IGFBP3, a transcriptional target of homeobox D10, is correlated with the prognosis of gastric cancer

PLoS One. 2013 Dec 27;8(12):e81423. doi: 10.1371/journal.pone.0081423. eCollection 2013.

Abstract

Homeobox D10 (HoxD10) plays important roles in the differentiation of embryonic cells and progression of breast cancer. Our previous report revealed that insulin-like growth factor binding protein-3 (IGFBP3) was regulated by HoxD10 in gastric cancer cells; however, the functional roles and underlying mechanisms of IGFBP3 in gastric cancer remain unclear. Here, we found that the expression of IGFBP3 were upregulated after ectopic expression of HoxD10 in gastric cancer cells. Chromatin immunoprecipitation assay showed that HoxD10 bound to three potential regions of IGFBP3 promoter. Exogenous HoxD10 significantly enhanced the activity of luciferase reporter containing these binding regions in gastric cancer cells. Further data showed that all of these binding sites had Hox binding element "TTAT". Immunohistochemical staining results revealed that IGFBP3 expression was significantly downregulated in 86 gastric adenocarcinomas tissues relative to their adjacent non-cancerous tissues (p<0.001). Moreover, IGFBP3 expression was significantly lower in gastric tumor with lymph node metastasis compared with that without lymph node metastasis (p=0.045). Patients with high expression level of IGFBP3 showed favorable 5 year overall survival (p=0.011). Knockdown of IGFBP3 accelerated gastric cancer cell migration and invasion and induced the expression of invasive factors including MMP14, uPA and uPAR. Thus, our data suggest that HoxD10-targeted gene IGFBP3 may suppress gastric cancer cell invasion and favors the survival of gastric cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement / genetics
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / physiology
  • Humans
  • Immunohistochemistry
  • Insulin-Like Growth Factor Binding Protein 3 / genetics*
  • Matrix Metalloproteinase 14 / genetics
  • Matrix Metalloproteinase 14 / metabolism
  • Neoplasm Invasiveness / genetics
  • Prognosis
  • Promoter Regions, Genetic
  • Receptors, Urokinase Plasminogen Activator / genetics
  • Receptors, Urokinase Plasminogen Activator / metabolism
  • Stomach Neoplasms / diagnosis
  • Stomach Neoplasms / genetics*
  • Survival Analysis
  • Transcription Factors / genetics
  • Transcription Factors / physiology
  • Up-Regulation
  • Urokinase-Type Plasminogen Activator / genetics
  • Urokinase-Type Plasminogen Activator / metabolism

Substances

  • Homeodomain Proteins
  • IGFBP3 protein, human
  • Insulin-Like Growth Factor Binding Protein 3
  • Receptors, Urokinase Plasminogen Activator
  • Transcription Factors
  • HOXD10 protein, human
  • Urokinase-Type Plasminogen Activator
  • MMP14 protein, human
  • Matrix Metalloproteinase 14

Grants and funding

This work was supported by the National Natural Science Foundation of China (81302070, 81272678, 81071961) (http://www.nsfc.gov.cn), National Basic Research Program of China (973 Program) (2012CB945004) (www.973.gov.cn) and Research Fund for the Doctoral Program of Higher Education of China (20100101110126) (www.cutech.edu.cn/cn/kyjj). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.