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Anti-parasite drug ivermectin can suppress ovarian cancer by regulating lncRNA-EIF4A3-mRNA axes.
Li, Na; Zhan, Xianquan.
  • Li N; University Creative Research Initiatives Center, Shandong First Medical University, 6699 Qingdao Road, Jinan, 250117 Shandong People's Republic of China.
  • Zhan X; Key Laboratory of Cancer Proteomics of Chinese Ministry of Health, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, 410008 Hunan People's Republic of China.
EPMA J ; 11(2): 289-309, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-1086691
Semantic information from SemMedBD (by NLM)
1. ivermectin DISRUPTS ovarian neoplasm
Subject
ivermectin
Predicate
DISRUPTS
Object
ovarian neoplasm
2. Malignant Neoplasms PROCESS_OF Homo sapiens
Subject
Malignant Neoplasms
Predicate
PROCESS_OF
Object
Homo sapiens
3. Pharmaceutical Preparations DISRUPTS Growth
Subject
Pharmaceutical Preparations
Predicate
DISRUPTS
Object
Growth
4. ivermectin INTERACTS_WITH RN
Subject
ivermectin
Predicate
INTERACTS_WITH
Object
RN
5. Study USES Quantitative Reverse Transcriptase PCR
Subject
Study
Predicate
USES
Object
Quantitative Reverse Transcriptase PCR
6. EIF4A3 gene|EIF4A3 LOCATION_OF protein expression
Subject
EIF4A3 gene|EIF4A3
Predicate
LOCATION_OF
Object
protein expression
7. ovarian neoplasm PROCESS_OF Patients
Subject
ovarian neoplasm
Predicate
PROCESS_OF
Object
Patients
8. ivermectin INHIBITS EIF4A3 gene|EIF4A3
Subject
ivermectin
Predicate
INHIBITS
Object
EIF4A3 gene|EIF4A3
9. American College of Cardiology/American Heart Association Lesion Complexity Score A PROCESS_OF Patients
Subject
American College of Cardiology/American Heart Association Lesion Complexity Score A
Predicate
PROCESS_OF
Object
Patients
10. American College of Cardiology/American Heart Association Lesion Complexity Score C PROCESS_OF Patients
Subject
American College of Cardiology/American Heart Association Lesion Complexity Score C
Predicate
PROCESS_OF
Object
Patients
11. EIF4A3 gene|EIF4A3 ASSOCIATED_WITH ovarian neoplasm
Subject
EIF4A3 gene|EIF4A3
Predicate
ASSOCIATED_WITH
Object
ovarian neoplasm
12. ivermectin DISRUPTS ovarian neoplasm
Subject
ivermectin
Predicate
DISRUPTS
Object
ovarian neoplasm
13. Malignant Neoplasms PROCESS_OF Homo sapiens
Subject
Malignant Neoplasms
Predicate
PROCESS_OF
Object
Homo sapiens
14. Pharmaceutical Preparations DISRUPTS Growth
Subject
Pharmaceutical Preparations
Predicate
DISRUPTS
Object
Growth
15. ivermectin INTERACTS_WITH RNA, Messenger
Subject
ivermectin
Predicate
INTERACTS_WITH
Object
RNA, Messenger
16. Study USES Quantitative Reverse Transcriptase PCR
Subject
Study
Predicate
USES
Object
Quantitative Reverse Transcriptase PCR
17. EIF4A3 gene|EIF4A3 LOCATION_OF protein expression
Subject
EIF4A3 gene|EIF4A3
Predicate
LOCATION_OF
Object
protein expression
18. ovarian neoplasm PROCESS_OF Patients
Subject
ovarian neoplasm
Predicate
PROCESS_OF
Object
Patients
19. ivermectin INHIBITS EIF4A3 gene|EIF4A3
Subject
ivermectin
Predicate
INHIBITS
Object
EIF4A3 gene|EIF4A3
20. American College of Cardiology/American Heart Association Lesion Complexity Score A PROCESS_OF Patients
Subject
American College of Cardiology/American Heart Association Lesion Complexity Score A
Predicate
PROCESS_OF
Object
Patients
21. American College of Cardiology/American Heart Association Lesion Complexity Score C PROCESS_OF Patients
Subject
American College of Cardiology/American Heart Association Lesion Complexity Score C
Predicate
PROCESS_OF
Object
Patients
22. EIF4A3 gene|EIF4A3 ASSOCIATED_WITH ovarian neoplasm
Subject
EIF4A3 gene|EIF4A3
Predicate
ASSOCIATED_WITH
Object
ovarian neoplasm
ABSTRACT
Relevance Ivermectin, as an old anti-parasite drug, can suppress almost completely the growth of various human cancers, including ovarian cancer (OC). However, its anticancer mechanism remained to be further studied at the molecular levels. Ivermectin-related molecule-panel changes will serve a useful tool for its personalized drug therapy and prognostic assessment in OCs.

Purpose:

To explore the functional significance of ivermectin-mediated lncRNA-EIF4A3-mRNA axes in OCs and ivermectin-related molecule-panel for its personalized drug therapy monitoring.

Methods:

Based on our previous study, a total of 16 lncRNA expression patterns were analyzed using qRT-PCR before and after ivermectin-treated different OC cell lines (TOV-21G and A2780). Stable isotope labeling with amino acids in cell culture (SILAC)-based quantitative proteomics was used to analyze the protein expressions of EIF4A3 and EIF4A3-binding mRNAs in ovarian cancer cells treated with and without ivermectin. A total of 411 OC patients from the Cancer Genome Atlas (TCGA) database with the selected lncRNA expressions and the corresponding clinical data were included. Lasso regression was constructed to examine the relationship between lncRNA signature and OC survival risk. The overall survival analysis between high-risk and low-risk groups used the Kaplan-Meier method. Heatmap showed the correlation between risk groups and clinical characteristics. The univariate and multivariate models were established with Cox regression.

Results:

SILAC-based quantitative proteomics found the protein expression levels of EIF4A3 and 116 EIF4A3-binding mRNAs were inhibited by ivermectin in OC cells. Among the analyzed 16 lncRNAs (HCG15, KIF9-AS1, PDCD4-AS1, ZNF674-AS1, ZNRF3-AS1, SOS1-IT1, LINC00565, SNHG3, PLCH1-AS1, WWTR1-AS1, LINC00517, AL109767.1, STARD13-IT1, LBX2-AS1, LEMD1-AS1, and HOXC-AS3), only 7 lncRNAs (HCG15, KIF9-AS1, PDCD4-AS1, ZNF674-AS1, ZNRF3-AS1, SOS1-IT1, and LINC00565) were obtained for further lasso regression when combined with the results of drug testing and overall survival analysis. Lasso regression identified the prognostic model of ivermectin-related three-lncRNA signature (ZNRF3-AS1, SOS1-IT1, and LINC00565). The high-risk and low-risk groups based on the prognostic model were significantly related to overall survival and clinicopathologic characteristics (survival status, lymphatic invasion, cancer status, and clinical stage) in OC patients and remained independent risk factors according to multivariate COX analysis (p < 0.05).

Conclusion:

Those findings provided the potential targeted lncRNA-EIF4A3-mRNA pathways of ivermectin in OC, and constructed the effective prognostic model, which benefits discovery of novel mechanism of ivermectin to suppress ovarian cancer cells, and the ivermectin-related molecule-panel changes benefit for its personalized drug therapy and prognostic assessment towards its predictive, preventive, and personalized medicine (PPPM) in OCs.
Keywords

Full text: Available Collection: International databases Database: MEDLINE Document Type: Article Language: English Journal: EPMA J Clinical aspect: Etiology / Prediction / Prognosis Year: 2020

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Full text: Available Collection: International databases Database: MEDLINE Document Type: Article Language: English Journal: EPMA J Clinical aspect: Etiology / Prediction / Prognosis Year: 2020
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