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

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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-α 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.

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Acknowledgements

This work was supported, in part, by Grants-in-Aid from the Ministry of Education, Culture, Sports, and Technology of Japan, and the Ministry of Health, Labor, and Welfare of Japan. The authors thank Masayoshi Takatani and Mutsumi Ueda for their skillful technical assistance. The authors are also grateful to Noriko Sagawa for her secretarial assistance.

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Authors and Affiliations

  1. Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima , Japan

    Reiko Ito, Hirofumi Nakayama, Shunji Matsumura & Wataru Yasui

  2. Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima , Japan

    Kazuhiro Yoshida

  3. Department of Human Nutrition, Faculty of Human Sciences, Hiroshima Bunkyo Women’s University, 1-2-1 Kabe-higashi, Asakita-ku, 731-0295, Hiroshima , Japan

    Noriko Oda

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  1. Reiko Ito
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  2. Hirofumi Nakayama
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Correspondence to Wataru Yasui.

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Ito, R., Nakayama, H., Yoshida, K. et al. Expression of Cbl linking with the epidermal growth factor receptor system is associated with tumor progression and poor prognosis of human gastric carcinoma. Virchows Arch 444, 324–331 (2004). https://doi.org/10.1007/s00428-004-0982-8

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  • DOI: https://doi.org/10.1007/s00428-004-0982-8

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