Expression of NOX1, a superoxide‐generating NADPH oxidase, in colon cancer and inflammatory bowel disease

Abstract

Reactive oxygen species (ROS) are at the centre of many physiological and pathological processes. NOX1, a ROS-producing NADPH oxidase, is highly expressed in the colon but its function in colonic physiology or pathology is still poorly understood. It has been suggested to play a role in host defence, but also in cell growth and possibly malignant transformation. In this study we characterized NOX1 expression in human colon samples derived from healthy control subjects and patients with colon cancer or inflammatory bowel disease (IBD). NOX1 mRNA expression was assessed by dot-blot hybridization, real-time PCR and in situ hybridization, using samples derived from surgical specimens from patients undergoing colon resection. In normal tissues, NOX1 expression was low in the ileum, intermediate in the right colon, and high in the left colon (p = 0.0056 right vs. left colon). NOX1 mRNA levels were not influenced by factors linked to colon tumourigenesis, such as age or sex. Moreover, there was no statistical difference in NOX1 expression between samples derived from adenomas, well differentiated or poorly differentiated colon adenocarcinomas. At a cellular level, NOX1 was highly expressed in colon epithelial cells, both within the crypts and on the luminal surface. In addition, a population of lymphocytes, particularly in the appendix, showed NOX1 expression. Lymphocytes in lesions of Crohn's disease and ulcerative colitis were also strongly positive for NOX1. In conclusion, NOX1 is an enzyme that is constitutively expressed in colon epithelium and is not associated with tumourigenesis. Its distribution in crypts and on the luminal surface, as well as its left-to-right gradient in the colon, suggests a role in host defence function. In addition to the known epithelial localization, we define lymphocytes as a novel site of NOX1 expression, where it may potentially be involved in the pathogenesis of inflammatory bowel diseases.

Nox enzymes, ROS, and chronic disease: An example of antagonistic pleiotropy

“…In many of cases, the source of this ROS is Nox enzymes: this includes melanoma (Nox4, [127]), prostate cancer (Nox5 [128] and Nox1 [129]), glioblastoma (Nox4 and sometimes Nox5 [130]), H. pylorusinduced gastric inflammation leading to gastric cancer (Nox1 [131]) and Barrett's esophageal adenocarcinoma (Nox5 [132]). Some, but not all reports have observed an increase in Nox1 expression in colon cancer, see [133][134][135][136]. In recent studies, we found that Nox1 protein and mRNA are over-expressed beginning at the adenoma (precancerous stage), and did not further increase at later stages [Laurent et al (unpublished data)], consistent with most other reports.…”

Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer

“…However, and in contrast to the effects of N1IC, we found that hes1 was not sufficient to induce tumor growth in vivo in the absence of ␤-catenin/TCF activity indicating that other Notch-targets down- stream of ␤-catenin participate in regulating colorectal tumorigenesis. Consistently, several of the identified Notch-target genes in our screening have been involved in different aspects of intestinal differentiation or cancer including SOX9 (38, 39) KLF5 (47), CD44 (32), or NOX1 (48). Mutations in the APC gene have been found in most sporadic colorectal tumors and in those arising in FAP patients.…”

Les Nox/Duox : une nouvelle famille de NADPH oxydases

“…Cependant plusieurs études récentes réfutent ce rôle pour Nox-1 dans les cancers colorectaux. Cette enzyme est exprimée à la fois dans les cryptes et les villosités intestinales [23], suggérant qu'elle jouerait un rôle préférentiel dans la différenciation plutôt que dans la prolifération.…”