European Union Horizon 2020 Marie Skłodowska-Curie Actions Research and Innovation
Staff Exchange...(645756)
János Bolyai Research Scholarship of the Hungarian Academy of Sciences
(ÚNKP-20-4-I-SE-26)
Szakterületek:
Onkológia
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.
