Abstract
Background: Failure to respond to treatment in epithelial ovarian cancer can often be attributed to platinum-based chemotherapy resistance. However, the possible mechanisms or candidate biomarkers associated with platinum resistance are yet to be elucidated, even though many researchers have performed related studies. Methods: We performed RNA sequencing of clinical specimens obtained from patients with platinum-sensitive or resistant epithelial ovarian cancer (EOC). Furthermore, various bioinformatics approaches, including spatial analysis of functional enrichment, were used to identify key regulators and associated underlying mechanisms of platinum resistance in EOC. Results: Through RNA-sequencing, we identified 263 differentially expressed genes (98 upregulated and 165 downregulated) and subjected them to Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, which were characterized to the traditional platinum-resistant characteristics. Subsequently, the gene interaction network and module analysis by spatial analysis of functional enrichment software demonstrated protein kinase C and casein kinase substrate in neurons 3 (PACSIN3) as the only upregulated hub gene, and neurotensin (NTS) and KIAA0319 as downregulated hub genes in platinum-resistant EOC. We selected PACSIN3 for further analysis because it has not been studied in relation to response to platinum-based chemotherapy. PACSIN3 was significantly upregulated in ovarian cancer cells compared to immortalized human ovarian surface epithelial cells. In addition, cisplatin-induced apoptosis was measured in PACSIN3 knockout OVCA433 and BRCA-mutated EOC cell line, SNU251, by a fluorescence-activated cell sorting-based Annexin-V/propium iodide double staining assay, which revealed a significant increase in apoptosis. Conclusions: Taken together, the present study presents PACSIN3 as a promising predictive biomarker associated with platinum resistance, especially in BRCA-mutated epithelial ovarian cancers.
| Original language | English |
|---|---|
| Article number | e3452 |
| Journal | Journal of Gene Medicine |
| Volume | 24 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 2022 Nov |
Bibliographical note
Funding Information:We thank the Bioinformatics Collaboration Unit (BiCU) in the Department of Biomedical Systems Informatics, Yonsei University College of Medicine, for RNA‐seq and downstream data analysis. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MIST) (NRF‐2020R1A2C2004782). The research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (NRF‐2017M3A9B8 069610). The study was also supported by a faculty research grant of Yonsei University College of Medicine (No. 6–2020‐0226).
Funding Information:
Sixteen EOC formalin‐fixed, paraffin‐embedded (FFPE) tissue samples of patients who were diagnosed with EOC and underwent debulking surgery at the Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine between 2018 and 2020 were provided by the Korean Gynecologic Cancer Bank, as part of the Bio & Medical Technology Development program of the Ministry of the National Research Foundation (NRF) funded by the Korean government (MIST) (NRF‐2017M3A9B8069610). In compliance with the Declaration of Helsinki, written informed consent was received from each patient before obtaining all specimens and patient information. This study received approval from the Institutional Review Board (IRB) of Gangnam Severance Hospital (IRB no.3–2020‐0377). All patients included in this study underwent combination treatment with carboplatin and paclitaxel after receiving maximal debulking surgery. Before the surgery, none of the patients had received chemotherapy. All specimens were histologically confirmed and were staged according to the International Federation of Gynecology and Obstetrics (FIGO) staging system and graded based on the World Health Organization grading system. The time interval between the surgery and either the last follow‐up visit or the date of recurrence/progression was referred to as progression‐free survival (PFS). The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), which considers CA‐125 levels, computed tomography or positron emission tomography to determine disease progression, was utilized to define the date of recurrence or progression [21]. Platinum resistance was defined as PFS of less than 6 months after the last platinum‐based treatment, and patients with PFS of over 12 months were categorized as platinum‐sensitive. Overall, eight platinum‐sensitive primary high‐grade serous ovarian cancer (HGSOC) FFPE tissues and eight platinum‐resistant primary HGSOC FFPE tissues were included.
Funding Information:
We thank the Bioinformatics Collaboration Unit (BiCU) in the Department of Biomedical Systems Informatics, Yonsei University College of Medicine, for RNA-seq and downstream data analysis. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MIST) (NRF-2020R1A2C2004782). The research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (NRF-2017M3A9B8 069610). The study was also supported by a faculty research grant of Yonsei University College of Medicine (No. 6–2020-0226).
Publisher Copyright:
© 2022 John Wiley & Sons Ltd.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Genetics
- Drug Discovery
- Genetics(clinical)
