Expression of receptors for advanced glycation end‐products (RAGE) is closely associated with the invasive and metastatic activity of gastric cancer

Abstract

The receptor for advanced glycation end-products (RAGE) is a newly recognized factor regulating cancer cell invasion and metastasis. This study investigated the expression of RAGE in gastric carcinomas and its association with invasion and metastasis. Of eight gastric cancer cell lines examined, seven constitutively expressed RAGE messenger ribonucleic acid (mRNA), MKN45 being the exception. RAGE protein expression of MKN28 cells treated with RAGE antisense S-oligodeoxynucleotide was nine times less than that of sense S-oligodeoxynucleotide-treated cells. Growth of cells under RAGE antisense S-oligodeoxynucleotide treatment was not different from that seen under sense S-oligodeoxynucleotide treatment in MKN28 (a cell line producing high levels of RAGE) and MKN45 (a non-RAGE-expressing cell line). RAGE antisense S-oligodeoxynucleotide treatment suppressed the invasive activity of RAGE-positive MKN28 cells, as estimated by in vitro invasion assay. The number of MKN28 cells invading the type IV collagen-coated membrane under RAGE antisense S-oligodeoxynucleotide treatment was significantly lower than under RAGE sense S-oligodeoxynucleotide treatment (p<0.0001). In contrast, antisense and sense S-oligodeoxynucleotide-treated RAGE-negative MKN45 cells showed no difference. A wound-healing assay showed that no RAGE antisense S-oligodeoxynucleotide-treated MKN28 cells migrated into the scraped area, whereas sense S-oligodeoxynucleotide-treated cells showed many budding nests in the scraped area. Immunohistochemistry of gastric carcinoma tissue showed that 62 (65%) of the 96 cases examined were RAGE-positive and that poorly differentiated adenocarcinomas preferentially expressed RAGE protein (38/42, 90%) (p<0.0001). Strong RAGE immunoreactivity was also correlated with depth of invasion and lymph node metastasis (p<0.0001). RAGE-positive cancer cells tended to be distributed at the invasive front of primary tumours and were detected in all metastatic foci in lymph nodes. In contrast, a major RAGE ligand, amphoterin, was expressed in 82 (85%) of the 96 cases, regardless of histological type and disease progression. RAGE expression appears to be closely associated with invasion and metastasis in gastric cancer.

Expression of HMGB1 and its Clinical Significance in T-cell Lymphoma

“…Our results showed that the expression of Survivin was upregulated in T-cell lymphoma compared to that in reactive lymphoid hyperplasia. Consistent with previous reports (Kuniyasu et al, 2002;Cheng et al, 2008;Chung et al, 2009), the expression of HMGB1 and Survivin was correlated with the aggressiveness and stage of tumors. Therefore, HMGB1 and Survivin may be involved in the development and progression of T-cell lymphoma and could be new targets for targeted molecular therapy.…”

Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation

“…RAGE transduces inflammatory responses and plays a role in the pathogenesis of several diseases including neurodegeneration, inflammation and cancer [32][33]. RAGE is able to bind a variety of structurally diverse ligands and the locations of RAGE upregulation tend to colocalize with molecules thought to bind to the receptor.…”

Lesiones gástricas en pacientes infectados con Helicobacter pylori: expresión de RAGE (receptor de productos de glicosilización avanzada) y otros inmunomarcadores

“…18 . A nivel gástrico, la sobreexpresión de RAGE no sólo ha sido observada en cáncer (asociada a un mayor nivel de invasión y generación de metástasis) 19 , también ha sido observada en procesos inflamatorios y particularmente participando de la adherencia de H. pylori al epitelio glandular de la mucosa gástrica 36 .…”

“…En neoplasias, la expresión de RAGE se ha descrito en cerebro, mama, colorrecto, pulmón, próstata, oral y ovario, también en linfomas y melanomas 18 . En cáncer gástrico, la sobreexpresión de RAGE ha sido asociada a mayor invasión y metástasis 19 . Además algunos polimorfismos del receptor otorgarían mayor susceptibilidad al desarrollo y mayor agresividad de dicha neoplasia 20 .…”