Overexpression of Human Syndecan-1 Protects against the Diethylnitrosamine-Induced Hepatocarcinogenesis in Mice

SIMPLE SUMMARY: Syndecan-1 is a Janus-faced proteoglycan: depending on the type of cancer, it can promote or inhibit the development of tumors. Our previous in vitro experiments revealed that transfection of human syndecan-1 (hSDC1) into hepatoma cells, initiating hepatocyte-like differentiation. To further confirm the antitumor action of hSDC1 in the context of liver carcinogenesis, mice transgenic for albumin promoter-driven hSDC1 were created with exclusive expression of hSDC1 in the liver. Indeed, hSDC1 interfered with the development of liver cancer in diethylnitrosamine (DEN)-induced hepatocarcinogenesis experiments. The mechanism was found to be related to lipid metabolism that plays an important role in the induction of nonalcoholic liver cirrhosis. Nonalcoholic fatty liver disease is known to promote the development of cancer; therefore, the oncoprotective effect of hSDC1 may be mediated by a beneficial modulation of lipid metabolism. ABSTRACT: Although syndecan-1 (SDC1) is known to be dysregulated in various cancer types, its implication in tumorigenesis is poorly understood. Its effect may be detrimental or protective depending on the type of cancer. Our previous data suggest that SDC1 is protective against hepatocarcinogenesis. To further verify this notion, human SDC1 transgenic (hSDC1(+/+)) mice were generated that expressed hSDC1 specifically in the liver under the control of the albumin promoter. Hepatocarcinogenesis was induced by a single dose of diethylnitrosamine (DEN) at an age of 15 days after birth, which resulted in tumors without cirrhosis in wild-type and hSDC1(+/+) mice. At the experimental endpoint, livers were examined macroscopically and histologically, as well as by immunohistochemistry, Western blot, receptor tyrosine kinase array, phosphoprotein array, and proteomic analysis. Liver-specific overexpression of hSDC1 resulted in an approximately six month delay in tumor formation via the promotion of SDC1 shedding, downregulation of lipid metabolism, inhibition of the mTOR and the β-catenin pathways, and activation of the Foxo1 and p53 transcription factors that lead to the upregulation of the cell cycle inhibitors p21 and p27. Furthermore, both of them are implicated in the regulation of intermediary metabolism. Proteomic analysis showed enhanced lipid metabolism, activation of motor proteins, and loss of mitochondrial electron transport proteins as promoters of cancer in wild-type tumors, inhibited in the hSDC1(+/+) livers. These complex mechanisms mimic the characteristics of nonalcoholic steatohepatitis (NASH) induced human liver cancer successfully delayed by syndecan-1.