Abstract

BACKGROUND:Increasing evidence indicates an important role oftranscription factor Yin Yang-1 (YY1) in human tumorigenesis. However, itsfunction in cancer remains controversial and the relevance of YY1 to pancreaticductal adenocarcinoma (PDAC) remains to be clarified.

METHODS:In this study, we detected YY1 expression inclinical PDAC tissue samples and cell lines using quantitative RT-PCR,immunohistochemistry and western blotting. We also detected MUC4 and MMP10 mRNAlevels in 108 PDAC samples using qRT-PCR and analyzed the correlations betweenYY1 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-8assay, cell migration and invasion assays. In vivo pancreatic tumor growth andmetastasis was studied by a xenogenous subcutaneously implant model and a tailvein metastasis model. The potential mechanisms underlying YY1 mediated tumorprogression 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 washigher compared with their adjacent non-tumorous tissues and normal pancreastissues. However, PDAC patients with high level overexpression of YY1 hadbetter outcome than those with low level overexpression. YY1 expression levelswere statistically negatively correlated with MMP10 expression levels, but notcorrelated with MUC4 expression levels. YY1 overexpression suppressed, whereasYY1 knockdown enhanced, the proliferation, invasion and metastatic propertiesof BXPC-3 cells, both in vitro and in vivo. YY1 suppresses invasion andmetastasis of pancreatic cancer cells by downregulating MMP10 in aMUC4/ErbB2/p38/MEF2C-dependent mechanism.

CONCLUSIONS:The present study suggested that YY1 plays anegative role, i.e. is a tumor suppressor, in PDAC, and may become a valuablediagnostic and prognostic marker of PDAC.