Targeting tumor exosomal circular RNA cSERPINE2 suppresses breast cancer progression by modulating MALT1-NF-𝜅B-IL-6 axis of tumor-associated macrophages.
Female
Humans
Breast Neoplasms
/ drug therapy
Cell Line, Tumor
Cell Proliferation
Interleukin-6
/ metabolism
Macrophages
/ metabolism
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
/ metabolism
RNA, Circular
/ genetics
Serpin E2
/ metabolism
Tumor Microenvironment
Tumor-Associated Macrophages
/ metabolism
Animals
Breast cancer
Exosome
Nanoparticles
Tumor-associated macrophages
cSERPINE2
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
17 Feb 2023
17 Feb 2023
Historique:
received:
25
10
2022
accepted:
09
02
2023
entrez:
16
2
2023
pubmed:
17
2
2023
medline:
22
2
2023
Statut:
epublish
Résumé
Circular RNAs (circRNAs) have important regulatory functions in cancer, but the role of circRNAs in the tumor microenvironment (TME) remains unclear. Moreover, we also explore the effects of si-circRNAs loaded in nanoparticles as therapeutic agent for anti-tumor in vivo. We conducted bioinformatics analysis, qRT-PCR, EdU assays, Transwell assays, co-culture system and multiple orthotopic xenograft models to investigate the expression and function of circRNAs. Additionally, PLGA-based nanoparticles loaded with si-circRNAs were used to evaluate the potential of nanotherapeutic strategy in anti-tumor response. We identified oncogene SERPINE2 derived circRNA, named as cSERPINE2, which was notably elevated in breast cancer and was closely related to poor clinical outcome. Functionally, tumor exosomal cSERPINE2 was shuttled to tumor associated macrophages (TAMs) and enhanced the secretion of Interleukin-6 (IL-6), leading to increased proliferation and invasion of breast cancer cells. Furthermore, IL-6 in turn increased the EIF4A3 and CCL2 levels within tumor cells in a positive feedback mechanism, further enhancing tumor cSERPINE2 biogenesis and promoting the recruitment of TAMs. More importantly, we developed a PLGA-based nanoparticle loaded with si-cSERPINE2, which effectively attenuated breast cancer progression in vivo. Our study illustrates a novel mechanism that tumor exosomal cSERPINE2 mediates a positive feedback loop between tumor cells and TAMs to promote cancer progression, which may serve as a promising nanotherapeutic strategy for the treatment of breast cancer.
Sections du résumé
BACKGROUND
BACKGROUND
Circular RNAs (circRNAs) have important regulatory functions in cancer, but the role of circRNAs in the tumor microenvironment (TME) remains unclear. Moreover, we also explore the effects of si-circRNAs loaded in nanoparticles as therapeutic agent for anti-tumor in vivo.
METHODS
METHODS
We conducted bioinformatics analysis, qRT-PCR, EdU assays, Transwell assays, co-culture system and multiple orthotopic xenograft models to investigate the expression and function of circRNAs. Additionally, PLGA-based nanoparticles loaded with si-circRNAs were used to evaluate the potential of nanotherapeutic strategy in anti-tumor response.
RESULTS
RESULTS
We identified oncogene SERPINE2 derived circRNA, named as cSERPINE2, which was notably elevated in breast cancer and was closely related to poor clinical outcome. Functionally, tumor exosomal cSERPINE2 was shuttled to tumor associated macrophages (TAMs) and enhanced the secretion of Interleukin-6 (IL-6), leading to increased proliferation and invasion of breast cancer cells. Furthermore, IL-6 in turn increased the EIF4A3 and CCL2 levels within tumor cells in a positive feedback mechanism, further enhancing tumor cSERPINE2 biogenesis and promoting the recruitment of TAMs. More importantly, we developed a PLGA-based nanoparticle loaded with si-cSERPINE2, which effectively attenuated breast cancer progression in vivo.
CONCLUSIONS
CONCLUSIONS
Our study illustrates a novel mechanism that tumor exosomal cSERPINE2 mediates a positive feedback loop between tumor cells and TAMs to promote cancer progression, which may serve as a promising nanotherapeutic strategy for the treatment of breast cancer.
Identifiants
pubmed: 36797769
doi: 10.1186/s13046-023-02620-5
pii: 10.1186/s13046-023-02620-5
pmc: PMC9936722
doi:
Substances chimiques
Interleukin-6
0
MALT1 protein, human
EC 3.4.22.-
Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
EC 3.4.22.-
RNA, Circular
0
Serpin E2
0
SERPINE2 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
48Subventions
Organisme : National Natural Science Foundation of China
ID : 81772613
Organisme : National Natural Science Foundation of China
ID : 81774378
Organisme : National Natural Science Foundation of China
ID : 82160559
Informations de copyright
© 2023. The Author(s).
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