Research Papers:
The cell polarity protein Scrib functions as a tumor suppressor in liver cancer
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Abstract
Shweta Kapil1,*, Bal Krishan Sharma1,*, Mallikarjun Patil1,*, Sawsan Elattar1, Jinling Yuan1, Steven X. Hou2, Ravindra Kolhe3, Ande Satyanarayana1
1Department of Biochemistry and Molecular Biology, Molecular Oncology & Biomarkers Program, Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA
2Stem Cell Regulation and Animal Aging Section, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA
3Department of Pathology, Augusta University, Augusta, GA 30912, USA
*These authors contributed equally to this work
Correspondence to:
Ande Satyanarayana, email: [email protected]
Keywords: HCC, nuclear localization, ERK, hippo signaling, Yap1
Received: January 13, 2017 Accepted: February 15, 2017 Published: February 24, 2017
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.
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