Genomic instability and cellular stress in organ biopsies and peripheral blood lymphocytes from patients with colorectal cancer and predisposing pathologies

Abstract

Inflammatory bowel disease (IBD) and polyps, are common colorectal pathologies in western society and are risk factors for development of colorectal cancer (CRC). Genomic instability is a cancer hallmark and is connected to changes in chromosomal structure, often caused by double strand break formation (DSB), and aneuploidy. Cellular stress, may contribute to genomic instability. In colorectal biopsies and peripheral blood lymphocytes of patients with IBD, polyps and CRC, we evaluated 1) genomic instability using the γH2AX assay as marker of DSB and micronuclei in mononuclear lymphocytes kept under cytodieresis inhibition, and 2) cellular stress through expression and cellular localization of glutathione-S-transferase omega 1 (GSTO1). Colon biopsies showed γH2AX increase starting from polyps, while lymphocytes already from IBD. Micronuclei frequency began to rise in lymphocytes of subjects with polyps, suggesting a systemic genomic instability condition. Colorectal tissues lost GSTO1 expression but increased nuclear localization with pathology progression. Lymphocytes did not change GSTO1 expression and localization until CRC formation, where enzyme expression was increased. We propose that the growing genomic instability found in our patients is connected with the alteration of cellular environment. Evaluation of genomic damage and cellular stress in colorectal pathologies may facilitate prevention and management of CRC.

The ratio of STAT1 to STAT3 expression is a determinant of colorectal cancer growth

“…The role for STAT3 in carcinomas remains controversial - nuclear STAT3 (pYSTAT3) is regarded as a biomarker for prognosis prediction in solid tumours [20]. Several studies reported elevated and tumor promoting STAT3 signaling in CRC [5, 6, 7, 21]. In contrast, others have reported that STAT3 suppresses CRC [15, 22].…”

GSTO1*CC Genotype (rs4925) Predicts Shorter Survival in Clear Cell Renal Cell Carcinoma Male Patients

“…The GSTO1 upregulation has been reported in different cancers, including bladder [35], pancreatic, ovarian cancer [24,36] and esophageal adenocarcinoma [37]. Moreover, nuclear localization of GSTO1 in Barrett's esophagus [38] and colorectal carcinoma [39] suggests its probable involvement in the protection of specific nuclear components in conditions of oxidative stress, thus promoting malignant transformation. Unfortunately, there are no literature data on GSTO2 expression in cancer, as yet.…”

Photoreceptor Survival Is Regulated by GSTO1-1 in the Degenerating Retina

“…GSTO1-1 has been implicated in the regulation of oxidative stress and inflammation in various organ systems, where both overexpression and polymorphisms in the encoding gene have been linked to pathological diseases, including cancer, and neurological disorders. [5][6][7][8][9] GSTO1-1 is required for lipopolysaccharide (LPS)-mediated inflammatory responses in macrophages, inducing reactive oxygen species (ROS) production and proinflammatory cytokine expression through the toll-like receptor 4 (TLR4) pathway. 10,11 GSTO1-1-deficient macrophages consequently demonstrate lower levels of oxidative stress and inflammation.…”