title: Down-regulated desmocollin-2 promotes cell aggressiveness through redistributing adherens junctions and activating beta-catenin signalling in oesophageal squamous cell carcinoma.
abstract: In contrast to the well-recognized loss of adherens junctions in cancer progression, the role of desmosomal components in cancer development has not been well explored. We previously demonstrated that desmocollin-2 (DSC2), a desmosomal cadherin protein, is reduced in oesophageal squamous cell carcinoma (ESCC), and is associated with enhanced tumour metastasis and poor prognosis. Here, we report that restoration of DSC2 in ESCC cells impeded cell migration and invasion both in vitro and in vivo, whereas siRNA-mediated suppression of DSC2 expression increased cell motility. In E-cadherin-expressing ESCC cells, DSC2 restoration strengthened E-cadherin-mediated adherens junctions and promoted the localization of β-catenin at these junctions, which indirectly inhibited β-catenin-dependent transcription. These effects of DSC2 were not present in EC109 cells that lacked E-cadherin expression. ESCC patients with tumours that had reduced E-cadherin and negative DSC2 had poorer clinical outcomes than patients with tumours that lacked either E-cadherin or DSC2, implying that the invasive potential of ESCC cells was restricted by both DSC2 and E-cadherin-dependent junctions. Further studies revealed that DSC2 was a downstream target of miR-25. Enhanced miR-25 promoted ESCC cell invasiveness, whereas restoration of DSC2 abolished these effects. Collectively, our work suggests that miR-25-mediated down-regulation of DSC2 promotes ESCC cell aggressiveness through redistributing adherens junctions and activating beta-catenin signalling.
authors.affiliation: Department of Biochemistry and Molecular Biology, Shantou University Medical College, Shantou, China; The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, Shantou, China.
authors.forename: Wang-Kai
authors.initials: WK
authors.lastname: Fang
authors.forename: Lian-Di
authors.initials: LD
authors.lastname: Liao
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Li
authors.forename: Yang-Min
authors.initials: YM
authors.lastname: Xie
authors.forename: Xiu-E
authors.initials: XE
authors.lastname: Xu
authors.forename: Wei-Jiang
authors.initials: WJ
authors.lastname: Zhao
authors.forename: Jian-Yi
authors.initials: JY
authors.lastname: Wu
authors.forename: Meng-Xiao
authors.initials: MX
authors.lastname: Zhu
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Wu
authors.forename: Ze-Peng
authors.initials: ZP
authors.lastname: Du
authors.forename: Bing-Li
authors.initials: BL
authors.lastname: Wu
authors.forename: Dong
authors.initials: D
authors.lastname: Xie
authors.forename: Ming-Zhou
authors.initials: MZ
authors.lastname: Guo
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Xu
authors.forename: En-Min
authors.initials: EM
authors.lastname: Li
mesh_terms: D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D051187:Desmocollins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D014183:Transplantation, Heterologous; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C081561:DSC2 protein, human; D051187:Desmocollins; D035683:MicroRNAs; D051176:beta Catenin
keywords: DSC2; E-cadherin; invasion; miR-25; oesophageal squamous cell carcinoma