Title: Anti-parasite drug ivermectin can suppress ovarian cancer by regulating lncRNA-EIF4A3-mRNA axes - PubMed

URL Source: https://pubmed.ncbi.nlm.nih.gov/32549918/

Markdown Content:
## Anti-parasite drug ivermectin can suppress ovarian cancer by regulating lncRNA-EIF4A3-mRNA axes

Na Li et al. EPMA J.2020.

## 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:** EIF4A3; Ivermectin; Ovarian cancer; Personalized drug therapy; Predictive preventive personalized medicine (PPPM); Prognostic assessment; Prognostic model; TCGA; lncRNAs.

© European Association for Predictive, Preventive and Personalised Medicine (EPMA) 2020.

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## Conflict of interest statement

Competing interestsThe authors declare that they have no competing interests.

## Figures

[![Image 1: Fig. 1](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/2b03fab0d6f1/13167_2020_209_Fig1_HTML.gif)](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/013d422fbc0e/13167_2020_209_Fig1_HTML.jpg)

**Fig. 1**
Signaling pathways enriched with EIF4A3-binding mRNAs and effects of ivermectin on ovarian cancer cell migration. **a** Signaling pathways enriched with EIF4A3-binding mRNAs were clustered into 8 groups. sp = signaling pathway. sp1 = EGFR1; sp2 = Cell cycle; sp3 = Retinoblastoma gene in cancer; sp4 = Hedgehog; sp5 = Notch; sp6 = Metabolism of proteins; sp7 = Mitochondrial translation; sp8 = Mitochondrial translation elongation; sp9 = Mitochondrial translation initiation; sp10 = Mitochondrial translation termination; sp11 = Translation; sp12 = Ribosome; sp13 = Selenoamino acid metabolism; sp14 = Metabolism of proteins; sp15 = Cargo recognition for clathrin-mediated endocytosis; sp16 = Clathrin-mediated endocytosis; sp17 = Membrane trafficking; sp18 = Nucleotide excision repair; sp19 = Transcription coupled nucleotide excision repair (TC-NER); sp20 = Purine metabolism; sp21 = Purine metabolism Homo sapiens (human); sp22 = Purine nucleotides nucleosides metabolism; sp23 = Pyrimidine metabolism; sp24 = RNA degradation Homo sapiens (human); sp25 = Metabolism of RNA; sp26 = Processing of capped intron-containing pre-mRNA; sp27 = mRNA splicing; sp28 = mRNA splicing - major pathway; and sp29 = Spliceosome Homo sapiens (human). **b** Cell viability was measured with CCK8 assay in OC cells A2780 and TOV-21G treated with ivermectin (0–60 μM) for 24 h (_n_ = 3; X = Log (ivermectin concentration)). **c** Wound healing test of OC cells A2780 and TOV-21G treated with ivermectin (0–30 μM) for 24 h (_n_ = 3). **d** Histogram statistics of wound healing test of OC cells A2780 and TOV-21G treated with ivermectin (0–30 μM) (_n_ = 3). *_p_< 0.05; **_p_< 0.01; ***_p_< 0.001

[![Image 2: Fig. 2](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/13a7346a42b9/13167_2020_209_Fig2_HTML.gif)](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/9edae66bca19/13167_2020_209_Fig2_HTML.jpg)

**Fig. 2**
LncRNA expression profile in cells A2780 treated with ivermectin (0–30 μM). *_p_< 0.05; **_p_< 0.01; ***_p_< 0.001

[![Image 3: Fig. 3](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/be4f9dc11e5a/13167_2020_209_Fig3_HTML.gif)](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/5eddccaf1538/13167_2020_209_Fig3_HTML.jpg)

**Fig. 3**
LncRNA expression profile in cells TOV-21G treated with ivermectin (0–30 μM). *_p_< 0.05; **_p_< 0.01; ***_p_< 0.001

[![Image 4: Fig. 4](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/6b87cd4d3177/13167_2020_209_Fig4_HTML.gif)](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/91ba184cacf5/13167_2020_209_Fig4_HTML.jpg)

**Fig. 4**
Overall survival analysis of HCG15, KIF9-AS1, LINC00565, PDCD4-AS1, SOS1-IT1, ZNF674-AS1, and ZNRF3-AS1 in ovarian cancers

[![Image 5: Fig. 5](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/4d3eca8489a7/13167_2020_209_Fig5_HTML.gif)](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/5a5ea3ac7ece/13167_2020_209_Fig5_HTML.jpg)

**Fig. 5**
Lasso regression identified the prognostic model of three-lncRNA signature. **a**, **b** Lasso regression complexity is controlled by lambda using the glmnet R package. **c** Overall survival analysis of three-lncRNA signature between high-risk and low-risk groups

[![Image 6: Fig. 6](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/54f5cc759776/13167_2020_209_Fig6_HTML.gif)](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/18e2a3a00cc4/13167_2020_209_Fig6_HTML.jpg)

**Fig. 6**
The heatmap of sample risk groups and the related clinical characteristics in ovarian cancers. The clinical characteristics include survival status, PANCAN, additional radiation therapy, age at initial pathologic diagnosis, anatomic neoplasm subdivision, clinical stage, lymphatic invasion, neoplasm histologic grade, cancer status, primary therapy outcome success, and tumor residual disease. *_p_< 0.05; **_p_< 0.01; ***_p_< 0.001

[![Image 7: Fig. 7](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/8cbd1579f19e/13167_2020_209_Fig7_HTML.gif)](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/717e/7272521/9931ef323042/13167_2020_209_Fig7_HTML.jpg)

**Fig. 7**
The univariate (**a**) and multivariate (**b**) analyses of risk factors in ovarian cancers

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