Increased expression of high mobility group box 1 (HMGB1) is associated with an elevated level of the antiapoptotic c-IAP2 protein in human colon carcinomas

Abstract

Background: High mobility group box 1 (HMGB1) is a non-histone chromosomal protein implicated in a variety of biologically important processes, including transcription, DNA repair, V(D)J recombination, differentiation, and development. Overexpression of HMGB1 inhibits apoptosis, arguing that the molecule may act as an antiapoptotic oncoprotein. Indeed, increased expression of HMGB1 has been reported for several different tumour types. In this study, we analysed human colon carcinoma for HMGB1 as well as for c-IAP2 expression levels. c-IAP2 is an antiapoptotic protein which may be upregulated as a consequence of nuclear factor kB (NFkB) activation via HMGB1. Methods: A comparative genomic hybridisation (CGH) database comprising 1645 cases from different human tumour types was screened to detect cytogenetic changes at the HMGB1 locus. Immunohistochemical staining of human colon tissue microarrays and tumour biopsies, as well as western blot analysis of tumour lysates, were performed to detect elevated HMGB1 and c-IAP2 expression in colon carcinomas. The antiapoptotic potential of HMGB1 was analysed by measuring caspase activities, and luciferase reporter assays and quantitative polymerase chain reaction analysis were employed to confirm NFkB activation and c-IAP2 mRNA upregulation on HMGB1 overexpression. Results: According to CGH analysis, the genomic locus containing the HMGB1 gene was overrepresented in one third (35/96) of colon cancers. Correspondingly, HMGB1 protein levels were significantly elevated in 90% of the 60 colon carcinomas tested compared with corresponding normal tissues evaluable from the same patients. HMGB1 increased NFkB activity and led to co-overexpression of the antiapoptotic NFkB target gene product c-IAP2 in vitro. Furthermore, increased HMGB1 levels correlated with enhanced amounts of c-IAP2 in colon tumours analysed by us. Finally, we demonstrated that HMGB1 overexpression suppressed caspase-9 and caspase-3 activity, suggesting that HMGB1 interferes with the apoptotic machinery at the level of apoptosomal caspase-9 activation. Conclusions: We identified in vitro a molecular pathway triggered by HMGB1 to inhibit apoptosis via c-IAP2 induction. Our data indicate a strong correlation between upregulation of the apoptosis repressing HMGB1 and c-IAP2 proteins in the pathogenesis of colon carcinoma.

Fibroblasts mediate induction of high mobility group box protein 1 in lung epithelial cancer cells by diffusible factors

“…Although the expression of HMGB1 is under strict developmental control (4,5) and essential for animal survival (6), HMGB1 is apparent in several mature cells (7)(8)(9) as well as in transformed cells (10,11). In cancer cells, HMGB1 supports cell transformation, growth and cellular resistance (11)(12)(13). For this reason, HMGB1 seems to be a crucial factor in cancer development.…”

Genistein Increase Intracellular Distribution of the High Motility Group Box-1 through p38 Pathway in HeLa culture cells induced by Tumor Necrosis Factor-α

“…Outside the cell, it bounded firmly to the RAGE receptor which is a potent mediator for inflammation [10]. HMGB1 overexpression inhibits apoptosis, which supports the argument that these molecules may act as antiapoptotic oncoprotein, and HMGB1 expression found increase in several different tumor types [11]. Thus, allegedly HMGB1 translocation from nucleus into the cytoplasm of the cancer cells can affect defense toward apoptosis.…”

Serum high mobility group box protein 1 as a clinical marker for ovarian cancer

“…Recent researches have shown that HMGB1 overexpression can improve proliferation [21] and decrease drug sensitivity of cancer cell [22]. In addition, HMGB1 functions as an antiapoptotic oncoprotein by activating NF-κB and the apoptosis inhibitor c-IAP [23]. Moreover, a variety of agents such as cancer chemotherapeutic agents, oncolytic viruses, ultraviolet or gamma irradiation, cytolytic T and nature killer cells that leading to tumor cell death can indicate classic apoptosis markers that were associated with HMGB1 release [24].…”