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基于生物信息学和实验验证的卵巢癌顺铂耐药相关枢纽基因的综合分析及治疗药物筛选。

Comprehensive analysis of hub genes associated with cisplatin-resistance in ovarian cancer and screening of therapeutic drugs through bioinformatics and experimental validation.

机构信息

Department of Obstetrics and Gynecology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Key Laboratory of Reproductive Dysfunction Management of Zhejiang Province, Hangzhou, 310016, China.

出版信息

J Ovarian Res. 2024 Jul 10;17(1):142. doi: 10.1186/s13048-024-01461-w.

DOI:10.1186/s13048-024-01461-w
PMID:38987777
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11234624/
Abstract

BACKGROUND: To identify key genes associated with cisplatin resistance in ovarian cancer, a comprehensive analysis was conducted on three datasets from the GEO database and through experimental validation. METHODS: Gene expression profiles were retrieved from the GEO database. DEGs were identified by comparing gene expression profiles between cisplatin-sensitive and resistant ovarian cancer cell lines. The identified genes were further subjected to GO, KEGG, and PPI network analysis. Potential inhibitors of key genes were identified through methods such as LibDock nuclear molecular docking. In vitro assays and RT-qPCR were performed to assess the expression levels of key genes in ovarian cancer cell lines. The sensitivity of cells to chemotherapy and proliferation of key gene knockout cells were evaluated through CCK8 and Clonogenic assays. RESULTS: Results showed that 12 genes influenced the chemosensitivity of the ovarian cancer cell line SKOV3, and 9 genes were associated with the prognosis and survival outcomes of ovarian cancer patients. RT-qPCR results revealed NDRG1, CYBRD1, MT2A, CNIH3, DPYSL3, and CARMIL1 were upregulated, whereas ERBB4, ANK3, B2M, LRRTM4, EYA4, and SLIT2 were downregulated in cisplatin-resistant cell lines. NDRG1, CYBRD1, and DPYSL3 knock-down significantly inhibited the proliferation of cisplatin-resistant cell line SKOV3. Finally, photofrin, a small-molecule compound targeting CYBRD1, was identified. CONCLUSION: This study reveals changes in the expression level of some genes associated with cisplatin-resistant ovarian cancer. In addition, a new small molecule compound was identified for the treatment of cisplatin-resistant ovarian cancer.

摘要

背景：为了鉴定与卵巢癌顺铂耐药相关的关键基因，我们对 GEO 数据库中的三个数据集进行了综合分析，并通过实验验证。

方法：从 GEO 数据库中检索基因表达谱。通过比较顺铂敏感和耐药卵巢癌细胞系的基因表达谱，鉴定差异表达基因。进一步对鉴定出的基因进行 GO、KEGG 和 PPI 网络分析。通过 LibDock 核分子对接等方法鉴定关键基因的潜在抑制剂。通过体外实验和 RT-qPCR 检测卵巢癌细胞系中关键基因的表达水平。通过 CCK8 和集落形成实验评估细胞对化疗的敏感性和关键基因敲除细胞的增殖能力。

结果：结果表明，有 12 个基因影响卵巢癌细胞系 SKOV3 的化疗敏感性，有 9 个基因与卵巢癌患者的预后和生存结局相关。RT-qPCR 结果显示，顺铂耐药细胞系中 NDRG1、CYBRD1、MT2A、CNIH3、DPYSL3 和 CARMIL1 上调，而 ERBB4、ANK3、B2M、LRRTM4、EYA4 和 SLIT2 下调。NDRG1、CYBRD1 和 DPYSL3 敲低显著抑制了顺铂耐药细胞系 SKOV3 的增殖。最后，鉴定出一种针对 CYBRD1 的小分子化合物 Photofrin。

结论：本研究揭示了一些与顺铂耐药卵巢癌相关的基因表达水平的变化。此外，还鉴定出一种新的小分子化合物，用于治疗顺铂耐药卵巢癌。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/a8711c1faa01/13048_2024_1461_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/b48c546fe366/13048_2024_1461_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/3c88283e33d2/13048_2024_1461_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/4368ddec434c/13048_2024_1461_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/8395f5963960/13048_2024_1461_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/5c09d9144393/13048_2024_1461_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/9fb913061cd8/13048_2024_1461_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/a8711c1faa01/13048_2024_1461_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/b48c546fe366/13048_2024_1461_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/3c88283e33d2/13048_2024_1461_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/4368ddec434c/13048_2024_1461_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/8395f5963960/13048_2024_1461_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/5c09d9144393/13048_2024_1461_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/9fb913061cd8/13048_2024_1461_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1f51/11234624/a8711c1faa01/13048_2024_1461_Fig7_HTML.jpg

相似文献

[1]
Comprehensive analysis of hub genes associated with cisplatin-resistance in ovarian cancer and screening of therapeutic drugs through bioinformatics and experimental validation.

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[2]
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[3]
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[5]
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J Ovarian Res. 2020-1-27

[6]
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[7]
[Lumican enhanced the therapeutic effect of cisplatin-resistant ovarian cancer by inhibiting the differentiation of Th1 cells].

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[8]
Long non-coding RNA Linc00312 modulates the sensitivity of ovarian cancer to cisplatin via the Bcl-2/Caspase-3 signaling pathway.

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[9]
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[10]
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引用本文的文献

[1]
Unveiling ammonia-induced cell death: a new frontier in clear cell renal cell carcinoma prognosis.

Front Immunol. 2025-7-31

[2]
Prognostic Value of Ubiquitination-Related Genes in Ovarian Cancer and Their Correlation With Tumor Immunity.

Hum Mutat. 2025-7-15

[3]
Identification and validation of matrix metalloproteinase hub genes as potential biomarkers for Skin Cutaneous Melanoma.

Front Oncol. 2024-10-18

本文引用的文献

[1]
Cisplatin in Ovarian Cancer Treatment-Known Limitations in Therapy Force New Solutions.

Int J Mol Sci. 2023-4-20

[2]
Identification of EMP1 as a critical gene for cisplatin resistance in ovarian cancer by using integrated bioinformatics analysis.

Cancer Med. 2023-4

[3]
NDRG1 in Cancer: A Suppressor, Promoter, or Both?

Cancers (Basel). 2022-11-22

[4]
HJURP regulates cell proliferation and chemo-resistance via YAP1/NDRG1 transcriptional axis in triple-negative breast cancer.

Cell Death Dis. 2022-4-22

[5]
Molecular mechanisms of platinum‑based chemotherapy resistance in ovarian cancer (Review).

Oncol Rep. 2022-4

[6]
Selected by bioinformatics and molecular docking analysis, Dhea and 2-14,15-Eg are effective against cholangiocarcinoma.

PLoS One. 2022

[7]
Upregulated Expression of CYBRD1 Predicts Poor Prognosis of Patients with Ovarian Cancer.

J Oncol. 2021-9-21

[8]
Metallothionein 2A Expression in Cancer-Associated Fibroblasts and Cancer Cells Promotes Esophageal Squamous Cell Carcinoma Progression.

Cancers (Basel). 2021-9-10

[9]
Changes in SLIT2 expression are associated with the migration of human ovarian clear cell carcinoma cells.

Oncol Lett. 2021-7

[10]
Bioinformatics analysis of mRNA and miRNA microarray to identify the key miRNA-mRNA pairs in cisplatin-resistant ovarian cancer.

BMC Cancer. 2021-4-23

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