Elevation of GPRC5A expression in colorectal cancer promotes tumor progression through VNN-1 induced oxidative stress.
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.
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.
Long
L
Zhang
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.
Liang
L
Li
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.|Southern Medical University, Fengxian Hospital, Shanghai, 201499, China.
Ganglong
G
Gao
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.
Gaigai
G
Wei
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.
Yansen
Y
Zheng
Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
Chunmei
C
Wang
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.
Na
N
Gao
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.
Yongliang
Y
Zhao
Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai, 200025, China.
Jiong
J
Deng
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.
Huaqing
H
Chen
Southern Medical University, Fengxian Hospital, Shanghai, 201499, China.
Jialiang
J
Sun
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.
Dali
0000-0002-0679-8477
D
Li
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.|Southern Medical University, Fengxian Hospital, Shanghai, 201499, China.
Xueli
X
Zhang
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.|Institute of Biosciences and Technology, Department of Molecular and Cellular Medicine, Texas A&M University Health Science Center, Houston, TX.
Mingyao
M
Liu
D000581:Amidohydrolases / Q000235:genetics*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D003092:Colitis / Q000150:complications; D015179:Colorectal Neoplasms / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D058851:GPI-Linked Proteins / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000378:metabolism; D057809:HEK293 Cells; D019073:HT29 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; C116760:GPRC5A protein, human; C554251:GPRC5A protein, mouse; D043562:Receptors, G-Protein-Coupled; D000581:Amidohydrolases; C022314:pantetheinase; D005978:Glutathione
GPRC5A; NF-κB; VNN1; colorectal cancer; oxidative stress