Role of Extracellular High-Mobility Group Box-1 as a Therapeutic Target of Gastric Cancer

Abstract

Background: High-mobility group box-1 (HMGB1) is involved in the tumorigenesis and metastasis of various cancers. The present study investigated the roles of extracellular HMGB1 in the progression of gastric cancer (GC) and the therapeutic effects of recombinant human soluble thrombomodulin (rTM) targeting HMGB1. Methods: The effects of extracellular HMGB1 and rTM on GC cells were assessed using proliferation and Transwell assays. Their effects on local tumor growth and metastasis were evaluated using subcutaneous tumor and liver metastasis mouse models, respectively. Plasma HMGB1 concentrations in GC patients were measured using ELISA. The relationships between plasma HMGB1 concentrations and the prognosis and clinicopathological factors of patients were also investigated. Results: GC proliferation, migration, and invasion abilities were promoted by increases in extracellular HMGB1 concentrations and alleviated by rTM. In the subcutaneous tumor model, local tumor growth was promoted by the addition of rhHMGB1 and alleviated by rTM. Similar changes occurred in the liver metastasis model. Recurrence-free survival (p < 0.01) and overall survival (p = 0.01) were significantly worse in patients with high plasma HMGB1 concentrations. Conclusion: Plasma HMGB1 concentrations are a prognostic marker in GC patients. Extracellular HMGB1 promotes cancer progression and has potential as a novel treatment target in GC cells for rTM.

Function of hsa_circ_0006646 as a competing endogenous RNA to promote progression in gastric cancer by regulating the miR-665–HMGB1 axis

“…By overlapping the results of analysis, we found 6 genes exhibiting possibly regulated by miR - 665 : HMGB1 , limb and CNS expressed 1 like ( LIX1L ), calcium regulated heat stable protein 1 ( CARHSP1 ), proteasome inhibitor subunit 1 ( PSMF1 ), solute carrier family 37 member 3 ( SLC37A3 ), and synaptotagmin 2 ( SYT2 ) ( Figure 4A ). Among these genes, only HMGB1 was reported to be involved in the progression of GC ( 24 , 25 ). Thus, we chose HMGB1 as the target gene of miR - 665 in subsequent study.…”

Obesity paradox as a new insight from postoperative complications in gastric cancer

“…HMGB-1 has been identified as a proinflammatory mediator and is expressed twofold more in adipose tissue from obese compared to normal-weight individuals 32 . It was reported to interact with the NF-κB pathway to initiate the transcription of various proinflammatory cytokines including TNF-α, IL-6, and IL-1b to promote inflammation 33 , 34 . In clinical settings, Osoegawa et al demonstrated that higher surgical invasion increased the concentration of postoperative plasma HMGB-1 35 .…”

Gastric alarmin release: A warning signal in the development of gastric mucosal diseases

“…In the stomach under physiological conditions, HMGB1 is mainly localized in the nucleus and cytoplasm of gastric epithelial cells ( 39 ) and is involved in transcriptional regulation as a chromatin-binding factor associated with specific DNA-binding proteins ( 158 , 159 ). HMGB1 is significantly upregulated in gastric mucosal diseases, and upon upregulation, HMGB1 acts as a potent chemokine, triggering the infiltration of inflammatory immune cells and increasing the progression of gastric mucosal diseases ( 40 , 160 ).…”