Elevation of GPRC5A expression in colorectal cancer promotes tumor progression through VNN‐1 induced oxidative stress

Abstract

The clearance of oxidative stress compounds is critical for the protection of the organism from malignancy, but how this key physiological process is regulated is not fully understood. Here, we found that the expression of GPRC5A, a well-characterized tumor suppressor in lung cancer, was elevated in colorectal cancer tissues in patients. In both cancer cell lines and a colitis-associated cancer model in mice, we found that GPRC5A deficiency reduced cell proliferation and increased cell apoptosis as well as inhibited tumorigenesis in vivo. Through RNA-Seq transcriptome analysis, we identified oxidative stress associated pathways were dysregulated. Moreover, in GPRC5A deficient cells and mouse tissues, the oxidative agents were reduced partially due to increased glutathione (GSH) level. Mechanistically, GPRC5A regulates NF-κB mediated Vanin-1 expression which is the predominant enzyme for cysteamine generation. Administration of cystamine (the disulfide form of cysteamine) in GPRC5A deficient cell lines inhibited γ-GCS activity, leading to reduction of GSH level and increase of cell growth. Taken together, our studies suggest that GPRC5a is a potential biomarker for colon cancer and promotes tumorigenesis through stimulation of Vanin-1 expression and oxidative stress in colitis associated cancer. This study revealed an unexpected oncogenic role of GPRC5A in colorectal cancer suggesting there are complicated functional and molecular mechanism differences of this gene in distinct tissues.

Anti-tumor Effect of Rhaponticum uniflorum Ethyl Acetate Extract by Regulation of Peroxiredoxin1 and Epithelial-to-Mesenchymal Transition in Oral Cancer

“…Interestingly, inflammation can induce Ki-67 overexpression in some diseases ( Hafez and Tahoun, 2011 ). Oxidative stress can induce DNA injury and regulate the progression of various cancers ( Zhang et al, 2017 ). Indeed, Saed et al (2017) found that oxidative stress was involved in carcinogenesis and metastasis by inducing phenotypic modifications in ovarian cancer cells.…”

GPRC5A: An Emerging Biomarker in Human Cancer

“…What is more, GPRC5A deficiency reduces cell proliferation and promotes cell apoptosis in vitro and inhibits tumorigenesis of a colitis-associated cancer model in vivo . Furthermore, GPRC5A can be induced by hypoxia, regulates the NF- κ B-mediated expression of Vanin-1 (a key enzyme of cysteamine generation), and influences the reactive oxygen levels contributing to tumor progression [ 88 , 90 ].…”

Correlation between Oxidative Stress, Nutrition, and Cancer Initiation

“…There are several studies confirming that oxidative stress may have a core relationship with human pathophysiological diseases [ 14 , 15 , 16 ]. Specifically, oxidative stress is prominently known to damage the DNA molecule, alter signaling pathways, and regulate progression of various cancers, including those of the breast, lung, liver, colon, prostate, ovary, and brain [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Moreover, it is reported that the whole DNA molecule can bind with hydroxyl radicals, and consequently, damage the deoxyribose backbone, including purine and pyrimidine bases.…”