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Summary: Extrachromosomal circular DNAs (eccDNAs) are defined as distinct genomic entities of circular and mobile DNA molecules, but their molecular functions in and impact on breast cancer (BC) are rarely known. This study used Circle-seq to analyze eccDNAs from 19 BC tissues and 17 adjacent normal tissues. We found that eccDNAs are present on all chromosomes and enriched in seven eccDNA hotspot genes (HSGs) associated with the BC pathway. Several eccDNAs harboring entire genes (eccGenes) and eccDNAs harboring miRNAs (eccMIRs) were identified and linked to cancer-relevant pathways. Synthetic eccMIR6748, eccMIR6508, and eccMIR3142 elevated miRNA expression in MCF-7 cells, with eccMIR6748 promoting BC cell migration and invasion by upregulating miR-6748, which suppresses tumor suppressor candidate factor 5 (TUSC5) at the post-transcriptional level. eccMIR6748 also influences BC progression via the p38 mitogen-activated protein kinase (MAPK) signaling pathway. These findings suggest that eccDNAs, which contain functional genomic segments, play a role in BC initiation and progression, offering a dynamic source of genomic plasticity and potential as biomarkers and therapeutic targets.

Abstract Background Emerging evidence has revealed that tumor‐associated macrophages (TAMs) and exosomes play a crucial role in the microenvironment for tumor growth. However, the mechanisms through which exosomal miRNAs modulate TAMs and tumor development in breast cancer are not fully understood. Methods We constructed a macrophage model and an indirect coculture system consist of breast cancer cells and macrophages. Exosomes were isolated from BC cells culture supernatant and identified by transmission electron microscopy, Western blot and Nanosight LM10 system. The expression of miR‐148b‐3p in exosomes was determined by qRT‐PCR and the effect of exosomal miR‐148b‐3p on macrophage polarization was measured using qRT‐PCR and ELISA. The proliferation, migration and invasion of BC cells were estimated by EdU, wound healing assay and transwell assay. We employed bioinformatics, luciferase reporter assay and Western blot to identify the target gene of miR‐148b‐3p. Western blot was used to clarify the mechanism of exosomal miR‐148b‐3p mediated the crosstalk between BC cells and M2 macrophages. Results Cancer‐derived exosomes could induce M2 polarization of macrophages, which promoted the migration and invasion of breast cancer cells. We found that exosomal miR‐148b‐3p was overexpressed in breast cancer cell‐derived exosomes and correlated with lymph node metastasis, late tumor stage and worse prognosis. Upregulated miR‐148b‐3p expression in exosomes modulated macrophage polarization by targeting TSC2, which promoted the proliferation and might affect migration and invasion of breast cancer cells. Interestingly, we found that exosomal miR‐148b‐3p could induce M2 macrophage polarization via the TSC2/mTORC1 signaling pathway in breast cancer. Conclusion Overall, our study elucidated that miR‐148b‐3p could be transported by exosomes from breast cancer cells to surrounding macrophages and induced M2 polarization by targeting TSC2, providing novel insights for breast cancer therapy.

Abstract Studies have shown that cancer-associated fibroblasts (CAFs) play an irreplaceable role in the occurrence and development of tumors. Therefore, exploring the action and mechanism of CAFs on tumor cells is particularly important. In this study, we compared the effects of CAFs-derived exosomes and normal fibroblasts (NFs)-derived exosomes on breast cancer cells migration and invasion. The results showed that exosomes from both CAFs and NFs could enter into breast cancer cells and CAFs-derived exosomes had a more enhancing effect on breast cancer cells migration and invasion than NFs-derived exosomes. Furthermore, microRNA (miR)-18b was upregulated in CAFs-derived exosomes, and CAFs-derived exosomes miR-18b can promote breast cancer cell migration and metastasis by specifically binding to the 3′UTR of Transcription Elongation Factor A Like 7 (TCEAL7). The miR-18b-TCEAL7 pathway promotes nuclear Snail ectopic activation by activating nuclear factor-kappa B (NF-κB), thereby inducing epithelial-mesenchymal transition (EMT) and promoting cell invasion and metastasis. Moreover, CAFs-derived exosomes miR-18b could promote mouse xenograft model tumor metastasis. Overall, our findings suggest that CAFs-derived exosomes miR-18b promote nuclear Snail ectopic by targeting TCEAL7 to activate the NF-κB pathway, thereby inducing EMT, invasion, and metastasis of breast cancer. Targeting CAFs-derived exosome miR-18b may be a potential treatment option to overcome breast cancer progression.

Background and objective ANXA2 plays a very important role in cancer progression. chemokine ligand 18 (CCL18) is associated with the invasion, migration, metastasis and poor prognosis of lung adenocarcinoma (LUAD). In this study, we aimed to explore whether CCL18 promotes LUAD invasion through ANXA2, and its role and molecular mechanism in LUAD invasion. Methods Western blot was used to detect ANXA2 expression in LUAD tissues and adjacent non-tumor tissues, the transfection efficiency of SiANXA2#2 in cells and the role of ANXA2 as an upstream regulator in the AKT/cofilin signaling pathway. In vitro cytological experiments such as chemotaxis experiment and transwell invasion test was used to explore the mechanism of ANXA2 on LUAD metastasis. F-actin polymerization experiment and Western blot were used to detect whether invasion ability alteration of SiANXA2#2 A549 cells are related to F-actin. Results Western blot analysis showed that compared with adjacent non-tumor tissues, the protein expression level of ANXA2 in cancer tissues increased (P