The Impacts of ERCC1 Gene Exon VIII Alternative Splicing on Cisplatin-Resistance in Ovarian Cancer Cells

Sun, Yehong; Li, Tiyuan; Ma, Kewei; Tian, Zhongkai; Zhu, Ying; Chen, Fuqiang; Hu, Gang

doi:10.3109/07357900902744536

Cited by 25 publications

(14 citation statements)

References 28 publications

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“…However, the physiological relevance of these findings in a breast cancer cell line to RBM38 function in vivo is unknown, but could potentially be linked to cancer. For example, one RBM38-regulated splicing event, activation of excision repair cross complementation group-1 (ERCC1) exon 8, occurs in ovarian cancer cells and has been linked to cisplatin-resistance [40]. Nonetheless, to further investigate the in vivo functions of RBM38 regulated splicing we sought to identify potential roles of RBM38 in non-transformed cell types that more closely resemble cells where it is expressed in vivo .…”

Section: Resultsmentioning

confidence: 99%

The RNA Binding Protein RBM38 (RNPC1) Regulates Splicing during Late Erythroid Differentiation

et al. 2013

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Alternative pre-mRNA splicing is a prevalent mechanism in mammals that promotes proteomic diversity, including expression of cell-type specific protein isoforms. We characterized a role for RBM38 (RNPC1) in regulation of alternative splicing during late erythroid differentiation. We used an Affymetrix human exon junction (HJAY) splicing microarray to identify a panel of RBM38-regulated alternatively spliced transcripts. Using microarray databases, we noted high RBM38 expression levels in CD71+ erythroid cells and thus chose to examine RBM38 expression during erythroid differentiation of human hematopoietic stem cells, detecting enhanced RBM38 expression during late erythroid differentiation. In differentiated erythroid cells, we validated a subset of RBM38-regulated splicing events and determined that RBM38 regulates activation of Protein 4.1R (EPB41) exon 16 during late erythroid differentiation. Using Epb41 minigenes, Rbm38 was found to be a robust activator of exon 16 splicing. To further address the mechanism of RBM38-regulated alternative splicing, a novel mammalian protein expression system, followed by SELEX-Seq, was used to identify a GU-rich RBM38 binding motif. Lastly, using a tethering assay, we determined that RBM38 can directly activate splicing when recruited to a downstream intron. Together, our data support the role of RBM38 in regulating alternative splicing during erythroid differentiation.

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Section: Resultsmentioning

confidence: 99%

The RNA Binding Protein RBM38 (RNPC1) Regulates Splicing during Late Erythroid Differentiation

et al. 2013

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“…A number of studies correlated the overexpression of ERCC1 or XPA proteins with cisplatin resistance [31–34]. The existence of ERCC1 exon VIII alternative splicing was observed in ovarian cancer cells [35]. Although this splicing did not affect the level of ERCC1, it decreased its excision repair function.…”

Section: Formation and Repair Of Cisplatin Dna Adductmentioning

confidence: 99%

Cellular Responses to Cisplatin‐Induced DNA Damage

Basu

Krishnamurthy

2010

Journal of Nucleic Acids

434

408

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Cisplatin is one of the most effective anticancer agents widely used in the treatment of solid tumors. It is generally considered as a cytotoxic drug which kills cancer cells by damaging DNA and inhibiting DNA synthesis. How cells respond to cisplatin-induced DNA damage plays a critical role in deciding cisplatin sensitivity. Cisplatin-induced DNA damage activates various signaling pathways to prevent or promote cell death. This paper summarizes our current understandings regarding the mechanisms by which cisplatin induces cell death and the bases of cisplatin resistance. We have discussed various steps, including the entry of cisplatin inside cells, DNA repair, drug detoxification, DNA damage response, and regulation of cisplatin-induced apoptosis by protein kinases. An understanding of how various signaling pathways regulate cisplatin-induced cell death should aid in the development of more effective therapeutic strategies for the treatment of cancer.

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“…An ERCC1-201–like mutation and the ERCC1-203 isoform have appeared to be nonfunctional in nucleotide excision repair capacity. 31–33 We measured repair of platinum–DNA adducts 34 and cisplatin sensitivity in A549-derived cell lines expressing only a single ERCC1 isoform and found that only one of the four ERCC1 isoforms was functional.…”

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confidence: 99%

ERCC1 Isoform Expression and DNA Repair in Non–Small-Cell Lung Cancer

et al. 2013

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BACKGROUND The excision repair cross-complementation group 1 (ERCC1) protein is a potential prognostic biomarker of the efficacy of cisplatin-based chemotherapy in non–small-cell lung cancer (NSCLC). Although several ongoing trials are evaluating the level of expression of ERCC1, no consensus has been reached regarding a method for evaluation. METHODS We used the 8F1 antibody to measure the level of expression of ERCC1 protein by means of immunohistochemical analysis in a validation set of samples obtained from 494 patients in two independent phase 3 trials (the National Cancer Institute of Canada Clinical Trials Group JBR.10 and the Cancer and Leukemia Group B 9633 trial from the Lung Adjuvant Cisplatin Evaluation Biology project). We compared the results of repeated staining of the entire original set of samples obtained from 589 patients in the International Adjuvant Lung Cancer Trial Biology study, which had led to the initial correlation between the absence of ERCC1 expression and platinum response, with our previous results in the same tumors. We mapped the epitope recognized by 16 commercially available ERCC1 antibodies and investigated the capacity of the different ERCC1 isoforms to repair platinum-induced DNA damage. RESULTS We were unable to validate the predictive effect of immunostaining for ERCC1 protein. The discordance in the results of staining for ERCC1 suggested a change in the performance of the 8F1 antibody since 2006. We found that none of the 16 antibodies could distinguish among the four ERCC1 protein isoforms, whereas only one isoform produced a protein that had full capacities for nucleotide excision repair and cisplatin resistance. CONCLUSIONS Immunohistochemical analysis with the use of currently available ERCC1 antibodies did not specifically detect the unique functional ERCC1 isoform. As a result, its usefulness in guiding therapeutic decision making is limited. (Funded by Eli Lilly and others.)

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The Impacts of ERCC1 Gene Exon VIII Alternative Splicing on Cisplatin-Resistance in Ovarian Cancer Cells

Cited by 25 publications

References 28 publications

The RNA Binding Protein RBM38 (RNPC1) Regulates Splicing during Late Erythroid Differentiation

The RNA Binding Protein RBM38 (RNPC1) Regulates Splicing during Late Erythroid Differentiation

Cellular Responses to Cisplatin‐Induced DNA Damage

ERCC1 Isoform Expression and DNA Repair in Non–Small-Cell Lung Cancer

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