K. Yuza1, M. Nagahashi1, Y. Shimada1, M. Nakano1, Y. Tajima1, H. Kameyama1, M. Nakajima1, H. Ichikawa1, J. Sakata1, T. Kobayashi1, K. Takabe2,3, T. Wakai1 1Niigata University Graduate School Of Medical And Dental Sciences,Division Of Digestive And General Surgery,Niigata City, NIIGATA, Japan 2Roswell Park Cancer Institute,Breast Surgery, Department Of Surgical Oncology,Buffalo, NY, USA 3University At Buffalo Jacobs School Of Medicine And Biomedical Sciences, The State University Of New York,Department Of Surgery,Buffalo, NY, USA
Introduction:
Colorectal cancer (CRC) that developed from inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is known as colitis-associated cancer (CAC). Significant advances have been made in understanding the link between chronic inflammation and cancer by advancements in molecular biology and animal models that recapitulate human diseases in recent years. It has been implicated that sphingosine-1-phosphate (S1P), a bioactive lipid mediator, is a key mediator of inflammation, tumorigenesis and cancer progression. We have recently shown that S1P produced by upregulation of sphingosine kinase 1 (SphK1) links chronic intestinal inflammation to CAC utilizing animal models (Cancer Cell 2013). However, the role of S1P in human CAC has never been investigated due to the difficulty to measure S1P levels directly in human samples. We have previously shown that high expression of phosphorylated-SphK1 (pSphK1) is associated with higher levels of S1P in human tissue, and detecting pSphK1 by immunohistochemistry could be an alternative method to examine the role of S1P in human patients (JSR 2016). The aim of this study is to determine the expression levels of pSphK1 in sporadic CRC and CAC, and to clarify the importance of S1P in CAC patients.
Methods:
Tissue samples of sporadic CRC (N = 10) and ulcerative colitis-associated cancer (N = 10), respectively, were randomly selected from patients who underwent curative resection between April 2012 and May 2017. The expression of pSphK1 in these samples was examined by immunohistochemistry staining. Semi-quantitative evaluation of the staining of pSphK1 in CRC cells was performed as follows; a staining score was calculated by multiplying two points of staining intensity (0-3) and the ratio (1-4). The staining score of 0 to 5 points was considered as pSphK1-negative, and 6 to 12 was considered as pSphK1-positive.
Results:
Immunohistochemistry analysis of pSphK1 revealed that sporadic CRC had a median staining score of 4 (range 0-12), while ulcerative colitis-associated cancer had a median staining score of 12 (range 4-12) (Mann Whitney test, P<0.05). Based on the staining scoring described in Methods, three out of 10 (30%) patients with sporadic CRC, and nine out of 10 (90%) patients with ulcerative colitis-associated cancer were considered as pSphK1-positive (Fisher’s exact test, P<0.05).
Conclusion:
To our knowledge, this is the first report that compared pSphK1 expression levels in CAC and those in sporadic CRC. The high levels of pSphK1 expression in CAC implicate an important role of S1P in the disease process of CAC.