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

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.

Effect of 5‐fluorouracil on excision repair cross‐complementing 1 expression and consequent cytotoxicity regulation in human gastric cancer cells

“…Increasing clinical evidence has indicated that the lower ERCC1 expression might result in a better outcome for gastric cancer patients with platinum‐containing anticancer drugs‐based chemotherapy. However, the higher expression of ERCC1 might lead to the drug resistance development in cancer cells . Our present results also further supported the biomarker role of ERCC1 in evaluating the curative rate of patients with chemotherapy because we demonstrated that ERCC1 induction could attenuate the cytotoxicity of 5‐FU in AGS gastric cancer cells.…”

“…However, the higher expression of ERCC1 might lead to the drug resistance development in cancer cells. 12,14,16,17,[19][20][21]27 Our present results also further supported the biomarker role of ERCC1 in evaluating the curative rate of patients with chemotherapy because we demonstrated that ERCC1 induction could attenuate the cytotoxicity of 5-FU in AGS gastric cancer cells.…”

“…Both ERK1/2 and p38 kinases, which are the important members of MAPK pathway, have been shown to regulate the cell growth and death and could be activated under DNA damage stimulator treatment . Moreover, previous studies have also shown that ERK1/2 activation could affect the development of drug resistance to 5‐FU in hepatoma and breast cancer cells or cisplatin in lung cancer, ovarian cancer, and melanoma cells . C‐jun has been indicated to play the major role in regulating the transcription of ERCC1 and other NER enzyme genes .…”

“…In gastric cancer therapy, 5‐FU and platinum‐containing anticancer drugs are main clinical medication for patients . It has been demonstrated that NER system, including ERCC1, is the major inducer of drug resistance to platinum‐containing anticancer drugs in gastric cancer cells . ERCC1 gene knockdown in gastric cancer cells has been shown to effectively ameliorate the development of drug resistance for platinum‐based medication .…”

“…After combining with the ERCC4, the ERCC1‐ERCC4 complex could contribute to the 5′‐incision activity in regulating the process of DNA repair and DNA recombination . However, accumulating evidence has further shown an inverse correlation between the expression level of ERCC1 and cellular and clinical resistance to platinum‐containing anticancer drugs in many types of cancers, such as gastric cancer, ovarian cancer, and non–small‐cell lung carcinoma . Hence, although it still has controversy, ERCC1 has been suggested to be a potential clinical predictor candidate for the therapeutic efficiency and survival evaluations of patients with gastric cancer administered with the platinum‐containing anticancer drugs chemotherapy.…”