Cytoglobin attenuates pancreatic cancer growth via scavenging reactive oxygen species

• Published in: Oncogenesis (New York, NY) NY), 2022-05, Vol.11 (1), p.23-23, Article 23
• Main Authors: Hoang, Dinh Viet, Thuy, Le Thi Thanh, Hai, Hoang, Hieu, Vu Ngoc, Kimura, Kenjiro, Oikawa, Daisuke, Ikura, Yoshihiro, Dat, Ninh Quoc, Hoang, Truong Huu, Sato-Matsubara, Misako, Dong, Minh Phuong, Hanh, Ngo Vinh, Uchida-Kobayashi, Sawako, Tokunaga, Fuminori, Kubo, Shoji, Ohtani, Naoko, Yoshizato, Katsutoshi, Kawada, Norifumi
• Format: Article
• Language: English
• Subjects: 13/31; 14/34; 14/63; 38/91; 42/109; 631/67/1504/1713; 631/67/395; 631/80/83; 64/110; 82/29; 82/51; Adenocarcinoma; Anthracene; Antioxidants; Apoptosis; Cell activation; Cell Biology; Cell cycle; Cell growth; Cell migration; Cell proliferation; Collagen; Fibrosis; G1 phase; Glutathione; Heme proteins; Human Genetics; Hydrogen peroxide; Internal Medicine; Liver cancer; Malignancy; Medicine; Medicine & Public Health; Oncology; Oxidative phosphorylation; Pancreatic cancer; Pancreatitis; Pericytes; Phosphorylation; Reactive oxygen species; Stellate cells; Transgenic animals; Transgenic mice; Tumors
• ISSN: 2157-9024; 2157-9024
• DOI: 10.1038/s41389-022-00389-4

Pancreatic cancer is a highly challenging malignancy with extremely poor prognosis. Cytoglobin (CYGB), a hemeprotein involved in liver fibrosis and cancer development, is expressed in pericytes of all organs. Here, we examined the role of CYGB in the development of pancreatic cancer. CYGB expression appeared predominately in the area surrounding adenocarcinoma and negatively correlated with tumor size in patients with pancreatic cancer. Directly injecting 7, 12-dimethylbenz[a]anthracene into the pancreatic tail in wild-type mice resulted in time-dependent induction of severe pancreatitis, fibrosis, and oxidative damage, which was rescued by Cygb overexpression in transgenic mice. Pancreatic cancer incidence was 93% in wild-type mice but only 55% in transgenic mice. Enhanced CYGB expression in human pancreatic stellate cells in vitro reduced cellular collagen synthesis, inhibited cell activation, increased expression of antioxidant-related genes, and increased CYGB secretion into the medium. Cygb -overexpressing or recombinant human CYGB (rhCYGB) -treated MIA PaCa-2 cancer cells exhibited dose-dependent cell cycle arrest at the G1 phase, diminished cell migration, and reduction in colony formation. RNA sequencing in rhCYGB-treated MIA PaCa-2 cells revealed downregulation of cell cycle and oxidative phosphorylation pathways. An increase in MIA PaCa-2 cell proliferation and reactive oxygen species production by H 2 O 2 challenge was blocked by rhCYGB treatment or Cygb overexpression. PANC-1, OCUP-A2, and BxPC-3 cancer cells showed similar responses to rhCYGB. Known antioxidants N-acetyl cysteine and glutathione also inhibited cancer cell growth. These results demonstrate that CYGB suppresses pancreatic stellate cell activation, pancreatic fibrosis, and tumor growth, suggesting its potential therapeutic application against pancreatic cancer.