Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
Hepatic Surgery Center and Hubei Key Laboratory of Hepato-Pancreatic-Biliary Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hepatology. 2021 Sep;74(3):1411-1428. doi: 10.1002/hep.31817. Epub 2021 May 24.
Existing therapeutic approaches to treat cholangiocarcinoma (CCA) have limited effectiveness, prompting further study to develop therapies for CCA. We report a 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. Up-regulation of SULF2 in CCA leads to increased platelet-derived growth factor receptor beta (PDGFRβ)-Yes-associated protein (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.
These results suggest that SULF2 monoclonal antibody 5D5 or related agents may be potentially promising therapeutic agents in CCA.
现有的胆管癌（CCA）治疗方法效果有限，促使我们进一步研究开发 CCA 的治疗方法。我们报告了硫酸乙酰肝素修饰酶磺基转移酶 2（SULF2）在 CCA 发病机制中的作用机制。
通过计算机分析发现，人类 CCA 样本中 SULF2 表达升高，部分是通过 SULF2 拷贝数增加引起的。我们在体外研究了 SULF2 敲低或过表达对人 CCA 细胞系肿瘤生长、化疗耐药和信号通路活性的影响。CCA 中 SULF2 的上调导致血小板衍生生长因子受体β（PDGFRβ）-Yes 相关蛋白（YAP）信号活性增加，促进肿瘤生长和化疗耐药。为了探索在 CCA 治疗中靶向肿瘤微环境中 SULF2 的应用，我们在小鼠 CCA 异种移植模型中测试了抗 SULF2 单克隆抗体 5D5。单克隆抗体 5D5 靶向 SULF2 抑制了小鼠异种移植模型中的 PDGFRβ-YAP 信号和肿瘤生长。
这些结果表明，SULF2 单克隆抗体 5D5 或相关制剂可能是 CCA 有前途的治疗药物。
