Human scribble accumulates in colorectal neoplasia in association with an altered distribution of beta-catenin.
The loss of epithelial polarity and tissue architecture is a diagnostic feature of malignant tumors. In Drosophila, genetic studies identified 3 neoplastic tumor suppressor genes (nTSGs), and a loss of nTSGs has been shown to result in a disruption of apical-basal polarity and neoplastic growth in epithelial cells. Scribble is one type of the Drosophila nTSGs, which encodes a membrane-associated cytoplasmic protein containing the multi-PDZ domain. In contrast to Drosophila scribble, the oncogenic roles of its mammalian homologues have not yet been established. We herein immunohistochemically examined the distributions of hScrib protein in human colorectal neoplasia using affinity-purified antibody. In 50 cases of colorectal adenomas and adenocarcinomas, the accumulation of hScrib protein was commonly observed in comparison with the adjacent normal epithelia. Furthermore, the overexpression and distribution of hScrib was observed to extensively overlap with the cytoplasmic accumulation of beta-catenin. Like beta-catenin, the intense immunoreactivity of hScrib was often observed in small adenomas, thus, suggesting that hScrib could be involved in an early step of colon carcinogenesis. Five corresponding liver metastases showed a comparable immunoreactivity for anti-hScrib in comparison with their primary sites. In an immunofluorescence analysis on cultured cell lines, the loss of membranous staining of hScrib was observed according to the cytoplasmic translocation of beta-catenin. We herein demonstrate that the accumulation of hScrib protein might therefore be involved in colon carcinogenesis while also providing a possible link between hScrib and beta-catenin.