HMGA2 protein expression correlates with lymph node metastasis and increased tumor grade in pancreatic ductal adenocarcinoma.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Modern Pathology (Impact Factor: 5.25). 09/2008; 22(1):43-9. DOI: 10.1038/modpathol.2008.140
Source: PubMed

ABSTRACT Pancreatic ductal adenocarcinoma is a highly aggressive, lethal human malignancy that continues to elude successful treatment. Although most patients present with metastatic disease, the molecular pathways that underlie tumor progression and metastases are poorly understood. The high mobility group A2 (HMGA2) protein is an architectural transcription factor that has recently been implicated in the development and progression of malignant tumors. Here, we examined HMGA2 gene expression in pancreatic ductal adenocarcinoma to determine if it could be a marker for more advanced disease. By real time quantitative RT-PCR, we showed a marked increase in HMGA2 mRNA in two of three cultured pancreatic ductal adenocarcinoma cell lines compared to normal pancreatic tissue. Using tissue microarrays generated from 124 pancreatic ductal adenocarcinoma cases, we also assessed HMGA2 protein levels by immunohistochemical analysis. We found that HMGA2 nuclear immunoreactivity correlates positively with lymph node metastases and high tumor grade. Our results support a role for HMGA2 in the progression of pancreatic ductal adenocarcinoma and suggest that it could be a useful biomarker and rational therapeutic target in more advanced disease.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Long-standing studies have clearly established that the architectural chromatinic proteins High Mobility Group A (HMGA) are among the most widely expressed cancer-associated proteins. Indeed, their overexpression represents a constant feature of human malignancies, and correlates with a poor prognosis. Moreover, HMGA dysregulation, as a result of specific chromosomal rearrangements, occurs in a broad variety of common benign mesenchymal tumors, making HMGA genes among the most commonly rearranged genes in human neoplasms. Nevertheless, recent data propose a critical role of HMGA overexpression also in the generation of pituitary adenomas. Here, we review the involvement of HMGA proteins in cancer, analyzing the mechanisms underlying their crucial role in tumorigenesis, and, finally, discuss the potentiality of a cancer treatment based on HMGA targeting.
    Biochimica et Biophysica Acta 01/2010; 1799(1-2):48-54. · 4.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is associated with a pronounced collagen-rich stromal reaction that has been shown to contribute to chemo-resistance. We have previously shown that PDAC cells are resistant to gemcitabine chemotherapy in the collagen microenvironment because of increased expression of the chromatin remodeling protein high mobility group A2 (HMGA2). We have now found that human PDAC tumors display higher levels of histone H3K9 and H3K27 acetylation in fibrotic regions. We show that relative to cells grown on tissue culture plastic, PDAC cells grown in three-dimensional collagen gels demonstrate increased histone H3K9 and H3K27 acetylation, along with increased expression of p300, PCAF and GCN5 histone acetyltransferases (HATs). Knocking down HMGA2 attenuates the effect of collagen on histone H3K9 and H3K27 acetylation and on collagen-induced p300, PCAF and GCN5 expression. We also show that human PDAC tumors with HMGA2 demonstrate increased histone H3K9 and H3K27 acetylation. Additionally, we show that cells in three-dimensional collagen gels demonstrate increased protection against gemcitabine. Significantly, down-regulation of HMGA2 or p300, PCAF and GCN5 HATs sensitizes the cells to gemcitabine in three-dimensional collagen. Overall, our results increase our understanding of how the collagen microenvironment contributes to chemo-resistance in vitro and identify HATs as potential therapeutic targets against this deadly cancer.
    PLoS ONE 01/2013; 8(5):e64566. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: HMGA2, the High Mobility Group A2 gene, plays a very important role in fetal development and carcinogenesis. As an oncofetal gene, it is upregulated in tumors of both epithelial and mesenchymal tissue origin. Chromosomal translocations of HMGA2 are common in mesenchymal tumors, whereas the regulatory mechanisms of HMGA2 in malignant epithelial tumors are much more complex. As an architectural transcription factor, it is involved in multiple biological pathways by targeting different downstream genes in different cancers. HMGA2 is upregulated in both the early and late stages of high-grade serous ovarian carcinoma (HGSOC) and, according to The Cancer Genomic Atlas, is among a signature of genes overexpressed in ovarian cancer. Recent identification of miR-182 as a mediator of BRCA1 and HMGA2 deregulation in ovarian cancer cells may guide us toward a better understanding of the roles of HMGA2 in ovarian carcinogenesis. In this article, we will review recent developments and findings related to HMGA2, including its regulation, oncogenic properties, major functional pathways associated with the tumorigenesis of HGSOC, and its potential role as a biomarker for clinical application.
    Journal of Molecular Medicine 05/2013; · 4.77 Impact Factor

Full-text (2 Sources)

Available from
Jun 1, 2014