Overexpression of High-Mobility Group Box 2 Is Associated with Tumor Aggressiveness and Prognosis of Hepatocellular Carcinoma
ABSTRACT We investigated the expression of high-mobility group box 2 (HMGB2) in patients with hepatocellular carcinoma (HCC) and its clinical effects with underlying mechanisms.
HMGB2 mRNA levels were measured in 334 HCC patients by real-time reverse transcription-PCR and HMGB2 protein levels in 173 HCC patients by immunohistochemical studies. The HMGB2 expression level was measured by Western blotting for three HCC cell lines. To clarify the precise role of HMGB2 on cell proliferation, we did in vitro analysis with expression vectors and small interfering RNAs.
HMGB2 mRNA and protein expression were significantly higher in HCC than in noncancerous surrounding tissues (P < 0.0001) and showed a positive correlation (ρ = 0.35, P < 0.001). HMGB2 overexpression was significantly correlated with shorter overall survival time, both at mRNA (P = 0.0054) and protein level (P = 0.023). Moreover, HMGB2 mRNA level was an independent prognostic factor for overall survival in a multivariate analysis (P = 0.0037). HMGB2 knockdown by small interfering RNAs decreased cell proliferation, and overexpression of HMGB2 by expression vectors diminished cisplatin- and etoposide-induced cell death.
Our clinical and in vitro data suggest that HMGB2 plays a significant role in tumor development and prognosis of HCC. These results can partly be explained by altered cell proliferations by HMGB2 associated with the antiapoptotic pathway.
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ABSTRACT: The aim of this study was to investigate the roles of renal tumor antigen (RAGE) in the progression and clinical outcome of hepatocellular carcinoma (HCC). RAGE mRNA levels in 350 cases of HCC were investigated by quantitative real-time reverse transcription polymerase chain reaction. We analyzed the relationship of RAGE mRNA level with clinicopathologic parameters and clinical outcome. To identify the possible role of RAGE on cellular invasion, we performed in vitro analyses using small interfering RNAs (siRNAs). RAGE mRNA level was significantly higher in HCC than in noncancerous hepatic tissues (P < 0.001). Overexpression of RAGE was significantly correlated with the presence of multiple tumors (P = 0.021), high alfa-fetoprotein level (P = 0.042), and advanced tumor stage (P = 0.016). Higher levels of RAGE expression were associated with significantly shorter overall survival time (P = 0.029). Knockdown of RAGE expression by siRNAs suppressed the invasive ability of HCC cells and the expression and secretion of matrix metalloproteinase-9 (MMP-9). We found that RAGE and MMP-9 expressions were correlated in HCCs, and furthermore, the combination of RAGE and MMP-9 expression was associated with the survival of patients (P = 0.0066). Our results suggest that RAGE may be important in tumor invasion and could be a potential predictor for the prognosis of HCC patients.Annals of Surgical Oncology 06/2011; 19 Suppl 3:S404-11. DOI:10.1245/s10434-011-1856-3 · 3.94 Impact Factor
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ABSTRACT: DOC-2/DAB2 interactive protein gene (DAB2IP) is a novel member of the Ras GTPase-activating protein family and plays a tumor suppressive role in cancer progression, but its function in hepatocellular carcinoma (HCC) remains unclear. This aims of this study were to analyze the clinicopathological features of DAB2IP expression in HCC, and to determine the effect of DAB2IP on HCC cell behaviors in vitro. The expression of DAB2IP was detected in hepatocyte cell line and HCC cell lines by real-time reverse transcription-polymerase chain reaction and western blot. DAB2IP expression was then examined in 120 cases of clinical paraffin-embedded HCC tissue by immunohistochemistry (IHC). 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) method and in vitro invasive assay were finally performed to evaluate the effect of DAB2IP depletion on cell proliferation or invasion of HCC cells. DAB2IP expression was lower in HCC cell lines or tissues than in hepatocyte cell lines, adjacent cirrhotic livers or normal livers (P < 0.05). Its expression was positively correlated with tumor size (P = 0.01). Patients with lower DAB2IP expression had shorter overall survival time (P = 0.013). DAB2IP suppresses proliferation and invasion of HCC cells in vitro. DAB2IP is a valuable marker for progression of HCC patients. Downregulation of DAB2IP is associated with poor prognosis in HCC patients. DAB2IP silence alone is sufficient to promote HCC cell proliferation and invasion in vitro.Journal of Gastroenterology and Hepatology 12/2011; 27(6):1117-25. DOI:10.1111/j.1440-1746.2011.07049.x · 3.63 Impact Factor
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ABSTRACT: A fundamental question in biology is how genome-wide changes in gene expression are enacted in response to a finite stimulus. Recent studies have mapped changes in nucleosome localization, determined the binding preferences for individual transcription factors, and shown that the genome adopts a nonrandom structure in vivo. What remains unclear is how global changes in the proteins bound to DNA alter chromatin structure and gene expression. We have addressed this question in the mouse heart, a system in which global gene expression and massive phenotypic changes occur without cardiac cell division, making the mechanisms of chromatin remodeling centrally important. To determine factors controlling genomic plasticity, we used mass spectrometry to measure chromatin-associated proteins. We have characterized the abundance of 305 chromatin-associated proteins in normal cells and measured changes in 108 proteins that accompany the progression of heart disease. These studies were conducted on a high mass accuracy instrument and confirmed in multiple biological replicates, facilitating statistical analysis and allowing us to interrogate the data bioinformatically for modules of proteins involved in similar processes. Our studies reveal general principles for global shifts in chromatin accessibility: altered linker to core histone ratio; differing abundance of chromatin structural proteins; and reprogrammed histone post-translational modifications. Using small interfering RNA-mediated loss-of-function in isolated cells, we demonstrate that the non-histone chromatin structural protein HMGB2 (but not HMGB1) suppresses pathologic cell growth in vivo and controls a gene expression program responsible for hypertrophic cell growth. Our findings reveal the basis for alterations in chromatin structure necessary for genome-wide changes in gene expression. These studies have fundamental implications for understanding how global chromatin remodeling occurs with specificity and accuracy, demonstrating that isoform-specific alterations in chromatin structural proteins can impart these features.Molecular & Cellular Proteomics 01/2012; 11(6):M111.014258. DOI:10.1074/mcp.M111.014258 · 7.25 Impact Factor