Xiang-Guang Wu1, Chen-Fei Zhou1, Yan-Mei Zhang2, Rui-Ming Yan3, Wen-Fei Wei3, Xiao-Jing Chen3, Hong-Yan Yi3, Luo-Jiao Liang3, Liang-Sheng Fan1, Li Liang4, Sha Wu5, Wei Wang6,7. 1. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, 510120, Guangzhou, China. 2. Department of Immunology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, 510515, Guangzhou, China. 3. Department of Obstetrics and Gynecology, Nanfang Hospital/The First School of Clinical Medicine, Southern Medical University, 510515, Guangzhou, China. 4. Department of Pathology, Nanfang Hospital/The First School of Clinical Medicine, Southern Medical University, 510515, Guangzhou, China. redsnow007@hotmail.com. 5. Department of Immunology, School of Basic Medical Sciences, Guangdong Provincial Key Laboratory of Proteomics, Southern Medical University, 510515, Guangzhou, China. shawu99@outlook.com. 6. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, 510120, Guangzhou, China. smugowwang@126.com. 7. Department of Obstetrics and Gynecology, Nanfang Hospital/The First School of Clinical Medicine, Southern Medical University, 510515, Guangzhou, China. smugowwang@126.com.
Abstract
AIMS: Recently, cancer-derived exosomes were shown to have pro-metastasis function in cancer, but the mechanism remains unclear. Angiogenesis is essential for tumor progression and is a great promising therapeutic target for advanced cervical cancer. Here, we investigated the role of cervical cancer cell-secreted exosomal miR-221-3p in tumor angiogenesis. METHODS AND RESULTS: miR-221-3p was found to be closely correlated with microvascular density in cervical squamous cell carcinoma (CSCC) by evaluating the microvascular density with immunohistochemistry and miR-221-3p expression with in situ hybridization in clinical specimens. Using the groups of CSCC cell lines (SiHa and C33A) with miR-221-3p overexpression and silencing, the CSCC exosomes were characterized by electron microscopy, western blotting, and fluorescence microscopy. The enrichment of miR-221-3p in CSCC exosomes and its transfer into human umbilical vein endothelial cells (HUVECs) were confirmed by qRT-PCR. CSCC exosomal miR-221-3p promoted angiogenesis in vitro in Matrigel tube formation assay, spheroid sprouting assay, migration assay, and wound healing assay. Then, exosome intratumoral injection indicated that CSCC exosomal miR-221-3p promoted tumor growth in vivo. Thrombospondin-2 (THBS2) was bioinformatically predicted to be a direct target of miR-221-3p, and this was verified by using the in vitro and in vivo experiments described above. Additionally, overexpression of THBS2 in HUVECs rescued the angiogenic function of miR-221-3p. CONCLUSIONS: Our results suggest that CSCC exosomes transport miR-221-3p from cancer cells to vessel endothelial cells and promote angiogenesis by downregulating THBS2. Therefore, CSCC-derived exosomal miR-221-3p could be a possible novel diagnostic biomarker and therapeutic target for CSCC progression.
AIMS: Recently, cancer-derived exosomes were shown to have pro-metastasis function in cancer, but the mechanism remains unclear. Angiogenesis is essential for tumor progression and is a great promising therapeutic target for advanced cervical cancer. Here, we investigated the role of cervical cancer cell-secreted exosomal miR-221-3p in tumor angiogenesis. METHODS AND RESULTS:miR-221-3p was found to be closely correlated with microvascular density in cervical squamous cell carcinoma (CSCC) by evaluating the microvascular density with immunohistochemistry and miR-221-3p expression with in situ hybridization in clinical specimens. Using the groups of CSCC cell lines (SiHa and C33A) with miR-221-3p overexpression and silencing, the CSCC exosomes were characterized by electron microscopy, western blotting, and fluorescence microscopy. The enrichment of miR-221-3p in CSCC exosomes and its transfer into human umbilical vein endothelial cells (HUVECs) were confirmed by qRT-PCR. CSCC exosomal miR-221-3p promoted angiogenesis in vitro in Matrigel tube formation assay, spheroid sprouting assay, migration assay, and wound healing assay. Then, exosome intratumoral injection indicated that CSCC exosomal miR-221-3p promoted tumor growth in vivo. Thrombospondin-2 (THBS2) was bioinformatically predicted to be a direct target of miR-221-3p, and this was verified by using the in vitro and in vivo experiments described above. Additionally, overexpression of THBS2 in HUVECs rescued the angiogenic function of miR-221-3p. CONCLUSIONS: Our results suggest that CSCC exosomes transport miR-221-3p from cancer cells to vessel endothelial cells and promote angiogenesis by downregulating THBS2. Therefore, CSCC-derived exosomal miR-221-3p could be a possible novel diagnostic biomarker and therapeutic target for CSCC progression.
Authors: Marissa J Harmsen; Caroline F C Wong; Velja Mijatovic; Arjan W Griffioen; Freek Groenman; Wouter J K Hehenkamp; Judith A F Huirne Journal: Hum Reprod Update Date: 2019-09-11 Impact factor: 15.610
Authors: Víctor Acevedo-Sánchez; Ruth M Rodríguez-Hernández; Sergio R Aguilar-Ruíz; Honorio Torres-Aguilar; María de Los A Romero-Tlalolini Journal: Membranes (Basel) Date: 2021-06-20