Significance of the association between heparin‐binding epidermal growth factor‐like growth factor and CD9 in human gastric cancer

Abstract

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a member of the EGF family. Juxtacrine activity of proHB-EGF (the membrane-anchored form of HB-EGF) has been shown to be significantly potentiated when it is coexpressed with CD9 in vitro. The purpose of our study was to investigate the issue of whether proHB-EGF and CD9 are coexpressed in gastric cancer. HB-EGF gene expression and protein production in human gastric cancers was investigated, and EGF receptor and CD9 expressions were also evaluated. HB-EGF mRNA levels in gastric cancers were elevated, compared with normal gastric tissues, especially in the intestinal type. ProHB-EGF immunoreactivity was detected primarily in the cytoplasm and plasma membrane of gastric cancer cells. Of 66 patients, 40 (60.6%) exhibited proHB-EGF immunoreactivity and the level of its expression was significantly associated with tumor status (p < 0.01) and histological differentiation (p < 0.001). In addition, proHB-EGF mRNA was detected at high levels in the intestinal type by in situ hybridization. CD9 immunoreactivity was found to be preserved in 26 of 36 patients (72.2%) and CD9 protein expression was inversely associated with lymph node status (p < 0.05). A significant correlation between its expression and histological differentiation (p < 0.01) was found, and the association of CD9 with proHB-EGF was increased in the intestinal type, as evidenced by an immunoprecipitation method. These results indicate that the coexpression of proHB-EGF and CD9 may be involved in the tumorigenesis and/or proliferation of gastric cancers in a juxtacrine manner.

Validation of Genomics-Based Prognostic Tests in Malignant Pleural Mesothelioma

“…TM4SF1) previously reported by our laboratory (11) and the plasmolipin gene previously reported by Pass et al (12). In other studies, low expression of CD9 is thought to contribute to a more aggressive (metastatic) phenotype in small cell lung cancer (19), gastric cancer (20), and breast cancer (21). These observations are generally consistent with our finding of CD9 expressed at significantly higher levels in tumors from patients with relatively good prognosis.…”

Crucial involvement of the CCL3‐CCR5 axis‐mediated fibroblast accumulation in colitis‐associated carcinogenesis in mice

“…EGFR is expressed ubiquitously by various types of epithelial cells although the cellular distribution of ErbB4 still remains to be investigated. Immunohistochemical analyses detected HB-EGF protein in various types of cancer cells including pancreatic, 36 hepatocellular, 37 colonic, 38 gastric 39 and ovarian cancer cells. 40 However, in uterine cervical cancer tissues, HG-EGF was expressed primarily in stromal fibroblasts, rather than cancer cells, 21 consistent with our observation that HB-EGF was predominantly expressed in type I collagen-positive cells.…”

A Novel Anti-Human HB-EGF Monoclonal Antibody with Multiple Antitumor Mechanisms against Ovarian Cancer Cells

“…Thus, ectodomain shedding is critical for HB-EGF functions. The elevated expression of HB-EGF has been reported in several kinds of cancers, such as ovarian (6,7), gastric (8,9), and breast cancer (10)(11)(12). Especially, increasing evidence has suggested a critical role for HB-EGF in ovarian cancer progression.…”