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: 6.19). 09/2008; 22(1):43-9. DOI: 10.1038/modpathol.2008.140
Source: PubMed


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.

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Available from: Alexandra Hristov, Mar 21, 2014
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    • "HMGA2 is expressed during embryogenesis, but is absent or presented at low levels in terminally differentiated tissues. Overexpression of HMGA2 is associated with aggressive tumor growth, early metastasis, and poor prognosis [44], [45], [46], [47]. Yang et al. showed that the expression of HMGA1 and HMGA2 in RMS with relapse or metastasis is higher than that in RMS without relapse or metastasis. "
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    ABSTRACT: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. The genetic etiology of RMS remains largely unclear underlying its development and progression. To reveal novel genes more precisely and new therapeutic targets associated with RMS, we used high-resolution array comparative genomic hybridization (aCGH) to explore tumor-associated copy number variations (CNVs) and genes in RMS. We confirmed several important genes by quantitative real-time polymerase chain reaction (QRT-PCR). We then performed bioinformatics-based functional enrichment analysis for genes located in the genomic regions with CNVs. In addition, we identified miRNAs located in the corresponding amplification and deletion regions and performed miRNA functional enrichment analysis. aCGH analyses revealed that all RMS showed specific gains and losses. The amplification regions were 12q13.12, 12q13.3, and 12q13.3-q14.1. The deletion regions were 1p21.1, 2q14.1, 5q13.2, 9p12, and 9q12. The recurrent regions with gains were 12q13.3, 12q13.3-q14.1, 12q14.1, and 17q25.1. The recurrent regions with losses were 9p12-p11.2, 10q11.21-q11.22, 14q32.33, 16p11.2, and 22q11.1. The mean mRNA level of GLI1 in RMS was 6.61-fold higher than that in controls (p = 0.0477) by QRT-PCR. Meanwhile, the mean mRNA level of GEFT in RMS samples was 3.92-fold higher than that in controls (p = 0.0354). Bioinformatic analysis showed that genes were enriched in functions such as immunoglobulin domain, induction of apoptosis, and defensin. Proto-oncogene functions were involved in alveolar RMS. miRNAs that located in the amplified regions in RMS tend to be enriched in oncogenic activity (miR-24 and miR-27a). In conclusion, this study identified a number of CNVs in RMS and functional analyses showed enrichment for genes and miRNAs located in these CNVs regions. These findings may potentially help the identification of novel biomarkers and/or drug targets implicated in diagnosis of and targeted therapy for RMS.
    PLoS ONE 04/2014; 9(4):e94924. DOI:10.1371/journal.pone.0094924 · 3.23 Impact Factor
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    • "Recently, we published that PDAC cells in the three-dimensional collagen microenvironment induce high mobility group A2 (HMGA2), an architectural protein that regulates chromatin structure and also mediates chemo-resistance in the collagen-rich microenvironment [6], [10], [11]. Significantly, HMGA2 is upregulated in human PDAC tumors, particularly in high-grade tumors with lymph node metastases [12], [13]. "
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    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 05/2013; 8(5):e64566. DOI:10.1371/journal.pone.0064566 · 3.23 Impact Factor
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    • "Reexpression of the HMGA2 gene was observed in the cells of many human malignancies such as breast and non-small lung cancers [18], pancreatic carcinoma [19], breast cancer [20], squamous cell carcinomas [21], and myeloproliferative disorders [22]. HMGA2 is being studied for its oncogenic properties [23,24], stem cell self-renewal [25,26], DNA damage response [27], and tumor cell growth and differentiation [28–30]. However, the precise role of HMGA2 in malignant transformation and the gene’s regulation of tumorigenesis are still not clear. "
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    ABSTRACT: To explore the molecular mechanisms deregulated by high mobility group protein A2 (HMGA2) gene silencing in retinoblastoma (RB) cells. Synthetic anti-HMGA2 short interfering RNA (siRNA) was used to silence the HMGA2 gene in cultured Y79 RB cells that were subjected to whole genome microarray analysis. The expression of differentially regulated key genes was confirmed with quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) in post-silenced RB cell lines (Y79 and WERI Rb1). These deregulated genes were compared for their constitutive expression in primary RB tumors (n=10). Zymographic determination of matrix metalloproteinase (MMP) activity was performed in RB cells. A cell cycle assay and a proliferation assay were performed in post-transfected RB cells. HMGA2 gene silencing in cultured RB cells results in reduced cell proliferation and transition in the G1/S phase. The whole genome microarray analysis of HMGA2 silenced Y79 cells revealed overall upregulation of 1,132 genes (≥1.0 fold) and downregulation of 1,562 genes (≤ -1.0 fold). Specific quantitative pathway analysis of the deregulated genes (using Biointerpreter) revealed 150 upregulated genes and 77 downregulated genes (≥1.0 fold) involved in vital pathways, namely, mitogen-activated protein kinase, Janus kinase/signal transducers and activators of transcription, Ras pathway, Ras-induced extracellular signal-regulated protein kinases 1 and 2, and tumor protein p53. The differential expression of genes obtained from microarray analysis (Homo sapiens ELK1, member of ETS oncogene family [ELK1], Homo sapiens cyclin-dependent kinase 6 [CDK6], Homo sapiens E2F transcription factor 4, p107/p130-binding [E2F4], Homo sapiens G-2 and S-phase expressed 1 [GTSE1], Damage-regulated autophagy modulator [DRAM], Homo sapiens cadherin 1, type 1,E-cadherin (epithelial) [CDH1], Homo sapiens snail homolog 1 (Drosophila) [SNAI1], Homo sapiens matrix metallopeptidase 2 [MMP2], and Homo sapiens matrix metallopeptidase 9 [MMP9]) was confirmed with quantitative reverse-transcriptase polymerase chain reaction in post-silenced RB cells. Zymographic analysis revealed that the increase in MMP mRNA expression in the post-silenced RB cells did not correlate with corresponding enzyme activity. Our study revealed molecular regulatory changes induced by HMGA2 silencing in RB cancer cells, offering mechanistic insights into the anticancer potential. HMGA2 may be considered a promising candidate for gene silencing therapy in RB.
    Molecular vision 10/2012; 18:2420-37. · 1.99 Impact Factor
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