Abstract
Scrib is a membrane protein that is involved in the maintenance of apical-basal cell polarity of the epithelial tissues. However, Scrib has also been shown to be mislocalized to the cytoplasm in breast and prostate cancer. Here, for the first time, we report that Scrib not only translocates to the cytoplasm but also to the nucleus in hepatocellular carcinoma (HCC) cells, and in mouse and human liver tumor samples. We demonstrate that Scrib overexpression suppresses the growth of HCC cells in vitro, and Scrib deficiency enhances liver tumor growth in vivo. At the molecular level, we have identified the existence of a positive feed-back loop between Yap1 and c-Myc in HCC cells, which Scrib disrupts by simultaneously regulating the MAPK/ERK and Hippo signaling pathways. Overall, Scrib inhibits liver cancer cell proliferation by suppressing the expression of three oncogenes, Yap1, c-Myc and cyclin D1, thereby functioning as a tumor suppressor in liver cancer.
Highlights
Scrib (Scrib), along with Discs large (Dlg) and Lethal giant larvae (Lgl), is an evolutionarily conserved component of a common genetic pathway involved in apical-basal cell polarity [1, 2]
For the first time, we report that Scrib translocates to the cytoplasm and to the nucleus in hepatocellular carcinoma (HCC) cells, and in mouse and human liver tumor samples
We have identified the existence of a positive feed-back loop between Yap1 and c-Myc in HCC cells, which Scrib disrupts by simultaneously regulating the MAPK/ERK and Hippo signaling pathways
Summary
Scrib (Scrib), along with Discs large (Dlg) and Lethal giant larvae (Lgl), is an evolutionarily conserved component of a common genetic pathway involved in apical-basal cell polarity [1, 2]. The apical (Crumbs and Par) and basolateral (Scrib) modules function in a mutually antagonistic relationship to regulate various polarization processes such as apical-basal polarity, planar cell polarity, asymmetric cell division and migration [3]. Initial work on these proteins has mainly been focused on identifying their localization in various cell types and their coordination in establishing cell polarity [1, 2]. Genetic studies indicate that the polarity proteins influence distinct pathways in order to regulate various cellular processes [14]
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