title: Yin Yang-1 suppresses invasion and metastasis of pancreatic ductal adenocarcinoma by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism.
abstract: BACKGROUND
  Increasing evidence indicates an important role of transcription factor Yin Yang-1 (YY1) in human tumorigenesis. However, its function in cancer remains controversial and the relevance of YY1 to pancreatic ductal adenocarcinoma (PDAC) remains to be clarified.
  
  
  METHODS
  In this study, we detected YY1 expression in clinical PDAC tissue samples and cell lines using quantitative RT-PCR, immunohistochemistry and western blotting. We also detected MUC4 and MMP10 mRNA levels in 108 PDAC samples using qRT-PCR and analyzed the correlations between YY1 and MUC4 or MMP10 expression. The role of YY1 in the proliferation, invasion and metastatic abilities of PDAC cells in vitro was studied by CCK-8 assay, cell migration and invasion assays. In vivo pancreatic tumor growth and metastasis was studied by a xenogenous subcutaneously implant model and a tail vein metastasis model. The potential mechanisms underlying YY1 mediated tumor progression in PDAC were explored by digital gene expression (DGE) sequencing, signal transduction pathways blockage experiments and luciferase assays. Statistical analysis was performed using the SPSS 15.0 software.
  
  
  RESULTS
  We found that the expression of YY1 in PDACs was higher compared with their adjacent non-tumorous tissues and normal pancreas tissues. However, PDAC patients with high level overexpression of YY1 had better outcome than those with low level overexpression. YY1 expression levels were statistically negatively correlated with MMP10 expression levels, but not correlated with MUC4 expression levels. YY1 overexpression suppressed, whereas YY1 knockdown enhanced, the proliferation, invasion and metastatic properties of BXPC-3 cells, both in vitro and in vivo. YY1 suppresses invasion and metastasis of pancreatic cancer cells by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism.
  
  
  CONCLUSIONS
  The present study suggested that YY1 plays a negative role, i.e. is a tumor suppressor, in PDAC, and may become a valuable diagnostic and prognostic marker of PDAC.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Kun-Ling
authors.initials: KL
authors.lastname: Xie
authors.forename: Yun-Peng
authors.initials: YP
authors.lastname: Peng
authors.forename: Jin-Qiu
authors.initials: JQ
authors.lastname: Tao
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Ze-Kuan
authors.initials: ZK
authors.lastname: Xu
authors.forename: Cun-Cai
authors.initials: CC
authors.lastname: Dai
authors.forename: Zhu-Yin
authors.initials: ZY
authors.lastname: Qian
authors.forename: Kui-Rong
authors.initials: KR
authors.lastname: Jiang
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Wu
authors.forename: Wen-Tao
authors.initials: WT
authors.lastname: Gao
authors.forename: Qing
authors.initials: Q
authors.lastname: Du
authors.affiliation: Department of General Surgery, The first Affiliated Hospital of Nanjing Medical University, Jiangsu Province Academy of Clinical Medicine, Institute of Tumor Biology, 300 Guangzhou Road, Nanjing 210029, People's Republic of China. miaoyi@njmu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Miao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D064326:MEF2 Transcription Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D055264:Mucin-4 / Q000235:genetics / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays; D050986:YY1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D064326:MEF2 Transcription Factors; D053506:Matrix Metalloproteinase 10; D055264:Mucin-4; D018719:Erb-b2 Receptor Tyrosine Kinases; D050986:YY1 Transcription Factor; D048051:p38 Mitogen-Activated Protein Kinases; C578040:MEF2C protein, human; C524658:MUC4 protein, human; C494698:YY1 protein, human; C508053:ERBB2 protein, human; C511770:MMP10 protein, human