Role of Glycated High Mobility Group Box-1 in Gastric Cancer

Abstract

Advanced glycation end products (AGEs) are produced in response to a high-glucose environment and oxidative stress and exacerbate various diseases. Nε-(Carboxymethyl)lysine (CML) is an AGE that is produced by the glycation of lysine residues of proteins. There are a few reports on alterations in protein function due to CML modification; however, its association with cancer is not clear. We investigated the significance of CML modification in high mobility group box protein-1 (HMGB1), a cytokine that is significantly associated with cancer progression. Treatment of the gastric cancer cell lines TMK1 and MKN74 with glyoxal or glucose resulted in increased CML modification compared to untreated cells. CML-HMGB1 was modified via oxidation and more pronouncedly activated the receptor for AGE and downstream AKT and NF-κB compared to naïve HMGB1 and oxidized HMGB1. CML-HMGB1 bound with reduced affinity to DNA and histone H3, resulting in enhanced extranuclear translocation and extracellular secretion. Treatment of gastric cancer cells with CML-HMGB1 enhanced cell proliferation and invasion, sphere formation, and protection from thapsigargin-induced apoptosis, and decreased 5-FU sensitivity in comparison to HMGB1. Further, CML-HMGB1 was detected at various levels in all the 10 gastric cancer tumor specimens. HMGB1 levels correlated with primary tumor progression and distant metastasis, whereas CML-HMGB1 levels were associated with primary tumor progression, lymph node metastasis, distant metastasis, and stage. In addition, CML-HMGB1 levels correlated with oxidative stress in cancer tissues and resistance to neoadjuvant therapy. Therefore, CML modification of HMGB1 enhanced the cancer-promoting effect of HMGB1. In this study, CML-HMGB1 has been highlighted as a new therapeutic target, and analysis of the molecular structure of CML-HMGB1 is desired in the future.

Oxidized high mobility group B‐1 enhances metastability of colorectal cancer via modification of mesenchymal stem/stromal cells

“… 35 In our previous study, phosphorylation of RAGE and AKT and nuclear translocation of NF‐κB p65 are at low levels by reduced HMGB1 and high levels by oxidized HMGB1. 30 Therefore, oxidized HMGB1 was considered to be a highly functional ligand for RAGE in cancer. In contrast, in MSCs, RAGE is induced and activated by HMGB1 to promote the expression of CXCR4, 57 TGFβ, and proinflammatory cytokines.…”

“…The cells were cultured in DMEM (Wako Pure Chemical, Osaka, Japan) supplemented with 10% FBS (Sigma Chemical, St. Louis, MO, USA) at 37°C in a 5% CO 2 atmosphere. For oxidization of HMGB1, recombinant human HMGB1 (50 μg; R&D Systems, Minneapolis, MN, USA) was incubated with 100 μl of 50 μM H 2 O 2 (Wako) on ice for 1 h. 30 To prevent HMGB1 from being naturally oxidized, oxidized HMGB1 was newly prepared for each experiment and used while it was fresh. For assessment of drug resistance, cells (1 × 10 6 ) were treated with 5‐fluorouracil (5‐FU; Sigma) as shown in Figure 4.…”

“…To assess murine mRNA expression, RT‐PCR was performed and PCR products images were measured using NIH ImageJ software (version 1.52; Bethesda, MD, USA). 30 The primer sets are listed in Table 1 .…”

The RAGE/multiligand axis: a new actor in tumor biology

“…A convincing body of evidence shows both increased expression of HMGB1 in several solid tumors and its critical role as an emerging prognostic factor in prostate cancer, breast cancer, and gastric cancer [122][123][124][125]. Biological responses downstream of HMGB1 are implicated in promoting tumor proliferation, migration, and invasion by stimulating production of pro-inflammatory cytokines through RAGE-dependent pathways [37]; however, HMGB1 can signal through TLRs (TLR2 and TLR4), as well as RAGE, thereby triggering NF-kB, STAT-3, and MyD88-dependent pathways and promoting inflammation and tumorigenesis [126][127][128].…”

The effect of HMGB1 and RAGE on the clinicopathological and prognostic features of prostate cancer

“…All these preclinical and clinical studies greatly exhibited that HMGB1 may play a crucial role in the progression of PCa. In addition, research in other laboratories has also shown that members of HMGB1 are consistently increased in different types of human malignancies, including renal cell carcinoma [33] , bladder cancer [40] , hepatocellular carcinoma [19] , gastric cancer [41] , colorectal cancer [42] , breast cancer [43] , and lung cancer [44] . Thus, it would be interesting to survey tumor samples to further examine the incidence of the abnormal expression of HMGB1 and RAGE in other types of tumors.…”