Dataset Information

Tanshinone IIA attenuates the stemness of breast cancer cells via targeting the miR-125b/STARD13 axis.

ABSTRACT:

Background

Tanshinone II A is an effective component extracted from Salvia miltiorrhiza and the roles of Tanshinone IIA in regulating the stemness of tumor cells remain unclear. This work aims to explore the roles and underlying mechanisms of Tanshinone IIA in breast cancer stemness.

Methods

In vitro mammary spheroid formation, flow cytometry assay on CD24^-/CD44⁺ sub-population, ALDH activity detection, cell viability assay and western blot analysis, and in vivo tumor-initiating analysis were performed to examine the effects of Tanshinone IIA on the stemness of breast cancer cells. MiRNAs-based transcriptome sequencing and data analysis, online dataset analysis, luciferase reporter assay combined with rescuing experiments were constructed to explore the underlying mechanisms.

Results

Tanshinone IIA attenuated the stemness of breast cancer cells, evident by downregulating the expression of stemness markers, hindering the capacity of spheroid formation, decreasing the CD24^-/CD44⁺ sub-population in a concentration-dependent manner and reducing the tumor-initiating ability of breast cancer cells. Additionally, Tanshinone IIA enhanced adriamycin sensitivity and attenuated adriamycin resistance of breast cancer cells. Combined with miRNAs-based transcriptome sequencing assay, it was found that Tanshinone IIA downregulated miR-125b level and upregulated its target gene STARD13 (StAR-related lipid transfer protein 13) level, thus inactivating the miR-125b/STARD13 axis, which had been previously confirmed to promote breast cancer progression. Notably, miR-125b overexpression enhanced the stemness of breast cancer cells, and miR-125b overexpression or STARD13 knockdown impaired the inhibitory effects of Tanshinone IIA on the stemness of breast cancer cells.

Conclusions

Tanshinone IIA could attenuate the stemness of breast cancer cells via targeting the miR-125b/STARD13 axis.

SUBMITTER: Li X

PROVIDER: S-EPMC8781032 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundBreast cancer stem cells have self-renewal capability and are resistant to conventional chemotherapy. PD-L1 could promote the expression of stemness markers (OCT4 and Nanog) in breast cancer stem cells. However, the mechanisms by which PD-L1 regulates the stemness of breast cancer cells and PD-L1 is regulated in breast cancer cells are still unclear.MethodsLentivirus infection was used to construct stable cell lines. The correlation between PD-L1 and stemness markers expression was evaluated in clinical samples. Additionally, luciferase reporter assay combined with RNA-Fluorescence in situ hybridization (RNA-FISH) and RNA-binding protein immunoprecipitation (RIP) assays were used to verify the direct binding of miR-873 on PD-L1. Furthermore, flow cytometry, mammosphere formation combined with nude mouse tumor xenograft model were carried out to examine the effects of miR-873/PD-L1 axis on the stemness of breast cancer cells. Finally, MTT assay was performed to determine the effects of miR-873/PD-L1 axis on drug resistance.FindingsPD-L1 expression was positively correlated with the expression of stemness markers, and overexpression of PD-L1 contributed to chemoresistance and stemness-like properties in breast cancer cells via activating PI3K/Akt and ERK1/2 pathways. Mechanistically, miR-873 inhibited PD-L1 expression through directly binding to its 3'-untranslated region (UTR), and miR-873 attenuated the stemness and chemoresistance of breast cancer cells which was dependent on PD-L1 and the downstream PI3K/Akt and ERK1/2 signaling. Notably, the promotion of PD-L1 on the stemness and chemoresistance was enhanced by recombinant PD-1 (rPD-1), this effect was attenuated by PD-1/PD-L1 inhibitor.InterpretationmiR-873/PD-L1 regulatory axis might serve as a therapeutic target to enhance the chemo-sensitivity and eliminate the stemness of breast cancer cells. FUND: This work was supported by the National Nature Science Foundation of China, No. 81702957, China Postdoctoral Science Foundation, No. 2017M620230, the Postdoctoral Research Funding Scheme of Jiangsu Province (2017), No. 1701197B, and the Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.