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Assessing the role of hepatocyte‐specific Wnts in hepatocellular carcinoma
Author(s) -
Preziosi Morgan,
Monga Satdarshan
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.805.6
Subject(s) - hepatocellular carcinoma , wnt signaling pathway , cirrhosis , hepatocyte , medicine , cancer research , cancer , fibrosis , liver cancer , pathology , biology , signal transduction , microbiology and biotechnology , biochemistry , in vitro
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, and the third most common cancer‐related mortality. Additionally, liver fibrosis or cirrhosis is a prerequisite to HCC in 70–90% of cases. Treatment options are limited, and HCC incidence continue to rise each year, it is of utmost importance to better understand mechanisms of liver injury and HCC to provide better options for patients. Overexpression of Wnts have been observed in different cancers including HCC, and we hypothesize hepatocyte‐specific Wnts affect HCC progression. We used hepatocyte‐specific Wntless knockout animals (KO) which are unable to secrete Wnts from hepatocytes, and subjected them to a strict regimen of diethylnitrosame and carbon tetrachloride (DEN/CCl 4 ) to induce hepatic injury, fibrosis, and cancer. Importantly, all tumors will be β‐catenin wild‐type, representing a majority of patients and making our study of Wnts relevant. At 3 months we noted no differences in injury or tumor nodules between control (CON) and KO. At 5 months all animals had HCC and in KO we noted increased cytoplasmic β‐catenin, increased target gene expression, and frequent CK19+ foci. We predict hepatocytes secrete noncanonical Wnts to prevent β‐catenin activation and tumor dedifferentiation, and we hypothesize KO will have more metastatic, dedifferentiated, and advanced tumors at 7 months. By identifying the cell type responsible for Wnt secretion and their conclusive roles in HCC, we will be providing a direction to develop therapies that minimize toxicity through selective inhibition of tumor‐promoting Wnts while leaving other Wnt signaling intact.