Expression of Receptor for Advanced Glycation End Products (RAGE) is Related to Prognosis in Patients with Esophageal Squamous Cell Carcinoma

Abstract

The receptor for advanced glycation end products (RAGE), known as a multiligand receptor for certain stress-associated factors, has been considered to affect the characteristic differences of various cancer cells. We analyzed the expression and clinicopathological significance of RAGE in esophageal squamous cell carcinoma. We investigated immunohistochemically the relationship between RAGE expression and clinicopathological factors, including prognosis, in surgical specimens of primary tumors in 216 patients with esophageal squamous cell carcinoma. Prognostic factors were examined by univariate and multivariate analyses (Cox proportional hazard regression model). The positive expression rate of RAGE was 50%. RAGE expression was negatively correlated with depth of invasion and venous invasion. Moreover, tumors with positive RAGE expression exhibited better prognosis than those with negative RAGE expression (5-year survival, 52% vs. 32%, respectively). Multivariate analysis indicated that the positive expression of RAGE was an independent prognostic factor, along with tumor depth and nodal metastasis. Our findings suggest that loss of RAGE expression may play an important role in the progression of esophageal squamous cell carcinoma. Evaluation of the expression of RAGE could be useful for determining the tumor properties, including those associated with prognosis, in patients with esophageal squamous cell carcinoma.The receptor for advanced glycation end products (RAGE) is a multiligand receptor classified as an immunoglobulin superfamily cell surface molecule; it acts as a counterreceptor for high-mobility group box 1 (HMGB1) proteins, RAGEs, S100/calgranulins, and amyloid-b peptides.1-3 These interactions trigger the activation of key cell signaling pathways (e.g., p38 and p44/42 MAP kinase, NFjB, cdc42/rac, and the generation of reactive oxygen species) and result in the production of proinflammatory cytokines.4-7 RAGE-mediated proinflammatory processes are now considered to contribute to the progression of many chronic diseases, such as neuropathy, nephropathy, macrovascular disease, amyloidoses, inflammatory conditions (e.g., rheumatoid arthritis and inflammatory bowel disease), and sepsis. [7][8][9] In addition to RAGE-mediated proinflammatory events, recent studies have revealed that the interaction of RAGE and its ligands and the resultant signaling play a causative role in the characteristic modulation of cancer cell functions, i.e., increasing tumor invasion and metastasis. 10 Furthermore, several clinical studies have demonstrated a strong association of RAGE expression with the malignant potential of various cancers such as gastric cancer, colon cancer, biliary cancer, pancreatic cancer, and prostate cancer, although several reports showed a reverse correlation between RAGE expression and tumor progression.

Prognostic significance of receptor for advanced glycation end products expression in hepatocellular carcinoma after hepatectomy

“…With regard to colorectal cancer, Kuniyasu et al [17] reported that RAGE was strongly expressed at the invasive front, and co-expression of RAGE and HMGB-1 was closely associated with invasion and metastasis. In contrast, RAGE expression is negatively associated with tumor progression in esophageal squamous cell carcinoma and nonesmall cell lung carcinoma [22,23]. These data suggest the organ-specific interaction of RAGE in tumor progression.…”

Knockdown of RAGE inhibits growth and invasion of gastric cancer cells

“…10 RAGE expression is negatively correlated with depth of invasion in esophageal squamous cell carcinoma, and tumors with positive RAGE expression exhibit better prognosis than those with negative RAGE expression. 11 Therefore, in order to expound the role of RAGE in gastric cancer, we investigated the expression of RAGE in human gastric cancer, and the effects of RAGE knockdown on biological behaviors of gastric cancer cells.…”

Different roles of S100P Overexpression in Intrahepatic Cholangiocarcinoma

“…5,20,27 RAGE is widely expressed in normal tissues, 12 and has been considered to affect the characteristic differences in various cancer cells. 21,25,27,35 Recent studies have shown that S100P-RAGE signaling plays a major role in tumor development. 5,6,17 Intrahepatic cholangiocarcinoma (ICC) shows the second most common primary liver cancer.…”