Fukui Yasuhisa
Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan Town 35053, Miaoli County, Taiwan, ROC.
Biochem Biophys Res Commun. 2014 Aug 8;450(4):1231-3. doi: 10.1016/j.bbrc.2014.07.025. Epub 2014 Jul 11.
Signet ring cell carcinomas are highly malignant dedifferentiated adenocarcinomas. There are no cell-cell interactions between these round-shaped cells. They contain huge numbers of vacuoles, filled with mucins, which are secreted from the cells. The mechanism behind this phenotype has recently begun to be elucidated. In highly differentiated adenocarcinomas the ErbB2/ErbB3 complex is activated, which is followed by phosphatidylinositol 3-kinase (PI3K) activation. p38 MAP kinase is activated downstream of PI3K and adherens junctions are disrupted via Rac1 activation. Loss of adherens junctions leads to the disappearance of tight junctions, which results in a loss of cell-cell interactions. Secretion of mucin is enhanced by activation of PI3K. One of the mucins - Muc4 - can activate ErbB2. Under normal conditions Muc4 and ErbB2 are separated by adherens and tight junctions, however in signet ring cells they are able to interact, since these junctions have been lost. Therefore, an activation loop is formed, consisting of ERbB2/ErbB3-Muc4-ErbB2/ErbB3. As a result, the ErbB2/ErbB3 signaling pathway becomes constitutively activated, cell-cell interactions are lost, and signet ring carcinomas are formed. As a result of constitutive activation of the ErbB2/ErbB3 complex, cell growth is continuously enhanced. Some signet ring cell carcinomas have been found to have mutations in the E-cadherin gene, which fits the above hypothesis.
印戒细胞癌是高度恶性的去分化腺癌。这些圆形细胞之间不存在细胞间相互作用。它们含有大量充满粘蛋白的空泡，这些粘蛋白由细胞分泌。这种表型背后的机制最近已开始得到阐明。在高分化腺癌中，表皮生长因子受体2/表皮生长因子受体3（ErbB2/ErbB3）复合物被激活，随后磷脂酰肌醇3激酶（PI3K）被激活。p38丝裂原活化蛋白激酶在PI3K下游被激活，黏附连接通过Rac1活化而被破坏。黏附连接的丧失导致紧密连接消失，从而导致细胞间相互作用丧失。PI3K的激活增强了粘蛋白的分泌。其中一种粘蛋白——Muc4——可以激活ErbB2。在正常情况下，Muc4和ErbB2被黏附连接和紧密连接分隔开，然而在印戒细胞中它们能够相互作用，因为这些连接已经丧失。因此，形成了一个由ErbB2/ErbB3 - Muc4 - ErbB2/ErbB3组成的激活环。结果，ErbB2/ErbB3信号通路被组成性激活，细胞间相互作用丧失，印戒癌形成。由于ErbB2/ErbB3复合物的组成性激活，细胞生长持续增强。已经发现一些印戒细胞癌在E - 钙黏蛋白基因中存在突变，这与上述假设相符。
