title: Reprogramming of Normal Fibroblasts into Cancer-Associated Fibroblasts by miRNAs-Mediated CCL2/VEGFA Signaling.
abstract: Cancer-associated fibroblasts (CAFs), the most common constituent of the tumor stoma, are known to promote tumor initiation, progression and metastasis. However, the mechanism of how cancer cells transform normal fibroblasts (NFs) into CAFs is largely unknown. In this study, we determined the contribution of miRNAs in the transformation of NFs into CAFs. We found that miR-1 and miR-206 were down-regulated, whereas miR-31 was up-regulated in lung CAFs when compared with matched NFs. Importantly, modifying the expression of these three deregulated miRNAs induced a functional conversion of NFs into CAFs and vice versa. When the miRNA-reprogrammed NFs and CAFs were co-cultured with lung cancer cells (LCCs), a similar pattern of cytokine expression profiling were observed between two groups. Using a combination of cytokine expression profiling and miRNAs algorithms, we identified VEGFA/CCL2 and FOXO3a as direct targets of miR-1, miR-206 and miR-31, respectively. Importantly, systemic delivery of anti-VEGFA/CCL2 or pre-miR-1, pre-miR-206 and anti-miR-31 significantly inhibited tumor angiogenesis, TAMs accumulation, tumor growth and lung metastasis. Our results show that miRNAs-mediated FOXO3a/VEGF/CCL2 signaling plays a prominent role in LCCs-mediated NFs into CAFs, which may have clinical implications for providing novel biomarker(s) and potential therapeutic target(s) of lung cancer in the future.
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.|Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Thoracic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.|Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Fengming
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Respiration, First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei Province, China.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Clinical Laborotory, First Affiliated Hospital of Hebei North University, Zhangjiakou, Hebei Province, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Nuclear Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.affiliation: National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Swati
authors.initials: S
authors.lastname: Choksi
authors.affiliation: Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand.
authors.forename: Siriporn
authors.initials: S
authors.lastname: Jitkaew
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.|Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Shu
mesh_terms: D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming / Q000235:genetics; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D000071316:Forkhead Box Protein O3 / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; C544547:MIRN1 microRNA, human; C546087:MIRN206 microRNA, human; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A