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Toxoplasma gondii suppresses proliferation and migration of breast cancer cells by regulating their transcriptome
Hengming Ye1,2, Xiaotao Zhou2, Bike Zhu2
1The School of Public Health, Sun Yat-Sen University, 74 Zhongshan 2nd Rd, Guangzhou, 510080, Guangzhou, China.
Background:
Breast cancer is the most common cancer in women worldwide. Toxoplasma gondii (T. gondii) has shown anticancer activity in breast cancer mouse models, and exerted beneficial effect on the survival of breast cancer patients, but the mechanism was unclear.
Methods:
The effect of tachyzoites of T. gondii (RH and ME49 strains) on human breast cancer cells (MCF-7 and MDA-MB-231 cells) proliferation and migration was assessed using cell growth curve and wound healing assays. Dual RNA-seq was performed for T. gondii-infected and non-infected cells to determine the differentially expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction Networks analysis (PPI) were performed to explore the related signaling pathway and hub genes. Hub genes were validated using the Kaplan-Meier plotter database, and Pathogen Host Interaction (PHI-base) database. The results were verified by qRT-PCR.
Results:
The tachyzoites of T. gondii decreased the expression of Ki67 and increased the expression of E-cadherin, resulting in suppressing the proliferation and migration of infected human breast cancer cells. The inhibitory effect of T. gondii on breast cancer cells showed a significant dose-response relationship. Compared with the control group, 2321 genes were transcriptionally regulated in MCF-7 cells infected with T. gondii, while 169 genes were transcriptionally regulated in infected MDA-MB-231 cells. Among these genes, 698 genes in infected MCF-7 cells and 67 genes in infected MDA-MB-231 cells were validated by the publicly available database. GO and KEGG analyses suggested that several pathways were involved in anticancer function of T. gondii, such as ribosome, interleukin-17 signaling, coronavirus disease pathway, and breast cancer pathway. BRCA1, MYC and IL-6 were identified as the top three hub genes in infected-breast cancer cells based on the connectivity of PPI analysis. In addition, after interacting with breast cancer cells, the expression of ROP16 and ROP18 in T. gondii increased, while the expression of crt, TgIST, GRA15, GRA24 and MIC13 decreased.
Conclusions:
T. gondii transcriptionally regulates several signaling pathways by altering the hub genes such as BRCA1, MYC and IL-6, which can inhibit the breast tumor growth and migration, hinting at a potential therapeutic strategy.
Insights
Toxoplasma gondii tachyzoites suppress breast cancer cell proliferation and migration by altering gene expression. This parasite shows potential as a therapeutic strategy for breast cancer treatment.
Area of Science:
- Oncology
- Parasitology
- Molecular Biology
Background:
- Breast cancer is a leading global cancer in women.
- Toxoplasma gondii (T. gondii) exhibits anticancer properties in preclinical models and improves patient survival, but mechanisms are unknown.
Purpose of the Study:
- To investigate the effects of T. gondii tachyzoites on human breast cancer cell proliferation and migration.
- To elucidate the molecular mechanisms underlying T. gondii's anticancer activity.
Main Methods:
- Assessed proliferation and migration of MCF-7 and MDA-MB-231 cells infected with T. gondii using cell growth curves and wound healing assays.
- Performed dual RNA-sequencing to identify differentially expressed genes (DEGs) in infected cells.
- Utilized Gene Ontology, KEGG, and Protein-Protein Interaction (PPI) network analyses to identify pathways and hub genes, validated with public databases and qRT-PCR.
Main Results:
- T. gondii suppressed breast cancer cell proliferation and migration, indicated by decreased Ki67 and increased E-cadherin expression.
- Significant transcriptional changes were observed in infected cells, with 698 validated DEGs in MCF-7 and 67 in MDA-MB-231 cells.
- BRCA1, MYC, and IL-6 were identified as key hub genes, and pathways like interleukin-17 signaling and the breast cancer pathway were implicated.
Conclusions:
- T. gondii manipulates host cell signaling pathways, including those involving BRCA1, MYC, and IL-6, to inhibit breast tumor growth and migration.
- These findings suggest T. gondii as a potential candidate for novel breast cancer therapeutic strategies.
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