Cytoglobin affects tumorigenesis and the expression of ulcerative colitis-associated genes under chemically induced colitis in mice

Abstract

Cytoglobin (Cygb) is a member of the hemoglobin family and is thought to protect against cellular hypoxia and oxidative stress. These functions may be particularly important in inflammation-induced cancer, e.g., in patients with ulcerative colitis (UC). In this study, we investigated the development of inflammation and tumors in a murine model of inflammation-induced colorectal cancer using a combined treatment of azoxymethane and dextran sulfate sodium. A bioinformatics analysis of genome-wide expression data revealed increased colonic inflammation at the molecular level accompanied by enhanced macroscopic tumor development in Cygb-deficient mice. Moreover, the expression of the UC-associated gene neurexophilin and PC-esterase domain family member 4 (Nxpe4) depended on the presence of Cygb in the inflamed colonic mucosa. Compared to wild type mice, RT-qPCR confirmed a 14-fold (p = 0.0003) decrease in Nxpe4 expression in the inflamed colonic mucosa from Cygb-deficient mice. An analysis of Cygb protein expression suggested that Cygb is expressed in fibroblast-like cells surrounding the colonic crypts. Histological examinations of early induced lesions suggested that the effect of Cygb is primarily at the level of tumor promotion. In conclusion, in this model, Cygb primarily seemed to inhibit the development of established microadenomas.

Cytoglobin Attenuates Neuroinflammation in Lipopolysaccharide-Activated Primary Preoptic Area Cells via NF-κB Pathway Inhibition

“…Cygb has been implicated in oxygen transport, nitric oxide scavenging, tumor suppression and protection against oxidative stress and inflammation (Ou et al, 2018;Yassin et al, 2018). Consistent with its described functions, the expression of Cygb is upregulated in conditions associated with hypoxia, oxidative stress and inflammation (Guo et al, 2007;Tae et al, 2017;Yassin et al, 2018).…”

“…Cygb also inhibited LPS-induced NADPH oxidase activity and ROS, NO, and O 2 •− generation (Wen et al, 2017). In addition, Cygb-deficient mice exhibited increased inflammation (Thuy et al, 2015;Van Thuy et al, 2017), as well as increased expression of TNF-α mRNA and many genes associated with inflammation (Yassin et al, 2018). These findings suggest that Cygb has a protective role in inflammation.…”

Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative‐nitrosative stress signals

“…Cygb is significantly deregulated by its promoter hypermethylation in most malignancies, 26,28,29 thereby promoting tumorigenesis and progression. [16][17][18][19][20][21][30][31][32] In this study, we found that Cygb is significantly deregulated in human HCC tissues, as compared with these adjacent non-tumor tissues and hepatolithiasis tissues ( Figure 1A-C), Cygb decrease promotes HCC proliferation, whereas Cygb restoration inhibits cell proliferation (Figure 2A-D). We proposed that Cytoglobin functions as tumor suppressor, and its decrease is negatively associated with HCC progression.…”

“…[15][16][17][18][19] Cygb absence accounts for a high incidence of multiple malignancies including liver, lung and colon cancer and lymphoma in aged Cygb −/− mice, compared with wide-type mice. 20,21 Its deficiency also contributes to tumor recurrence and poor prognosis in human gliomas. 22 Cygb restoration in cancer cell lines inhibits cell migration, invasion, and anchorage-independent growth.…”

“…Emerging evidences indicated that Cygb is negatively associated with liver fibrosis and HCC tumorigenesis via regulating oxidative stress pathways . Cygb absence accounts for a high incidence of multiple malignancies including liver, lung and colon cancer and lymphoma in aged Cygb −/− mice, compared with wide‐type mice . Its deficiency also contributes to tumor recurrence and poor prognosis in human gliomas .…”