| Background:Colorectal cancer is one of the malignant tumor with the highest incidenceamong the worldwide. As the growth in living standards, the changes of dietarypatterns and environmental deterioration, the incidence of colorectal cancer in Chinais rising. Epidemiology data shows that our country has become high risk areas forcolorectal cancer. And the incidence of colorectal cancer is40/100000, which isclose to the level of western developed country, by incidence rank from sixth up tosecond bits. However, the mechanism of tumorigenesis is still unclear. For themoment, there is no effective treatment for the disease.Hedgehog (Hh) signaling pathway plays an important role in embryonicdevelopment, the mature organ formation and maintenance. Recently studies showsthat abnormal activation of Hedgehog signaling pathway was found in many digestivesystem malignant tumors, for example, gastric cancer,, and pancreatic cancer, etc.Therefore, investigation of the role of Hh signaling in colorectal cancer and searchnew targets for diagnosis and therapy of colorectal cancer has great theoretical andpractical significance.Objectives:1. To determine the expression level of SuFu (a negative regulatory factor ofHedgehog signaling pathway) and Gli1(downstream regulatory factor) in humancolorectal carcinogenesis process.2. To analyse the relationship between the expression level of SuFu andGli1and clinical pathological parameters (histological type, tumor stage,invasion depth and so on).3. To investigate the relationship between SuFu and Gli1and overall survivaland disease-free survival rate in colorectal cancer.4. To explore the clinical value of SuFu and Gli1in prediciton of progress ofcolorectal cancer. Methods:1. The selection of clinical specimensThe total374cases of specimen were from gastrointestinal endoscope biopsy orsurgical operation in the first hospital of Nanchang during January2007to January2011. Among the374cases, there were98normal colorectal cases,99cases ofcolorectal adenoma and177colorectal cancer cases. The clinical specimen requestpatients with non history of cancer, non ulcerative colitis, Ron disease, tumor andother diseases whose age over18years old in healthy adult. Before taken thespecimen, we told the patient full information about the use of specimen, andobtained patient consent. At the same time, we noted age, sex, name, contactinformation, pathological diagnosis, pathology, tumor site, tumor stage, depth oftumor invasion, operation time, primary or recurrent. Then we follwed up the patientswho were under surgical removal of colorectal cancer in the first hospital ofNanchang University during January2007to June2009. All patients under surgicalremoval of colorectal cancer are without associated radiotherapy, chemotherapy andimmunotherapy, and preoperative imaging and intra-operative exploration were notsuggestive of tumor metastasis. Postoperative colorectal cancer specimens wereconfirm as colorectal cancer by pathology department of Nanchang University, noncancer tissue were seen in margin. Exclusion criteria: At the same time or alwayshistory of malignancy, ulcerative colitis, Ron disease, familial adenomatous polyposis,multiple primary colon cancer patients.2. Detection of the key components of Hedgehog pathwayConfirmed the pathological diagnosis again in374cases by using HE staining.Each group specimens were fixed, dehydrated, paraffined. We detected SuFu andGli1protein (critical components of Hedgehog signaling pathway) by using two stepsimmunohistochemistry; then observed the relationship between the expression changeof the key protein in Hedgehog signaling pathway and the clinicopathologicalparamenters by using Mann-Whitney U test, Kruskal-Wallis H Spearman rankcorrelation inspection, analysis and inspection, Kaplan-Meier survival analysis,statistical analysis.3. Patients with colon cancer follow-up We retrospectively analyzed the177cases, obtain the patients who werecolorectal cancer medical records date and pathological data (name, age, gender,medical record number, pathology, operation time, pathological types, pathologicalstaging, postoperative chemotherapy and cycle) from medical records room. Registethe corresponding outcom in patients undergoing follow-up by telephone follow-up,mail follow-up, outpatient reexaminaton and so on. The follow-up time form operat-ion data.Results:1. SuFu in normal colorectal mucosa, adenoma, colorectal cancer and its clinicalsignificance(1). From normal colorectal mucosa to colorectal carcinogenesis, expression ofSuFu (a negative regulation protien of Hedgehog signaling pathway) decreasedgradually, even disappear in some colorectal cancer. Positive expression rate of SuFuprotein in normal colorectal mucosa, adenoma, colorectal cancer were100%,96.9%,41.2%, respectively. And the expression of SuFu protein in colorectal carcinoma wassignificantly lower than in normal colorectal mucosa and colorectal adenoma group,the difference was statistically significant (p <0.05);(2). The expression of SuFu protein with patients sex ratio, age, histological typeof tumor and the degree of tumor differentiation were not significantly related (p <0.05);(3). SuFu protein expression was related with tumor site, and one rectal SuFuprotein expression was significantly lower than the other groups (p <0.05);(4). SuFu protein expression was related with tumor TNM stage. SuFu proteinexpression rate in patients with advanced colorectal cancer was significantly lower inpatients with early stage of colorectal cancer (p <0.05);(5). SuFu protein expression was related with tumor invasion depth, SuFuexpression in the tumor which invasion to serosa outside was significantly lower thanthe other groups (p <0.05).2. Gli1in normal colorectal mucosa, adenoma, colorectal cancer and its clinicalsignificance (1). From normal colorectal mucosa to colorectal carcinogenesis, the expressionof Hedgehog signaling pathway downstream regulation protien Gli1gradually rising.Positive expression rate of Gli1protein in normal colorectal mucosa, adenoma,colorectal cancer were34.69%,69.38%,74.01%, respectively. And Gli1proteinexpression in normal colorectal mucosa and colorectal adenoma group has obviousdifferences. The expression of Gli1in colorectal adenoma was significantly higherthan that in normal group (p <0.05), but Gli1expression in colorectal adenoma andin colorectal carcinoma group showed no statistically significant difference (p>0.05);(2). The expression of Gli1protein with patients sex ratio, age, histological typeof tumor, the degree of tumor differentiation, tumor site, tumor TNM stage were notsignificantly related (p <0.05);(3). Gli1protein expression was related with tumor invasion depth, SuFuexpression in the tumor which invasion to the muscle layer was significantly lowerthan the other groups (p <0.05).3. Correlation analysis of SuFu and Gli1protein expression in colorectal cancerand precancerous lesionsThe results showed that from normal colorectal mucosa to colorectal tumor, Gli1expression showed a trend of increase gradually, SuFu expression decreasedgradually, Gli1and SuFu expression showed significant negative correlation (R=-0.240, p <0.01).4. follow-upOverall survival and disease-free survival of patients were related to theexpression of SuFu and Gli1protein in Hedgehog signaling pathway. The patientswho negative expression of SuFu protein had poor overall survival and disease-freesurvival.The overall survival and disease-free survival in patients who negative expression ofSuFu protein were significantly lower than positive expression(p <0.05); The overallsurvival and disease-free survival in patients who positive expression of Gli1protein weresignificantly lower than negative expression(p <0.05).Conclusion: 1. Aberrant activation of Hedgehog signaling involved in the carcinogenesis ofcolorectal cancer;2. Colorectal tumor site, tumor TNM stage, depth of tumor invasion is possiblerelated with aberrant activation of Hedgehog signaling pathway;3. The overall survival and disease-free survival is possible related with aberrantactivation of Hedgehog signaling pathway. |
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