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
East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
Int J Cancer. 2017 Jun 15;140(12):2734-2747. doi: 10.1002/ijc.30698. Epub 2017 Apr 3.
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.
氧化应激化合物的清除对于保护机体免受恶性肿瘤侵害至关重要，但这一关键生理过程的调控机制尚未完全明确。在此，我们发现，在肺癌中已被充分表征的肿瘤抑制因子GPRC5A在结直肠癌患者组织中的表达升高。在癌细胞系和小鼠的结肠炎相关癌模型中，我们发现GPRC5A缺失会减少细胞增殖、增加细胞凋亡，并在体内抑制肿瘤发生。通过RNA测序转录组分析，我们确定与氧化应激相关的通路失调。此外，在GPRC5A缺失的细胞和小鼠组织中，由于谷胱甘肽（GSH）水平升高，氧化因子部分减少。从机制上讲，GPRC5A调节NF-κB介导的Vanin-1表达，而Vanin-1是半胱胺生成的主要酶。在GPRC5A缺失的细胞系中给予胱胺（半胱胺的二硫化物形式）会抑制γ-GCS活性，导致GSH水平降低并促进细胞生长。综上所述，我们的研究表明，GPRC5a是结肠癌的潜在生物标志物，并通过刺激Vanin-1表达和结肠炎相关癌中的氧化应激促进肿瘤发生。这项研究揭示了GPRC5A在结直肠癌中意想不到的致癌作用，表明该基因在不同组织中存在复杂的功能和分子机制差异。
