Inhibition of Nrf2/HO-1 signaling pathway by Dextran Sulfate suppresses angiogenesis of Gastric Cancer

Yuanyi Xu; Yuanyuan Yang; Yunning Huang; Qian Ma; Jing Shang; Jiaxin Guo; Xiangmei Cao; Xiaofei Wang; Mengqi Li

doi:10.7150/jca.50605

Inhibition of Nrf2/HO-1 signaling pathway by Dextran Sulfate suppresses angiogenesis of Gastric Cancer

J Cancer. 2021 Jan 1;12(4):1042-1060. doi: 10.7150/jca.50605. eCollection 2021.

Authors

Yuanyi Xu¹, Yuanyuan Yang¹, Yunning Huang², Qian Ma^{3

4}, Jing Shang⁵, Jiaxin Guo¹, Xiangmei Cao¹, Xiaofei Wang⁶, Mengqi Li¹

Affiliations

¹ Department of Pathology, Ningxia Medical University, Yinchuan, Ningxia 750004, China.
² Department of Gastrointestinal Surgery, The Affiliated People's Hospital of Ningxia Medical University, Yinchuan, Ningxia 750001, China.
³ College of Life Sciences, Ningxia University, Yinchuan, Ningxia 750021, China.
⁴ College of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia 750004, China.
⁵ Third Clinical Medical College, Ningxia Medical University, Yinchuan, Ningxia 750004, China.
⁶ Department of Pathology, North China University of Science and Technology Affiliated Hospital, Tangshan, Hebei 063000, China.

Abstract

Purpose: To investigate the role of Nrf2/HO-1 signaling pathway in angiogenesis and whether dextran sulfate (DS) could suppress angiogenesis by inhibiting Nrf2/HO-1 signaling pathway in gastric cancer. Methods: In vitro; Western blot analyzed the expression of Nrf2 in gastric cell lines. Tube formation assay observed the effect of gradient concentration DS on the angiogenic potential of HGC-27 cells. Immunofluorescence,western blot and qPCR analyzed the effects of DS on the expression of Nrf2, HO-1 and VEGF under gradient hypoxia time. Immunofluorescence,western blot,qPCR and tube formation assay analyzed the effects of up-regulating or down-regulating Nrf2/HO-1 signaling pathway on VEGF expression and angiogenic potential in HGC-27 cells. In vivo: Construct nude mouse intraperitoneal implantation metastasis model. Immunohistochemistry and western blot analyzed the effects of DS on the expression of Nrf2, HO-1, VEGF and MVD in nude mice. Immunohistochemistry detected the expression of Nrf2, HO-1, VEGF and MVD in human paracancerous tissue and gastric cancer tissues with different degrees of differentiation. Results: The expression of Nrf2 increased most significantly in HGC-27 cell line. DS reduced the angiogenic potential and the expression of Nrf2, HO-1 and VEGF in HGC-27 cells. Down-regulation of Nrf2/HO-1 signaling pathway decreased VEGF expression and angiogenic potential in HGC-27 cells. Up-regulation of Nrf2/HO-1 signaling pathway increased VEGF expression and angiogenic potential in HGC-27 cells. DS reduced the expression of Nrf2, HO-1, VEGF and MVD in nude mice. Nrf2, HO-1, VEGF and MVD showed low expression in paracancerous tissue but high expression in gastric cancer tissues. They were weak, moderate and strong in well, moderately and poorly differentiated gastric cancer tissues, respectively. Conclusion: Nrf2/HO-1 signaling pathway may positively regulate gastric cancer angiogenesis and DS may suppress the angiogenesis by inhibiting Nrf2/HO-1 signaling pathway in gastric cancer.

Keywords: Nrf2/HO-1; VEGF; angiogenesis; dextran sulfate; gastric cancer; metastasis.