Hepatology. 2021 Mar 18. doi: 10.1002/hep.31817. Online ahead of print.
ABSTRACT
Existing therapeutic approaches to treat cholangiocarcinoma (CCA) have limited effectiveness, prompting further study to develop novel therapies for CCA. Here we report a novel mechanistic role for the heparan sulfate editing enzyme sulfatase 2 (SULF2) in CCA pathogenesis. In silico analysis revealed elevated SULF2 expression in human CCA samples, occurring partly through gain of SULF2 copy number. We examined the effects of knockdown or overexpression of SULF2 on tumor growth, chemoresistance, and signaling pathway activity in human CCA cell lines in vitro. Upregulation of SULF2 in CCA leads to increased PDGFRβ-YAP signaling activity, promoting tumor growth and chemotherapy resistance. To explore the utility of targeting SULF2 in the tumor microenvironment for CCA treatment, we tested an anti-SULF2 mouse monoclonal antibody 5D5 in a mouse CCA xenograft model. Targeting SULF2 by monoclonal antibody 5D5 inhibited PDGFRβ-YAP signaling and tumor growth in the mouse xenograft model. Conclusion: These results suggest that SULF2 monoclonal antibody 5D5 or related agents may be potentially promising new therapeutic agents in CCA.
PMID:33735525 | DOI:10.1002/hep.31817
