Kobayashi Michimoto, Iwamatsu Akihiro, Shinohara-Kanda Azusa, Ihara Sayoko, Fukui Yasuhisa
Laboratory of Biological Chemistry, Department of Applied Biological Chemistry, Faculty of Agricultural and Life Science, University of Tokyo, Japan.
Oncogene. 2003 Mar 6;22(9):1294-301. doi: 10.1038/sj.onc.1206256.
Signet-ring cell carcinomas are malignant dedifferentiated carcinomas, which are frequently found in the stomach. We previously demonstrated that a 200 kDa protein is often constitutively phosphorylated on tyrosine and bound to phosphatidylinositol 3-kinase (PI3-kinase) in signet-ring cell carcinoma cells. In this study, we purified the 200 kDa protein from an extract of NUGC-4 cells, a cell line of signet-ring cell carcinoma, and identified it as ErbB3. ErbB3 was found to be phosphorylated selectively in dedifferentiated adenocarcinoma cell lines among various gastric cancer cell lines. Expression of a constitutively active chimeric receptor consisting of ErbB2 and ErbB3 in HCC2998 cells, a highly differentiated adenocarcinoma cell line, revealed that the signaling triggered by phosphorylation of ErbB3 was important for dedifferentiated phenotypes such as loss of cell-cell interaction and high expression of MUC1/DF3 antigen, a marker of the malignant tumors. Taken together, activation of ErbB3 pathway may contribute to the development of dedifferentiated carcinomas.
印戒细胞癌是恶性去分化癌，常见于胃部。我们之前证明，在印戒细胞癌细胞中，一种200 kDa的蛋白质经常在酪氨酸上组成性磷酸化，并与磷脂酰肌醇3激酶（PI3激酶）结合。在本研究中，我们从印戒细胞癌细胞系NUGC-4细胞的提取物中纯化了这种200 kDa的蛋白质，并将其鉴定为ErbB3。在各种胃癌细胞系中，发现ErbB3在去分化腺癌细胞系中选择性磷酸化。在高分化腺癌细胞系HCC2998细胞中表达由ErbB2和ErbB3组成的组成型活性嵌合受体，结果显示，ErbB3磷酸化触发的信号传导对于去分化表型（如细胞间相互作用丧失和恶性肿瘤标志物MUC1/DF3抗原的高表达）很重要。综上所述，ErbB3途径的激活可能有助于去分化癌的发展。
