SOX12 mRNA expression was up-regulated in human breast cancer tissues. SOX12 was critical for cell migration, invasion and proliferation of breast cancer cells.
Chemotherapy-resistant breast cancer displays aggressive clinical behavior, is poorly differentiated and is associated with the occurrence of epithelial-mesenchymal transition and the presence of cancer stem cells. The anthelmintic drug niclosamide has been shown to have numerous clinical applications in the treatment of malignant tumors, in addition to its traditional use in tapeworm disease. Our previous study demonstrated that niclosamide had an antiproliferative effect and could inhibit the stem-like phenotype of the breast cancer cells, suggesting that it might have the potential to be used in the treatment of triple-negative breast cancer. However, the specific function and underlying mechanism of action of niclosamide in chemoresistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer remain unknown. The present study aimed to determine whether niclosamide can inhibit cell proliferation, invasion and epithelial-to-mesenchymal transition, as well as the stem-like phenotype in cisplatin-resistant HER2-positive breast cancer. Alamar Blue and Annexin V/7-AAD staining, mammosphere formation and Transwell assays were performed to assess the viability, apoptosis, stem-like phenotype and invasion ability of breast cancer cell lines, respectively. Signaling molecule expression was detected via western blotting and a xenograft model was used to verify the inhibitory effect of niclosamide in vivo. The results from the present study demonstrated that niclosamide inhibited the resistance of HER2-positive breast cancer to cisplatin both in vitro and in vivo. Furthermore, niclosamide combined with cisplatin could inhibit breast cancer cell invasion, epithelial-mesenchymal transition and cell stemness. The inhibitory effect of niclosamide was mediated by apoptosis induction and Bcl-2 downregulation. Taken together, the results of the present study suggested that niclosamide combined with cisplatin may be considered as a novel treatment for chemoresistant HER2-positive breast cancer.
Aim To explore the function(s) of HSP90 in intermediate monocyte-mediated plaque erosion. Materials and methods We used single-cell RNA sequencing to map cardiac immune response composition in patients with plaque rupture and plaque erosion. By focusing our analyses on CD14 positive monocytes, we obtained a higher resolution identification of the immune cell subsets in patients experiencing plaque erosion and rupture. We interpreted our findings with analyses using gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases and by performing receiver operating characteristic (ROC) curve analysis. Results Single-cell sequencing analysis of mononuclear cells in the peripheral blood of five ACS patients experiencing plaque erosion and rupture confirmed that CD14 positive monocytes were the main immune cells leading to ACS. Interestingly, our results suggested a significant increase in the proportion of atypical monocytes (C4 subsets) in patients with plaque rupture, which was a novel finding. This increase may be caused by increased migration of atypical monocytes into a plaque during plaque rupture. We found that intermediate monocyte activation was most obvious in patients with plaque erosion (C1, C10, and C11), and the proportion of C1 subgroup monocytes (FCGR3B/CMTM2 double strong positive; subsequently defined as intermediate monocytes) was very high. To further explore the role of C1 subgroup intermediate monocytes in plaque erosion, GO and KEGG pathway analyses were performed. GO analysis indicated that C1 subgroup intermediate monocytes are highly involved in neutrophil metabolism. Because neutrophils are the main effector cells that induce plaque erosion, we reasonably infer that intermediate monocytes can induce plaque erosion. KEGG pathway analysis indicated that all subtypes of HSP90 were highly expressed in C1 subgroup intermediate monocytes. We thus collected peripheral blood from ACS patients with plaque rupture (n=150) and plaque erosion (n=150) for mononuclear cell transcriptomics and intracellular proteomics analysis. ROC curve analysis demonstrated that the area under the curve for HSP90-based prediction was 0.86, indicating that HSP90 could be used to predict if patients would experience plaque erosion. Conclusion Activation of intermediate mononuclear HSP90 expression may be the crucial event that induces neutrophil hyper-responsiveness and leads to plaque erosion. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): China,Shanghai Science and Technology Commission
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