NoxO1 Controls Proliferation of Colon Epithelial Cells

Abstract

AimReactive oxygen species (ROS) produced by enzymes of the NADPH oxidase family serve as second messengers for cellular signaling. Processes such as differentiation and proliferation are regulated by NADPH oxidases. In the intestine, due to the exceedingly fast and constant renewal of the epithelium both processes have to be highly controlled and balanced. Nox1 is the major NADPH oxidase expressed in the gut, and its function is regulated by cytosolic subunits such as NoxO1. We hypothesize that the NoxO1-controlled activity of Nox1 contributes to a proper epithelial homeostasis and renewal in the gut.ResultsNoxO1 is highly expressed in the colon. Knockout of NoxO1 reduces the production of superoxide in colon crypts and is not subsidized by an elevated expression of its homolog p47phox. Knockout of NoxO1 increases the proliferative capacity and prevents apoptosis of colon epithelial cells. In mouse models of dextran sulfate sodium (DSS)-induced colitis and azoxymethane/DSS induced colon cancer, NoxO1 has a protective role and may influence the population of natural killer cells.ConclusionNoxO1 affects colon epithelium homeostasis and prevents inflammation.

NoxO1 Knockout Promotes Longevity in Mice

“…By appreciating the fact, that the animal numbers are relatively small, we aimed to avoid overlooking an effect of lower body weight, which appeared to be obvious: The most prominent reason for low weight gain in young animals is caloric restriction. Caloric restriction may develop from enterocyte dysfunction, as suggested by our previous study [8]. Alternatively, gut pain may be a reason for less food consumption.…”

“…Both cytosolic subunits can be replaced by the activator NoxA1 and the constitutively active organizer NoxO1. Importantly, although NoxA1 and NoxO1 can be exchanged with p67phox and p47phox to activate Nox1-3 in vitro in an overexpression system, in vivo NoxO1 and p47phox are expressed in different cells and cannot substitute each other [7,8].…”

“…Recently we found a subunit of the Nox1 complex, namely NoxO1, in the colon to be involved in enterocyte differentiation [8]. In the colon, proliferation of partially differentiated epithelial cells was enhanced, while apoptosis was reduced in the absence of NoxO1 in murine colons, which leads to a reduced homeostasis and barrier function of the colon wall.…”

“…In NoxO1 knockout mice, ROS formation in the gut is reduced and the function of enterocytes may be disturbed. Eventually, NoxO1 knockout mice lose more weight and their colon was more prone to develop tumors in an AOM/DSS colon carcinoma model [8]. In humans, loss-of-function variants of Nox1 may not cause a disease, but represent context-specific modifiers that may worsen an inflammatory bowel disease [9].…”

A novel risk score model for stomach adenocarcinoma based on the expression levels of 10 genes

“…With the exception of MANEAL, which may be involved in neurological disorders (44), the other three genes with high expression levels in the samples with good prognosis are associated with cancer, particularly NOXO1 and TRIM31 (45)(46)(47)(48)(49). NOXO1 can be induced in tumor epithelial cells and serves an important role in tumorigenicity and the tumor-initiating property of GC cells (46). In addition, NOXO1 may affect colon epithelium homeostasis and prevent inflammation (45).…”