CCL18 promotes breast cancer progression by exosomal miR-760 activation of ARF6/Src/PI3K/Akt pathway
The small GTPase ADP-ribosylation factor 6 (ARF6) mediates chemokine (C-C motif) ligand 18 (CCL18)-induced activation of breast cancer (BC) metastasis through its downstream effector AMAP1. However, the molecular mechanisms underlying CCL18 up-regulating ARF6 remain largely unclear. Here, microRNAs...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-06-01
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| Series: | Molecular Therapy: Oncolytics |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2372770522000468 |
| _version_ | 1818393404519743488 |
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| author | Xiaojia Huang Shengqing Lai Fanli Qu Zongyan Li Xiaoyan Fu Qian Li Xiaofang Zhong Chao Wang Haiyan Li |
| author_facet | Xiaojia Huang Shengqing Lai Fanli Qu Zongyan Li Xiaoyan Fu Qian Li Xiaofang Zhong Chao Wang Haiyan Li |
| author_sort | Xiaojia Huang |
| collection | DOAJ |
| description | The small GTPase ADP-ribosylation factor 6 (ARF6) mediates chemokine (C-C motif) ligand 18 (CCL18)-induced activation of breast cancer (BC) metastasis through its downstream effector AMAP1. However, the molecular mechanisms underlying CCL18 up-regulating ARF6 remain largely unclear. Here, microRNAs (miRNAs) that target ARF6 were predicted and selected in high metastatic BC cells treated with CCL18. Next, we assessed the role of exosomal miR-760 in vitro and in vivo. We further analyzed the expression of ARF6, AMAP1, and phosphorylated (p)-AMAP1 in tumor and adjacent normal tissues. We first observed that CCL18 increased the expression of ARF6 and p-AMAP1 and activated the Src/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. ARF6 knockdown significantly impaired CCL18-induced malignant cellular behaviors and the Src/PI3K/Akt signaling pathway. Next, ARF6 was confirmed as a target gene of miR-760 in exosomes derived from CCL18-stimulated high metastatic BC cells. Moreover, recipient MCF-7 cells could effectively uptake these miR-760-rich exosomes that significantly promoted proliferation, tumor growth in vivo, migration, invasion, and chemoresistance by activating ARF6-mediated Src/PI3K/Akt signaling and the epithelial-mesenchymal transition (EMT) pathway. Together, our results support that exosomal miR-760 secreted by CCL18-stimulated high metastatic BC cells promoted the malignant behaviors in low metastatic BC cells by up-regulating the ARF6-mediated Src/PI3K/Akt signaling pathway. |
| first_indexed | 2024-12-14T05:44:46Z |
| format | Article |
| id | doaj.art-4082bc6a9fc141fb8d87618f822437be |
| institution | Directory Open Access Journal |
| issn | 2372-7705 |
| language | English |
| last_indexed | 2024-12-14T05:44:46Z |
| publishDate | 2022-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncolytics |
| spelling | doaj.art-4082bc6a9fc141fb8d87618f822437be2022-12-21T23:14:54ZengElsevierMolecular Therapy: Oncolytics2372-77052022-06-0125115CCL18 promotes breast cancer progression by exosomal miR-760 activation of ARF6/Src/PI3K/Akt pathwayXiaojia Huang0Shengqing Lai1Fanli Qu2Zongyan Li3Xiaoyan Fu4Qian Li5Xiaofang Zhong6Chao Wang7Haiyan Li8Department of Breast Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Erheng Road, Yuancun, Tianhe District, Guangzhou, Guangdong 510655, ChinaDepartment of Breast Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Erheng Road, Yuancun, Tianhe District, Guangzhou, Guangdong 510655, ChinaDepartment of Breast Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Erheng Road, Yuancun, Tianhe District, Guangzhou, Guangdong 510655, ChinaDepartment of Breast Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Erheng Road, Yuancun, Tianhe District, Guangzhou, Guangdong 510655, ChinaDepartment of Breast Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Erheng Road, Yuancun, Tianhe District, Guangzhou, Guangdong 510655, ChinaDepartment of Breast Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Erheng Road, Yuancun, Tianhe District, Guangzhou, Guangdong 510655, ChinaDepartment of Breast Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Erheng Road, Yuancun, Tianhe District, Guangzhou, Guangdong 510655, ChinaDepartment of Pathology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510655, ChinaDepartment of Breast Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Erheng Road, Yuancun, Tianhe District, Guangzhou, Guangdong 510655, China; Corresponding author Haiyan Li, Department of Breast Surgery, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, No. 26 Erheng Road, Yuancun, Tianhe District, Guangzhou, Guangdong 510655, China.The small GTPase ADP-ribosylation factor 6 (ARF6) mediates chemokine (C-C motif) ligand 18 (CCL18)-induced activation of breast cancer (BC) metastasis through its downstream effector AMAP1. However, the molecular mechanisms underlying CCL18 up-regulating ARF6 remain largely unclear. Here, microRNAs (miRNAs) that target ARF6 were predicted and selected in high metastatic BC cells treated with CCL18. Next, we assessed the role of exosomal miR-760 in vitro and in vivo. We further analyzed the expression of ARF6, AMAP1, and phosphorylated (p)-AMAP1 in tumor and adjacent normal tissues. We first observed that CCL18 increased the expression of ARF6 and p-AMAP1 and activated the Src/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. ARF6 knockdown significantly impaired CCL18-induced malignant cellular behaviors and the Src/PI3K/Akt signaling pathway. Next, ARF6 was confirmed as a target gene of miR-760 in exosomes derived from CCL18-stimulated high metastatic BC cells. Moreover, recipient MCF-7 cells could effectively uptake these miR-760-rich exosomes that significantly promoted proliferation, tumor growth in vivo, migration, invasion, and chemoresistance by activating ARF6-mediated Src/PI3K/Akt signaling and the epithelial-mesenchymal transition (EMT) pathway. Together, our results support that exosomal miR-760 secreted by CCL18-stimulated high metastatic BC cells promoted the malignant behaviors in low metastatic BC cells by up-regulating the ARF6-mediated Src/PI3K/Akt signaling pathway.http://www.sciencedirect.com/science/article/pii/S2372770522000468breast cancerexosomeCCL18miR-760ARF6/Src/PI3K/Akt signaling pathway |
| spellingShingle | Xiaojia Huang Shengqing Lai Fanli Qu Zongyan Li Xiaoyan Fu Qian Li Xiaofang Zhong Chao Wang Haiyan Li CCL18 promotes breast cancer progression by exosomal miR-760 activation of ARF6/Src/PI3K/Akt pathway Molecular Therapy: Oncolytics breast cancer exosome CCL18 miR-760 ARF6/Src/PI3K/Akt signaling pathway |
| title | CCL18 promotes breast cancer progression by exosomal miR-760 activation of ARF6/Src/PI3K/Akt pathway |
| title_full | CCL18 promotes breast cancer progression by exosomal miR-760 activation of ARF6/Src/PI3K/Akt pathway |
| title_fullStr | CCL18 promotes breast cancer progression by exosomal miR-760 activation of ARF6/Src/PI3K/Akt pathway |
| title_full_unstemmed | CCL18 promotes breast cancer progression by exosomal miR-760 activation of ARF6/Src/PI3K/Akt pathway |
| title_short | CCL18 promotes breast cancer progression by exosomal miR-760 activation of ARF6/Src/PI3K/Akt pathway |
| title_sort | ccl18 promotes breast cancer progression by exosomal mir 760 activation of arf6 src pi3k akt pathway |
| topic | breast cancer exosome CCL18 miR-760 ARF6/Src/PI3K/Akt signaling pathway |
| url | http://www.sciencedirect.com/science/article/pii/S2372770522000468 |
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