title: TGFβ1 secreted by cancer-associated fibroblasts induces epithelial-mesenchymal transition of bladder cancer cells through lncRNA-ZEB2NAT.
abstract: Urinary bladder cancer (UBC) patients at muscle invasive stage have poor clinical outcome, due to high propensity for metastasis. Cancer-associated fibroblasts (CAFs), one of the principal constituents of the tumor stroma, play an important role in tumor development. However, it is unclear whether CAFs from UBC induce cell invasion and which signaling pathway is involved. Herein, we found that conditional medium from UBC CAFs (CAF-CM) enhanced the invasion of UBC cells. CAF-CM induced the epithelial-mesenchymal transition (EMT) by regulating expression levels of EMT-associated markers in UBC cells. Higher concentration of TGFβ1 in CAF-CM, comparing with the CM from adjacent normal fibroblast, led to phosphorylation of Smad2 in UBC cells. Additionally, inhibition of TGFβ1 signaling decreased the EMT-associated gene expression, and cancer cell invasion. Interestingly, a long non-coding RNA, ZEB2NAT, was demonstrated to be essential for this TGFβ1-dependent process. ZEB2NAT depletion reversed CAF-CM-induced EMT and invasion of cancer cells, as well as reduced the ZEB2 protein level. Consistently, TGFβ1 mRNA expression is positively correlated with ZEB2NAT transcript and ZEB2 protein levels in human bladder cancer specimens. Our data revealed a novel mechanism that CAFs induces EMT and invasion of human UBC cells through the TGFβ1-ZEB2NAT-ZEB2 axis.
authors.affiliation: Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
authors.forename: Junlong
authors.initials: J
authors.lastname: Zhuang
authors.affiliation: Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Lu
authors.affiliation: Department of Urology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, 200080, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Shen
authors.affiliation: Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Huang
authors.affiliation: Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Shen
authors.affiliation: Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Ruimin
authors.initials: R
authors.lastname: Huang
authors.affiliation: Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: 1] Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China [2] Nanjing Urology Research Center, Nanjing, Jiangsu 210008, China.
authors.forename: Hongqian
authors.initials: H
authors.lastname: Guo
mesh_terms: D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000378:metabolism / Q000473:pathology; D014746:Vimentin / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2
chemical_list: D015820:Cadherins; D017077:Culture Media, Conditioned; D018398:Homeodomain Proteins; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D051899:Smad2 Protein; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D014746:Vimentin; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2