Expression of Cbl linking with the epidermal growth factor receptor system is associated with tumor progression and poor prognosis of human gastric carcinoma

Abstract

Cbl proteins play important roles in downregulation of growth factor receptors by acting as ubiquitin ligases and multi-adapter proteins. Ligand-induced desensitization of the epidermal growth factor receptor (EGFR) has been shown to be controlled by Cbl. In the present study, we examined the expression of Cbl in gastric carcinomas and studied the correlation of Cbl expression with clinicopathological characteristics as well as EGFR expression. Cbl protein was expressed in 67% (82/122) of gastric carcinomas, and diffuse expression of Cbl was detected in 29% (35/122) of the cases. The incidence of cases with diffuse expression of Cbl was significantly higher in advanced cases (28/70, 40%) than in early cases (7/52, 14%) (P=0.0010). Diffuse expression of Cbl was significantly associated with metastasis of tumor cells in lymph nodes (P=0.0318). Diffuse expression of EGFR was significantly associated with depth of invasion (P=0.0057), lymph-node metastasis (P=0.0371) and tumor stages (P=0.0278). As the grades of Cbl expression became stronger, the cases with diffuse EGFR expression increased, the positive correlation being significant (P=0.049). All the cases with diffuse expression of Cbl and EGFR were found to show nodal metastasis and to be at an advanced stage. Moreover, the prognosis of the patients with synchronous diffuse expression of Cbl and EGFR was significantly poorer than that of the patients negative for Cbl and focal or negative for EGFR (P=0.0086). The expression of Cbl protein was clearly induced in gastric carcinoma cell lines by transforming growth factor-alpha treatment. These results suggest that Cbl in connection with the EGFR system may be associated with stomach carcinogenesis, invasion and metastasis. Cbl may serve as a novel molecular marker for aggressive gastric carcinoma.

Dominant Negative Epidermal Growth Factor Receptor Inhibits Growth of Human Gastric Cancer Cells by Inducing Cell Cycle Arrest and Apoptosis

“…Additionally, there was a significant correlation of EGFR positive rate and tumor-node-metastasis (TNM) stage: The positive rate in TNM stage III and IV was higher than that in TNM stage I and II (P < 0.05). Our results were consistent with the previous reports, 17,18 suggesting its involvement in tumor progression of gastric cancer.…”

Prognostic implications of EGFR and HER-2 alteration assessed by immunohistochemistry and silver in situ hybridization in gastric cancer patients following curative resection

“…The percentage of EGFR positivity in gastric cancer patients has been reported with great variability [7,[18][19][20][21][22], and HER-2 positivity also varies extensively [7][8][9]. One possible explanation for this low rate of EGFR and HER2 alteration is the relatively high proportion of patients with diffuse-type histology in this analysis.…”

Overexpression of epidermal growth factor receptor as a prognostic factor in colorectal cancer on the basis of the Allred scoring system

“…Our study included more detailed data related to the EGFR status, and this could explain the correlation of EGFR status and poor survival we found. The available data in the literature concerning cutoffs for positive staining for EGFR expression is lacking or incoherent 27–30. A cutoff value of 1% of the stained cells served to determine positive or negative EGFR status, as in other studies 2,31…”