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Elevation of GPRC5A expression in colorectal cancer promotes tumor progression through VNN‐1 induced oxidative stress
Author(s) -
Zhang Long,
Li Liang,
Gao Ganglong,
Wei Gaigai,
Zheng Yansen,
Wang Chunmei,
Gao Na,
Zhao Yongliang,
Deng Jiong,
Chen Huaqing,
Sun Jialiang,
Li Dali,
Zhang Xueli,
Liu Mingyao
Publication year - 2017
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30698
Subject(s) - oxidative stress , carcinogenesis , colorectal cancer , cancer research , cell growth , transcriptome , cancer , chemistry , glutathione , cancer cell , biology , gene expression , biochemistry , enzyme , gene , genetics
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.