Expression Of COX-2 And E-cadherin In Hepatocellular Carcinoma And Its Clinical Significance

Backgrounds and ObjectivePrimary hepatocellular carcinoma (PHC) is one of the most common malignant tumors in our country, in which hepatocellular carcinoma(HCC) accounts for even more than 90%. HCC has a high incidence rate and its development is rather hiding, for lack of cilinical sympotoms in the early period, once detected, most of the cases turn out to be terminal, which leads to a high death rate. The development of HCC is of many steps and pHases with lots of factors participanting in, which leads to the complexity of its mechanism. cyclooxygenase is a rate-limiting enzyme in ptostaglandin synthesis, including COX-1 and COX-2. COX-2 is inducible, called "rapid response genes", which can not be detected in most organizations in normal pHysiological conditions. But when cells are stimulated by appropriate cytokines, endotoxin, tumor promoting agents and oncogenes, the expression of COX-2 can be induced. It has been reported that COX-2 is highly expressed in a variety of malignant tumors(hepatocellular carcinoma, pancreatic cancer, lung cancer,colon cancer,etc), and the expression of COX-2 is related to development, invasion and metastasis through a variety of methanisms and to various pHysiological and pathological processes, including acute and chronic inflammation, pain, and tumor. Epithelial cadherin is a class of intracellular Ca2+-dependent transmembrane glycoprotein adhesion molecules, and form complexes with the cytoplasm ofβ-catenin, which maintains cell adhesion stability and cell polarity. Such comlexes mainly take part in the intracellular adhesion. Previous studies have shown that decrease of E-cadherin expressions in malignant tumors can cause the reducing of intracellular adhesion, which may easily lead to its falling off the primary tumor and cause the invasion and metastasis of the tumors. The expressions of COX-2 and E-cadherin were reported in non-small cell cancer, stomach cancer, colon cancer and other malignant tumors. COX-2 expression was high, while E-cadherin expression was low, and they were negatively correlated. However there is few reports on liver cancer. By observing the expression of COX-2 and E-cadherin in the tissue of HCC, adjacent normal tissue, normal liver tissue specimens and their correlation with alinicopathological features of HCC, we can know about the developing machanism of the two kinds of expressions and their correlation in HCC.Materials and Methods64 surgically resected HCC tissues were collected. Among them male 38, female 26; aged 14-74 years, with an average age of (47±9); well-differentiated 20,moderate 25,poorly-differentiated 19; and the liver cancer was divided into three pHases by tumor size; metastasis and liver function classification according to 2001 National Conference of liver cancer:Ⅰof 19 cases;Ⅱof 26 cases; III of 19 cases; tumor diameter< 3cm 25 cases,≥3cm 39cases; AFP lever≥20 ng/ml 47 cases,<20 ng/ml 17 cases. All the patients had no chemotherapy and immunotherapy. Then took pathology -confirmed 20 adjacentl tissue specimens as comparison which was whose gender and age composition has no evident difference in the above -mentioned organizations, and took another 9 surrounding normal hepatic hemangioma tissue in the same period as comparison. All the tissues were fixed in 10% neutral formalin and embedded in paraffin. The expressions of COX-2 and E-cadherin were detected by the S-P two-way immunohistochemistry technique in HCC tissue and adjacent normal tissue, and the relationship of these results was analyzed. The data was analyzed by statistical software SPSS 16.0.x2 test and Fisher exact test were used to analyzed the differences of COX-2 and E-cadherin expressions in the tissue of HCC, adjacent normal tissue and normal liver tissue, and Spearman Correlation Analysis was used to examine the correlation of the COX-2 and E-cadherin expressions in HCC tissue. a=0.05 was considered as the level of tests. Results1. The correlation between the expression of COX-2 and the clinicopathological features of patients with HCCThe COX-2 positive staining was mainly located in the cytoplasm of HCC cells, taking on diffuse distribution. The COX-2 positive expression rates in the tissue of HCC, adjacent normal tissue and normal liver tissue were respectively 75.0%, 40.0%,0.0%. The COX-2 positive expression rates in HCC tissue was evidently higher than that in adjacent normal tissue (X2=8.400, P=0.004), and the adjacent normal tissue was higher than normal liver tissue (Fisher exact test, P=0.033), and there was evident difference among the three results (X2=22.873, P<0.001). The COX-2 positive expression rates in well-differentiated, moderately differentiated and poorly differentiated tissue in HCC were respectively 95.0%,72.0%,68.4%, and the rate in well-differentiated tissue was evidently higher than that in moderately differentiated (X2=4.021, P=0.045) and poorly differentiated tissue (X2=4.674, P=0.031), but there was no difference among the three results (X2=5.625,P=0.060). The positive rates of COX-2 in clinical stageⅠ,ⅡandⅢwere respectively 52.6%,76.9%,94.7%, and there was no evident difference among the three results(X2=9.069, P=0.011). The expression of COX-2 in the tissue of HCC had no correlated relationship with the age, sex, the diameter of the tumor and AFP content (P>0.05).2. The correlation between the expression of E-cadherin and the clinicopathological features of patients with HCCThe E-cadherin positive staining was mainly located in the cytoplasm of HCC cells, taking on diffuse distribution. The E-cadherin positive expression rates in the tissue of HCC, adjacent normal tissue and normal liver tissue were respectively 51.6%,80.0%,88.9%, and there was significantly different among the three results (X2=8.393, P=0.015).The E-cadherin positive expression rates in well-differentiated, moderately differentiated and poorly differentiated tissue in HCC were 75.0%, 48.0%,31.6%, and the difference was significant statistically(X2=7.564, P=0.023). The positive rates of E-cadherin in clinical stageⅠ,Ⅱand III were 73.7%,50.0%,31.6%,and there was evident difference among them (X2=6.786, P=0.034). The expression of E-cadherin in the tissue of HCC had no correlated relationship with the age, sex, the diameter of the tumor and AFP content (P> 0.05)3. The correlation-ship between COX-2 and E-cadherin in HCC tissueCOX-2 expression was negatively correlated with the expression of E-cadherin in HCC tissue, X2=7.528, r=-0.343, P=0.006.Conclusions1.COX-2 was highly expressed in HCC, which was gradually increasing with clinical stage, suggesting that COX-2 was likely to participate in the invasion and metastasis of HCC.2. E-cadherin was low expressed in HCC, which was gradually decreasing with tumor malignancy and clinical stage, suggesting that E-cadherin may play a role in inhibiting the process of tumor malignancy.3. Some researchs showed that COX-2 expression was negatively correlated with the expression of E-cadherin in HCC tissue, suggesting that the two markers may help to judge and predict the invasive and metastasis of HCC.