| BackgroundColon cancer is one of the most common malignancies worldwide.In recent years as the improvement of living standards,the incidence of colon cancer is rising year by year.Recent surveys demonstrated that colon cancer is the third leading cause of death by cancer and female is more than male patients.Approximately several hundreds of thousand patients died of colon cancer,therefore the research and treatment of colon cancer are extremely important.Epidemiological data has consistently demonstrated a positive relation between high fat diet,obesity,alcohol,physical inactivity with the increased incidence of colon malignancy.Previous reports have shown that the disease progression of colon cancer is associated with abnormal lipid levels,especially the declining of high density lipoprotein-cholesterol(HDL-c)levels.Scavenger receptor class B type I(SR-BI),the first confirmed HDL receptor is extensively expressed in human organs especially in liver and steroidogenic tissues(such as adrenal gland,ovary and testis).SR-BI is an important receptor of cholesterol and cholesterol ester and plays a key role in the reverse cholesterol transport process.As a HDL receptor,in addition to anti-inflammation,anti-thrombosis,anti-oxida tion,SR-BI performs many other biological roles,such as sepsis,entry of hepa titis C virus,inflammation,innate immune,normal mature of red blood cells a nd female fertility.Studies has confirmed that high expression of SR-BI in div erse cancer cell lines,including prostate,hepatoma,ovarian,breast,colorectal,pancreatic,and nasopharyngeal cancer.However,the status of SR-BI expression in colon cancer and its clinical significance have not been addressed.In the present study,we first evaluated the different expression of SR-BⅠ and other cholesterol related genes and the association of genes and clinicopathological factors between colon cancer patients and normal cases using bioinformatics.Bioinformatics show that among the 5 genes involved in cholesterol internalization,SCARB1 is the only up-regulated gene in colon cancer.Moreover,we employed a colon cancer tissue microarray containing 90 tumor tissues and adjacent non-tumor tissue samples to study the differential expression of SR-BⅠ,and the association between SR-BⅠ and clinicopathological factors and patient outcome.Our results indicate that no clinicopathological parameter was connected to SR-BⅠ and SR-BⅠ was an independent prognostic factor for patient outcome.Objective1.This study evaluated the different expression of SR-BⅠ and other cholesterol related genes and the association of genes and clinicopathological factors between colon cancer patients and normal cases using bioinformatics.2.To study the expression of SR-BⅠ in colon cancer and the corresponding adjacent non-cancerous tissues using a high-throughput tissue microarray.3.To study explored the association between SR-BⅠ expression and clinicopathological variables and patient outcome to determine whether SR-BⅠexpression was an independent prognostic factor and a potential therapeutic target for colon cancer.Methods1.We got the genes information from The Cancer Genome Altas(TCGA)which contains seventeen sets of transcriptomic data covering cholesterol metabolism and tumor invasion of 245 colon cancer patients and 21 normal cases.The T test was used to analyze the different expression levels of genes between colon cancer patients and normal cases.The one-way ANOVA was employed to analyze the associations between genes expression and clinicopathological factors.2.To evaluate the clinical significance of SR-BⅠ expression and its association with clinicopathological variables,and patient outcome in colon cancer,a well-documented tissue microarray with clinical follow-up data which was purchased from Shanghai Outdo Biotech Co.,Ltd was analyzed by immunohistochemistry.The immunohistochemical staining results were reviewed independently by two pathologists who were blind to the clinicopathological information,patients outcome and histologic origin.As to staining intensity,0 indicated no staining;1 indicated weak staining;2 indicated moderate staining;3 indicated strong staining.As to the percentage of stained cells,0 was for no staining;1 for<10%of cells;2 for 10-50%of cells;3 for 51-80%of cells;4 for>80%of cells.By multiplying the intensity and the percentage,we got a score ranging from 0 to 12.The final results were graded into 2 levels,specimens scoring 0-4 were considered as low expression and specimens scoring 6-12 as high expression.For analysis of the immunohistochemical staining results,Chi-Square test was used to demonstrate the correlations between SR-BⅠ expression and clinicopathological variables.Kaplan-Meier was employed for cumulative survival probabilities.A Cox proportional hazard model was used to express the statistical independence and significance of factors on OS which was reported using 95 percent confidence intervals(95%CI).All results were considered statistically significant at p<0.05.Results1.Five genes were significantly up-regulated SCARB1(P = 0.000),TIMP1(P =0.000),MMP-9(P = 0.000),SREBF1(P = 0.028),FASN(P = 0.000),while 9 genes were down-regulated in colon cancer patients compared with normal cases:CD36(P =0.000),VLDLR(P =0.000),ABCA1(P = 0.000),ACAT1(P =0.000),CAV1(P = 0.001),LXR-a(P = 0.000),SREBF2(P = 0.001),CTSS(P =0.000),HMG-CoR(P = 0.047).2.CD36(P = 0.002),CTSS(P = 0.028),VLDLR(P = 0.02)were strongly associated with the ratio of numbers of positive lymph nodes to the lymph nodes examined.CTSS(P = 0.025),ACATI(P =0.006),MMP-9(P=0.003),HMG-CoAR(P =0.005)were strongly associated with T stage.LDLRP(P = 0.041)and MMP-9(P= 0.047)were associated with pathological stage.Notably,no clinicopathological parameter was connected to SCARB1.3.High and low expression of SR-B I were detected in 51(56.7%)and 39(43.3%)cancer tissues,while in 48(53.3%)and 42(46.7%)adjacent non-tumor tissue samples.In most cases expression of SR-B I in cancer samples were higher than the corresponding adjacent non-tumor tissue samples with a significant statistical value(P = 0.000).4.The immunohistochemical staining results of association between SR-B I expression and clinicopathological characteristics was consistent with the bioinformatics results about SCARB1.High expression of SR-B I in colon cancer tissues had no significant statistical association with sex,age,pTNM stage,tumor size,pathological grade,total lymph nodes,positive lymph nodes,the ratio of numbers of positive lymph nodes to the lymph nodes and AJCC clinical stage.5.Patients with low SR-BI expression in colon cancer tissues had a shorter OS than those with high SR-BI expression(log-rank test P = 0.042).The multivariate analysis confirmed that high SR-BI expression was an independent favorable prognostic factor for OS,with the HR being 0.502(P = 0.039).In addition to SR-BI,ratio of positive nodes was also an independent prognostic factor for OS in colon cancer patients(P = 0.007).Conclusions1.The expression level of SCARB1 is up-regulated in colon cancer patients.2.Expression of SR-B I in colon cancer samples are higher than the corresponding adjacent non-tumor tissue samples.3.Low SR-BI expression is associated with unfavorable prognosis in colon cancer.4.SR-BI is an independent prognostic factor in colon cancer patients.SignificanceLow SR-BI expression independently predicts poor prognosis and could be used as a biomarker to predict malignant features of colon cancer. |
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