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Identification of ANXA1 as a Lymphatic Metastasis and Poor Prognostic Factor in Pancreatic Ductal Adenocarcinoma

  • Liu, Qing-Hua (Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute) ;
  • Shi, Mei-Lin (Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute) ;
  • Bai, Jin (Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute) ;
  • Zheng, Jun-Nian (Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute)
  • Published : 2015.04.14

Abstract

Objective: The aim of this study was to investigate the clinical significance of annexin a1 (ANXA1) and provide molecular evidence to support that decreased ANXA1 expression could enhance cancer migration and invasion in pancreatic ductal adenocarcinoma (PDAC). Materials and Methods: Immunohistochemistry of a tissue microarray with 162 surgically resected PDAC specimens was performed to examine the expression of ANXA1. We also investigated the relationship between ANXA1 expression and clinicopathological factors and prognosis of PDAC patients. We further studied the role of ANXA1 in PDAC cell proliferation, migration and invasion by cell proliferation assay, migration assay and matrigel invasion assay with reduced ANXA1 expression by RNAi. Western blotting was used to detect matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression. We also detected MMP-9 enzyme activity by gelatin zymography. Results: Decreased expression of ANXA1 was significantly associated with poor differentiation, lymph node metastasis and advanced TNM stage of PDAC patients (p<0.05). Moreover, decreased expression of ANXA1 was correlated with poor survival (p<0.05). Furthermore, we found that ANXA1 knockdown inhibited cell proliferation, induced G1 phase cell cycle arrest, increased PDAC cell migration and invasion capacity compared with controls. In addition, Western blotting showed that ANXA1 knockdown increased the MMP-9 protein level and decreased TIMP-1 expression. Gelatin zymography showed that MMP-9 enzyme activity was also elevated. Conclusions: Negative ANXA1 expression is a most unfavorable prognostic factor for PDAC patients. ANXA1 knockdown inhibits cell proliferation by inducing G1 phase cell cycle arrest and increases migration and invasion of PDAC cells through up-regulating MMP-9 expression and activity, implying that ANXA1 may serve as a promising prognostic biomarker and therapeutic target for PDAC.

Keywords

Annexin a1;pancreatic ductual adenocarcinoma;tissue microarray;lymphatic metastasis;prognostic

Acknowledgement

Supported by : National Natural Science Foundation of China

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