LDLR-mediated lipidome–transcriptome reprogramming in cisplatin insensitivity
| Autor: | Hsiao-Ching Wang, Lu-Min Chen, Yen-Pin Ho, Wei-Min Chung, Wei-Chung Cheng, Wei Chun Chang, Wen Lung Ma, Juan-Cheng Yang, Yao Ching Hung |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research endocrine system diseases Endocrinology Diabetes and Metabolism Mice Nude Antineoplastic Agents Apoptosis Carcinoma Ovarian Epithelial Transcriptome Mice 03 medical and health sciences 0302 clinical medicine Endocrinology Biomarkers Tumor Tumor Cells Cultured medicine Animals Humans Gene silencing Cell Proliferation Cisplatin business.industry Cancer Lipidome Cellular Reprogramming Prognosis medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic Survival Rate 030104 developmental biology Receptors LDL Oncology 030220 oncology & carcinogenesis Lipidomics LDL receptor Cancer cell Cancer research Biomarker (medicine) Female lipids (amino acids peptides and proteins) business medicine.drug |
| Zdroj: | Endocrine-Related Cancer. 27:81-95 |
| ISSN: | 1479-6821 1351-0088 |
| DOI: | 10.1530/erc-19-0095 |
| Popis: | Platinum-based therapy remains the cornerstone for cancer therapy; however, its efficacy varies. The role of lipoprotein receptor-mediated lipid entry for cancer development has been reported. Yet, the roles and mechanism of the low-density lipoprotein receptor (LDLR) in chemo-sensitivities are unknown. In the current report, we used epithelial ovarian cancer (EOC), composed of various cellularities, to study this issue. Using public cDNA microarray database and single cohort study, LDLR expressions were positively associated with epithelial ovarian carcinomas (EOCs) platinum-based chemotherapy patients’ disease prognosis. In vitro and in vivo add-in/silencing LDLR was introduced to determine cisplatin sensitivity and cancer growth. Results revealed that knocked-down LDLR could sensitize while overexpressed LDLR could insensitize EOC cells to the cytotoxic effects of cisplatin. Moreover, the trans-omics approaches depicted an LDLR→LPC (Lyso-phosphatidylcholine)→FAM83B (phospholipase-related)→FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis. Finally, the manipulation of LDLR expression in EOC cells was found to determine the efficacy of cisplatin therapy in terms of tumor suppression. In conclusion, the LDLR→LPC→FAM83B→FGFRs axis is an example of tumor macroenvironmental regulation of therapy outcomes. Relatedly, LDLR expression could serve as a biomarker of chemotherapy sensitivity in EOCs. Significance: this study describes the role of LDLR in the development of insensitivity to platinum-based chemotherapy in epithelial ovarian cancer. The lipidome (e.g., LPC) and transcriptome (e.g., FAM38B) interactions revealed using trans-omics approaches an LDLR→LPC→FAM83B→FGFRs regulatory axis in cancer cells, in an animal model, and in patients. |
| Databáze: | OpenAIRE |
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