1 in chemotherapy resistance of ovarian cancer.

Jia Liu,Lawrence Owusu,Guoqiang Jiang,Likun Liu,Wei Yang,Lin Zhang,Ping Mao,Weiling Li,Jing Wang

doi:10.18632/oncotarget.20482

Abstract

Approximately 15-20% of ovarian cancer patients receiving platinum-based chemotherapy are primary platinum-resistant. Identification of these patients and transfer to other more effective therapy could reduce the morbidity of ovarian cancer. ERCC1 is a DNA repair gene which can complex with XPF to repair cisplatin-induced DNA damage and cause chemotherapy resistance. In this study, we found a novel ERCC1 transcript initiated upstream of the normal transcription initiation site. The expression of this larger ERCC1 transcript dramatically increased following cisplatin treatment in ovarian cancer cells and was regulated by the MAPK pathway. This phenomenon conferred enhanced cisplatin resistance on ovarian cancer cells, and was confirmed with chemosensitive and chemoresistant patients’ samples. Our data suggested that larger ERCC1 transcript levels correlated with the outcome of platinum-based chemotherapy.

Highlights

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies in the world [1]
If novel Excision repair cross complementation group-1 (ERCC1) transcripts originating www.impactjournals.com/oncotarget upstream existed, these primers in combination with reverse primer H-exon 2-3, which is located in ERCC1 exon 2, should generate polymerase chain reaction (PCR) products from 291bp to 419bp
The sizes of the gel bands with the different primer pairs agreed with our prediction (Figure 1B). This indicated that the novel larger ERCC1 transcript originating upstream of ERCC1 existed in human ovarian cancer cells

Summary

Introduction

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies in the world [1]. The first line therapy for ovarian cancer patients is usually traditional surgery followed by combination platinumbased chemotherapy which may result in complete clinical remission in up to 75% of cases [2]. Most of platiumsensitive patients will eventually become refractory to the treatment. All recurrent ovarian cancer patients develop platinum-resistance over time in terms of secondary platinum-resistance [3]. The remaining 15-20% of patients will not respond to the initial chemotherapy [4]. There is no reliable diagnostic biomarker for the resistant patients [5]. It remains urgent to investigate the underlying mechanisms of chemotherapy resistance and to identify the patients who are resistant to traditional platinum-based chemotherapy to redirect them to alternative therapy

Methods

Results

Conclusion