title: Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling.
abstract: The activation of cancer-associated fibroblasts (CAFs) is a key event in tumor progression, and alternative extracellular matrix (ECM) proteins derived from CAFs induce ECM remodeling and cancer cell invasion. Here we found that miR-200 s, which are generally downregulated in activated CAFs in breast cancer tissues and in normal fibroblasts (NFs) activated by breast cancer cells, are direct mediators of NF reprogramming into CAFs and of ECM remodeling. NFs with downregulated miR-200 s displayed the traits of activated CAFs, including accelerated migration and invasion. Ectopic expression of miR-200 s in CAFs at least partially restored the phenotypes of NFs. CAF activation may be governed by the targets of miR-200 s, Fli-1 and TCF12, which are responsible for cell development and differentiation; Fli-1 and TCF12 were obviously elevated in CAFs. Furthermore, miR-200 s and their targets influenced collagen contraction by CAFs. The upregulation of fibronectin and lysyl oxidase directly by miR-200 or indirectly through Fli-1 or TCF12 contributed to ECM remodeling, triggering the invasion and metastasis of breast cancer cells both in vitro and vivo. Thus, these data provide important and novel insights into breast CAF activation and ECM remodeling, which trigger tumor cell invasion.
authors.affiliation: Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, #1 Yi-Xue-Yuan Road, Yu-zhong District, Chongqing 400016, China.
authors.forename: X
authors.initials: X
authors.lastname: Tang
authors.affiliation: Experimental Teaching Center of Basic Medicine Science, #1 Yi-Xue-Yuan Road, Yu-zhong District, Chongqing Medical University, Chongqing 400016, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, No. 1 You-Yi Road, Yu-zhong District, Chongqing 400016, China.
authors.forename: G
authors.initials: G
authors.lastname: Yang
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital, Chongqing Medical University, No. 76 Linjiang Road, Yu-zhong District, Chongqing 400010, China.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, #1 Yi-Xue-Yuan Road, Yu-zhong District, Chongqing 400016, China.
authors.forename: S
authors.initials: S
authors.lastname: Tang
authors.affiliation: Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, #1 Yi-Xue-Yuan Road, Yu-zhong District, Chongqing 400016, China.
authors.forename: Y-E
authors.initials: YE
authors.lastname: Du
authors.affiliation: Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, #1 Yi-Xue-Yuan Road, Yu-zhong District, Chongqing 400016, China.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, No. 1 You-Yi Road, Yu-zhong District, Chongqing 400016, China.
authors.forename: T
authors.initials: T
authors.lastname: Yu
authors.affiliation: Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, #1 Yi-Xue-Yuan Road, Yu-zhong District, Chongqing 400016, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, #1 Yi-Xue-Yuan Road, Yu-zhong District, Chongqing 400016, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, #1 Yi-Xue-Yuan Road, Yu-zhong District, Chongqing 400016, China.
authors.forename: S
authors.initials: S
authors.lastname: Wen
authors.affiliation: Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, #1 Yi-Xue-Yuan Road, Yu-zhong District, Chongqing 400016, China.
authors.forename: L
authors.initials: L
authors.lastname: Xu
authors.affiliation: Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, #1 Yi-Xue-Yuan Road, Yu-zhong District, Chongqing 400016, China.
authors.forename: M
authors.initials: M
authors.lastname: Liu
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology / Q000556:secondary; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008840:Microfilament Proteins / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D008249:Protein-Lysine 6-Oxidase / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D015534:Trans-Activators; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005353:Fibronectins; D035683:MicroRNAs; D008840:Microfilament Proteins; D008249:Protein-Lysine 6-Oxidase; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; C098179:FLII protein, human; C533896:MIRN200 microRNA, human; C073366:TCF12 protein, human