Overexpression of High-Mobility Group Box 2 Is Associated with Tumor Aggressiveness and Prognosis of Hepatocellular Carcinoma

Abstract

Purpose: We investigated the expression of high-mobility group box 2 (HMGB2) in patients with hepatocellular carcinoma (HCC) and its clinical effects with underlying mechanisms.Experimental Design: 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.Results: 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 cisplatinand etoposide-induced cell death.Conclusions: 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. Clin Cancer Res; 16(22); 5511-21. ©2010 AACR.

Dynamic localization and the associated translocation mechanism of HMGBs in response to GCRV challenge in CIK cells

“…7,10 Reports have also highlighted the interactions of HMGB1 with TLR9, retinoic acid-inducible gene I and TIM-3 10,37,38 and the vital role of HMGBs in autophagy regulation, 39 mitochondrial function and morphology [40][41][42] and cell proliferation. [43][44][45] Comparatively, an understanding of HMGBs in the nucleus is limited. In addition to their classical functions in transcriptional regulation or their DNA-binding properties, nuclear HMGBs may assist in the replication of some viruses.…”

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

“…In ALL, the upregulation of pseudogenes RP11-423H2.1, FAM86C2P, and HMGB1P41 was associated with the upregulation of their parent genes THOC3, FAM86A, and HMGB2. Previous studies have shown that HMGB2 is overexpressed in a variety of cancers and that there is a decline in the proliferation of cancer cells when siRNA is used to knockdown expression of HMGB2, 29,30 suggesting a putative role in the pathogenesis of ALL. Likewise, some pseudogenes were downregulated and their parent genes were also downregulated.…”

High-mobility group box 2 (HMGB2) modulates radioresponse and is downregulated by p53 in colorectal cancer cell

“…15 In hepatocellular carcinoma, HMGB2 overexpression has been significantly correlated with shorter overall survival time. 16 Despite extensive characterization of the diverse roles of HMGB1, relatively less is known of the specific biological function of HMGB2.…”