Enhanced colonic tumorigenesis in alkaline sphingomyelinase (NPP7) knockout mice.
Intestinal alkaline sphingomyelinase (alk-SMase) generates ceramide and inactivates platelet-activating factor (PAF) and was previously suggested to have anticancer properties. The direct evidence is still lacking. We studied colonic tumorigenesis in alk-SMase knockout (KO) mice. Formation of aberrant crypt foci (ACF) was examined after azoxymethane (AOM) injection. Tumor was induced by AOM alone, a conventional AOM/dextran sulfate sodium (DSS) treatment, and an enhanced AOM/DSS method. β-Catenin was determined by immunohistochemistry, PAF levels by ELISA, and sphingomyelin metabolites by mass spectrometry. Without treatment, spontaneous tumorigenesis was not identified but the intestinal mucosa appeared thicker in KO than in wild-type (WT) littermates. AOM alone induced more ACF in KO mice but no tumors 28 weeks after injection. However, combination of AOM/DSS treatments induced colonic tumors and the incidence was significantly higher in KO than in WT mice. By the enhanced AOM/DSS method, tumor number per mouse increased 4.5 times and tumor size 1.8 times in KO compared with WT mice. Although all tumors were adenomas in WT mice, 32% were adenocarcinomas in KO mice. Compared with WT mice, cytosol expression of β-catenin was significantly increased and nuclear translocation in tumors was more pronounced in KO mice. Lipid analysis showed decreased ceramide in small intestine and increased sphingosine-1-phosphate (S1P) in both small intestine and colon in nontreated KO mice. PAF levels in feces were significantly higher in the KO mice after AOM/DSS treatment. In conclusion, lack of alk-SMase markedly increases AOM/DSS-induced colonic tumorigenesis associated with decreased ceramide and increased S1P and PAF levels.
Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences Lund, University of Lund, Lund, Sweden. Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
Ying
Y
Chen
Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences Lund, University of Lund, Lund, Sweden.
Ping
P
Zhang
Gastroenterology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China. Rui-dong.duan@med.lu.se xschang@163.com.
Shu-Chang
SC
Xu
Cancer Research Center, Tumor Hospital of Nantong University, Nantong, China.
Liping
L
Yang
Neurogastroenterology, Department of Experimental Medical Science, University of Lund, Lund, Sweden.
Ulrikke
U
Voss
Neurogastroenterology, Department of Experimental Medical Science, University of Lund, Lund, Sweden.
Eva
E
Ekblad
Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.
Yunjin
Y
Wu
Cancer Research Center, Tumor Hospital of Nantong University, Nantong, China.
Yalan
Y
Min
Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences Lund, University of Lund, Lund, Sweden. Gastroenterology, Skåne University Hospital, Lund, Sweden.
Erik
E
Hertervig
Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences Lund, University of Lund, Lund, Sweden. Gastroenterology, Skåne University Hospital, Lund, Sweden.
Åke
Å
Nilsson
Gastroenterology and Nutrition Laboratory, Department of Clinical Sciences Lund, University of Lund, Lund, Sweden. Rui-dong.duan@med.lu.se xschang@163.com.
Rui-Dong
RD
Duan
D000230:Adenocarcinoma; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity*; D002352:Carrier Proteins / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity*; D007413:Intestinal Mucosa / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D013107:Sphingolipids / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C495267:CTNNB1 protein, mouse; D002352:Carrier Proteins; C561966:PAF protein, mouse; D013107:Sphingolipids; D051176:beta Catenin; D016264:Dextran Sulfate; D013108:Sphingomyelin Phosphodiesterase; C000601493:alkaline sphingomyelinase, mouse; D001397:Azoxymethane