The expression of HMGB1 protein and its receptor RAGE in human malignant tumors

Abstract

High Mobility Group Box 1 (HMGB1) is a nuclear non-histone protein discovered to be released in the extracellular medium as a response to various stimuli and implicated in cancerogenesis. High HMGB1 levels are reported in a variety of tumor types, but there are few data relating HMGB1 to the histological grade or to a particular cell type and cellular localization. We studied the expression of HMGB1 protein in malignant human tumors of different differentiation level and in tumor metastasis. In all tumor tissues, the protein level is elevated. In moderately differentiated carcinomas, the localization of the protein is perinuclear, while in the low differentiated; there is a tendency for non-specific nuclear localization. HMGB1 protein and its receptor RAGE are identified as a ligand-receptor pair that plays an important role in regulating the invasiveness of tumor cells. RAGE is not produced in all of the tested tumor specimens. We found high level of expression in hepatocellular, colorectal, and breast cribriform carcinomas, but not in malignant testicular specimens. Probably, the RAGE synthesis is related to distinctive tumor types. In metastatic cells, RAGE exhibits higher level of expression losing its specific granular cytosolic pattern characteristic for the primary tumors.

Tax is Involved in Up-regulation of HMGB1 Expression Levels by Interaction with C/EBP

“…Generally, HMGB1 is expressed at a basal level as an architectural chromatin-binding protein, but at a slightly elevated level via passive release from damaged or necrotic cells (Beyer et al, 2012;Yi et al, 2013) or active secretion (Akirav et al, 2012;Kang et al, 2013;Mohammad et al, 2013). Moreover, overexpression of HMGB1 protein is observed in breast, colon, and gastrointestinal cancers, as well as in leukemia and other diseases (Kostova et al, 2010;Ohmori et al, 2011;Jube et al, 2012;Lee et al, 2012;Liu et al, 2012;Xing et al, 2012;Yu et al, 2012;Stoetzer et al, 2013). ATL is an acute T-cell malignancy modulated by an oncogenic retrovirus, and the virally encoded Tax protein is believed to be critically involved in the development of ALT.…”

“…Aside from these pro-inflammatory functions, HMGB1 protein also promotes regeneration processes and accelerates cell cycle progression. This paradoxical function of HMGB1 protein has been revealed in the growth and spread of many types of tumors such as hepatocellular carcinoma, colon cancer, breast cancer, and leukemia (Kostova et al, 2010;Ohmori et al, 2011;Jube et al, 2012;Lee et al, 2012;Liu et al, 2012;Xing et al, 2012;Yu et al, 2012;Stoetzer et al, 2013). Thus, HMGB1 has become the focus of recent cancer research and is currently a relevant target for cancer treatment (Ohmori et al, 2011;Yu et al, 2012).…”

AGER genetic polymorphisms increase risks of breast and lung cancers

“…It has therefore been proposed that AGER expression might manifest in the pathogenesis of cancer proliferation and metastasis and might even be helpful for the clinical application of diagnosing multiple types of cancers (Riehl et al, 2009). It has further been demonstrated that sAGER can forcefully inhibit the production of tissue metalloproteinases, resolutely decreasing the speed of tumor cell aggression and migration into other tissues (Jing et al, 2010a;Kostova et al, 2010). Therefore, a potential function of AGER variation (rs1800625 T>C, rs1800624 T>A, rs184003 G>T, and rs2070600 G>A) might be to influence the bioavailability of AGER; this might in turn imply that AGER might represent a potential breast cancer-susceptibility gene (Pan et al, 2014).…”

High-Mobility Group Boxes Mediate Cell Proliferation and Radiosensitivity via Retinoblastoma-Interaction-Dependent and -Independent Mechanisms

“…[2][3][4][5] Moreover, there is increasing evidence that HMGB1 and HMGB2 are novel prognostic markers and potential therapeutic targets for different types of cancers, including breast carcinoma, hepatocellular carcinoma, and squamous-cell carcinoma. [6][7][8][9][10] Consistently, enforced expression of HMGB1 alters the sensitivity of cancer cells to DNA-damaging agents. [11][12][13][14] Our previous studies have revealed a novel role for the HMGB1 protein in the interaction with the retinoblastoma (RB) protein, an important regulator of the cell cycle and cell proliferation.…”