| Background:Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and the second most common cause of cancer mortality, with a male-female ratio of 4-5:1 in high incidence regions, such as China, which alone accounts for 55% of the world's cases. Hepatic resection and liver transplantation are the two main modalities that may cure HCC, but the long-term patient survival is dependent on the stage of tumor at the time of diagnosis. The treatment challenges of HCC include:①Most of HCC patients with a background in hepatitis B and cirrohsis, usually complicate with abnormal hepatic function;②HCC in the olderly are usually occult in onset and prone to intrahepatic and extrahepatic metastasis, and progress rapidly;③Surgical resection rate is less than 20%, and radical resection rate is lower;④The rate of postoperative recurrence is rather high.The one-year survival rate, three-year survival rate and five-year survival rate were 93.5%,70.1% and 59.1% respectively for the early stage HCC patients. and 65.3%,30.5% and 23.5% respectively for the median stage HCC patients. The half-year, one-year survival rate for the advanced stage HCC patients were 52.5% and 14.7% respectively. Longitudinally compared with the situation of past few decades, the prognosis of HCC has been improved greatly, which was due to improvement of diagnostic lever in the early stage, increasing of the overall resection rate and progress of non-operation treatment. However, in horizontal comparison with breast cancer and colorectal cancer, the outcome for patients with HCC still remains dismal. Currently the mechanism underlying the contribution to tumorigenesis and tumor promotion of HCC is not clear precisely, and the patients cannot receive targeted intervention, which causes poor prognosis of HCC. Therefore, futher exploring the molecular mechanisms that modulate the development and progression of HCC is crucial for the design of therapeutic strategies. There are several pivotal steps in the cell signal transduction and angiogenesis of HCC, whose abnormalities lead to the development, progress and metastasis of HCC, which are the theoretical principles of molecular targeted therapy and the potential key targets. In recent years, the research of HCC molecular targeted therapy has been hot spots. Sorafenib is an oral multikinase inhibitor with antiproliferative and antiangiogenic effects. Based on two multicenter phaseⅢ, randomized, double-blind, placebo-controlled clinical trial (SHARP and Oriental) which showed Sorafenib improved survival in patients with advanced (unresectable and metastatic) HCC, Sorafenib was approved to be used as standard treatment regimen in patients with advanced HCC by EMEA, FDA and SFDA at serial.Syndecan-1 is a member of syndecans subfamily which belongs to HSPGs. Syndecan-1 is expressed on the surfaces of many cell types and has been shown to modulate tumor cell proliferation, adhesion, migration and angiogenesis, by interacting with stromal cells, extracellular matrix and bioactive moleculars in tumor microenvironment. Expression of syndecan-1 is often alterd in cancer, and several studies suggest that loss of syndecan-1 expression in carcinomas accompany the malignant phenotype. It has been suggested that the loss of syndecan-1 expression render the tumor cells less adhesive, thereby increasing their potential to metatasize. However, in other cancers, such as pancreatic adenocarcinoma and multiple myeloma, syndecan-1 expression on the cell surface remains high even though these tumors disseminate to sites distal from the primary tumor.The research concerning the correlation between syndecan-1 and HCC has been carried on, mainly including the clinicopathological significance of expression of syndecan-1. The potential mechanism was litter reported. Several research results showed that the loss of syndecan-1 was associated with HCC malignant phenotype, such as poor differentiation, invasion and metastasis. However, the result of another similar research showed that syndecan-1 was highly expressed in poor differentiated HCC. It was contradictory to those of previous studies.Objective:To investigate the expression levers of syndecan-1 in HCC primary tumors, adjacent non-tumor live tissues and intrahepatic metastasis tumors, the clinicopathological significance of syndecan-1 in HCC primary tumors and the relationship between syndecan-1 and tumor metastasis, proliferation and angiogenesis in HCC.Methods:1. In the study, immunohistochemical staining was utilized for determing syndecan-1 expression in HCC primary tumors, adjacent non-tumor live tissues and intrahepatic metastasis tumors, VEGF and CD34-MVD in primary tumors and intrahepatic metastasis tumors, and Ki-67 in primary tumors.(1) Compare the differences of the expression levels of syndecan-1 in HCC primary tumors, adjacent non-tumor live tissues and intrahepatic metastasis tumors;(2) Analysis the correlations between syndecan-1 expression in HCC primary tumors and gender, age, clinical stage, tumor size, differentiation, serum AFP level, Child-Pugh grade, presence of cirrhosis and thrombosis;(3) Analysis the correlation between syndecan-1 expression and Ki-67 index in HCC primary tumors;(4) Compare the differences of VEGF expression and CD34-MVD in HCC primary tumors and intrahepatic metastasis tumors;(5) Analysis the correlations between syndecan-1 expression and VEGF expression and CD34-MVD in HCC primary tumors;(6) Analysis the correlations between syndecan-1 expression and VEGF expression and CD34-MVD in HCC intrahepatic metastasis tumors.2. Statistical methods:All statistical analyses were performed using SPSS program package 13.0. Differences were considered as significant when the P value was less than 0.05. Comparison among groups of the rank material was evaluated with the Kruska-Wallis's test, and the measurement material with the independent-samples t test; The clinicopathological significance of syndecan-1 expression in HCC primary tumors was estimated with the generalized Wilcoxon's test (or the Kruska-Wallis's test, where appropriate). The relationship between syndecan-1 expression and VEGF, CD34-MVD and Ki-67 index uses the Spearman correlation analysis.Results:1. Compared with adjacent non-tumor live tissues, syndecan-1 expression in HCC primary tumors were significantly enhanced. On contrast, syndecan-1 expression were significantly reduced in intrahepatic metastasis tumors.The cases of high, middle, low and no syndecan-1 expression in HCC primary tumors were 9,15,4 and 2 respectively. The cases of high, middle, low and no syndecan-1 expression in adjacent non-tumor live tissues were 1,15,14 and 0 respectively. The cases of high, middle, low and no syndecan-1 expression in intrahepatic metastasis tumors were 0,6,17 and 7 respectively. The difference of syndecan-1 expression among three groups was statistically significant (χ2=25.62, P<0.001).2. Syndecan-1 expression in primary tumors was not associated with HCC clinical stage, tumor size, differentiation, serum AFP level, Child-Pugh grade, presence of cirrhosis and thrombosis.Syndecan-1 expression in HCC primary tumors was not associated with HCC clinical stage (P=0.143), tumor size (P=0.980), differentiation (P=0.102), serum AFP level (P=0.432), Child-Pugh grade (P=0.822), presence of cirrhosis and thrombosis (P=0.573 and 0.137, respectively)3. Syndecan-1 expression was positively correlated with the Ki-67 index in HCC primary tumors.The Ki-67 index were 22.8±20.2%,21.6±21.5%,4.8±8.7% and 0.3±0.4% respectively in HCC patients with high, middle, low and no syndecan-1 expression in primary tumors. Syndecan-1 expression was positively associated with Ki-67 index (r= 0.386, P=0.035).4.The VEGF expression and CD34-MVD between HCC primary tumors and intrahepatic metastasis tumors was not different significantly.The cases of high, middle, low VEGF expression were 15,10,9 in HCC primary tumors respectively, and 13,15,2 in intrahepatic metastasis tumors respectively, there was no statistical significance between two groups (W=912.5, P=0.968)CD34-MVD were 308.3±150.0/mm2 and 329.1±155.4/mm2 in HCC primary tumors and intrahepatic metastasis tumors respectively, there was no statistical significance between two groups (t=-0.528, P=0.600). 5. In HCC primary tumors, syndecan-1 expression was not associated with the expression of VEGF; Even though there was no statistical significance, a tendency of positive correlation was found between syndecan-1 expression and CD34-MVD.Syndecan-1 expression was not associated with the expression of VEGF in HCC primary tumors (r= 0.319, P=0.086). There was no statistical significance but a positive correlation tendency between syndecan-1 expression and CD34-MVD in primary tumors (r= 0.200, P=0.290). CD34-MVD were 329.3±140.2/mm2, 319.7±176.0/mm2,206.3±66.0/mm2 and 331.9±8.9/mm2 respectively in HCC patients with high, middle, low and no syndecan-1 expression.6. In HCC intrahepatic metastasis tumors, syndecan-1 expression was not associated with the expression of VEGF; Syndecan-1 expression was positively correlated with CD34-MVD.Syndecan-1 expression was not associated with the expression of VEGF in intrahepatic metastasis tumors (r=0.124, P=0.513). Syndecan-1 expression was positively correlated with CD34-MVD in intrahepatic metastasis tumors (r= 0.370, P=0.044). CD34-MVD were 425.3±121.5/mm2,326.2±170.7/mm2 and 253.7±103.6/ mm2 respectively in HCC patients with middle, low and no syndecan-1 expression.Conclusions:1. Syndecan-1 expression in HCC intrahepatic metastasis tumors was significantly lower than primary tumors and adjacent non-tumor live tissues. It was suggested that the loss of syndecan-1 expression was associated with HCC metastasis. One possibility was that syndecan-1 function in both cell-cell and cell-extracellular matrix adhesion, and the tumor cells that lost syndecan-1 gain freedom (lost their attachment in matrix) and enable to go to circulation and home in distal sites.2. Syndecan-1 expression was positively associated with cell proliferation. Syndecan-1 may bind growth factors, decisively regulate growth factor signaling and stimulate tumor cell proliferation.3. Syndecan-1 expression was positively correlated with CD34-MVD, suggesting that as co-receptors, syndecan-1 may stimulate angiogenic factor receptor tyrosine kinase activity.4. Syndecan-1 on tumor cells surface may promote tumor growth and angiogenesis as co-receptors of many growth factors, but at same time syndecan-1 sticks tumor cells on matrix. Tumor cells need to reduce syndecan-1 on their surface (e.g., by shedding syndecan-1 to the matrix) to be able to gain freedom and perform metastasis. Once tumor cells arrive in metastatic site, they produce surface syndecan-1 again to support the growth and angiogenesis of the tumors. Syndecan-1 may affect tumor metastasis, proliferation and angiogenesis, suggesting that syndecan-1 play a special role in the progress of HCC and may provide new ideas for treatment strategies for HCC. |
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