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Exosomal miR-1304-3p promotes breast cancer progression in African Americans by activating cancer-associated adipocytes.

ABSTRACT: Breast cancer displays disparities in mortality between African Americans and Caucasian Americans. However, the exact molecular mechanisms remain elusive. Here, we identify miR-1304-3p as the most upregulated microRNA in African American patients. Importantly, its expression significantly correlates with poor progression-free survival in African American patients. Ectopic expression of miR-1304 promotes tumor progression in vivo. Exosomal miR-1304-3p activates cancer-associated adipocytes that release lipids and enhance cancer cell growth. Moreover, we identify the anti-adipogenic gene GATA2 as the target of miR-1304-3p. Notably, a single nucleotide polymorphism (SNP) located in the miR-1304 stem-loop region shows a significant difference in frequencies of the G allele between African and Caucasian American groups, which promotes the maturation of miR-1304-3p. Therefore, our results reveal a mechanism of the disparity in breast cancer progression and suggest a potential utility of miR-1304-3p and the associated SNP as biomarkers for predicting the outcome of African American patients.

SUBMITTER: Zhao D

PROVIDER: S-EPMC9751138 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Exosomal miR-1304-3p promotes breast cancer progression in African Americans by activating cancer-associated adipocytes.

Zhao Dan D Wu Kerui K Sharma Sambad S Xing Fei F Wu Shih-Ying SY Tyagi Abhishek A Deshpande Ravindra R Singh Ravi R Wabitsch Martin M Mo Yin-Yuan YY Watabe Kounosuke K

Nature communications 20221214 1

Breast cancer displays disparities in mortality between African Americans and Caucasian Americans. However, the exact molecular mechanisms remain elusive. Here, we identify miR-1304-3p as the most upregulated microRNA in African American patients. Importantly, its expression significantly correlates with poor progression-free survival in African American patients. Ectopic expression of miR-1304 promotes tumor progression in vivo. Exosomal miR-1304-3p activates cancer-associated adipocytes that r ...[more]

PMID: 36517516

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Project description:BackgroundColorectal cancer (CRC) is the leading cause of cancer-related death worldwide. Exosome shave emerged as crucial regulators of intercellular communication and that abundant Circular RNAs (circRNAs) are enriched within exosomes. CircRNAs are novel members of noncoding RNAs regulating cancer proliferation and progression. However, the function and regulatory mechanism of cancer-derived exosomal circRNAs in CRC remains unclear.MethodsCRC cells-derived exosomes were characterized using transmission electron microscopy, nanoparticle tracking analysis (NTA) and western blot. CCK-8, wound healing and transwell assays, and flow cytometry assays were conducted to assess whether exosomes would affect the proliferation, metastasis, and apoptosis of CRC cells, respectively. Moreover, we performed the RNA sequencing and RT-qPCR to identify circRNAs in exosome-stimulated CRC cells. Fluorescence in situ hybridization (FISH) assay was used to detect the cellular distribution of circPACRGL. Bioinformatic analyses (StarBase 2.0) were used to pool the miRNA targets of circPACRGL. Luciferase assays were performed to verify the direct interaction. Finally, flow cytometry was used to detect the differentiation of N1-N2 neutrophils.ResultsOur study identified a novel CRC-derived exosomal circRNA, circPACRGL. We found circPACRGL was significantly upregulated in CRC cells after tumor-derived exosomes addition. Moreover, circPACRGL serves as a sponge for miR-142-3p/miR-506-3p to facilitate the transforming growth factor-β1 (TGF-β1) expression. As a result, circPACRGL promoted CRC cell proliferation, migration and invasion, as well as differentiation of N1 to N2 neutrophils via miR-142-3p/miR-506-3p-TGF-β1 axis.ConclusionOur study, the first to reveal that cancer-derived exosomal circPACRGL plays an oncogenic role in CRC proliferation and metastasis, providing mechanistic insights into the roles of circRNAs in CRC progression and a valuable marker for CRC treatment.

Project description:BackgroundTumor-associated macrophages (TAM) are critical elements of intercellular communication in tumor microenvironment (TME), and exosomes are key mediators between tumor cells and the TME. According to previous reports, miRNAs exert a pivotal role in ovarian cancer (OC) development. The purpose of this work was to explore the function of TAM-derived exosomal miR-589-3p in OC development and elucidate the underlying molecular mechanisms.MethodsFirst, peripheral blood mononuclear cells (PBMC) were treated with IL-4 and IL-13 to polarize them into M2-type macrophages. Exosomes were separated from M2-type macrophages, and the physical properties of exosomes were evaluated using transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Next, quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) was applied to examine the expression of relevant genes. Subsequently, Targetscan and miRDB were utilized to predict miR-589-3p target genes, and then the interaction between miR-589-3p and BCL2L13 was verified by dual luciferase assay and RNA Binding Protein Immunoprecipitation (RIP) assay. Finally, Cell Counting Kit-8 (CCK-8) and flow cytometry experiments were employed to explore the changes in the proliferative and apoptotic abilities of OC cells.ResultsIn this research, we demonstrated that TAM-derived exosomes facilitated OC cell proliferation and suppressed OC cell apoptosis. Then, qRT-PCR results indicated that miR-589-3p were markedly elevated after co-culture of TAM-derived exosomes with OC cells. In addition, we discovered that miR-589-3p was bound to BCL-2-like protein 13 (BCL2L13), which was confirmed through luciferase assay and RIP assay. Furthermore, functional analysis displayed that TAM-derived exosomes treated with miR-589-3p inhibitor attenuated the promotion of OC cell progression by exosomes.ConclusionTAM-derived exosomal miR-589-3p enhanced OC progression through BCL2L13, which offers a novel for OC therapy.

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Exosomal miR-1304-3p promotes breast cancer progression in African Americans by activating cancer-associated adipocytes.

Publications

Exosomal miR-1304-3p promotes breast cancer progression in African Americans by activating cancer-associated adipocytes.

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