Expression Of Midkine And Heparanase In Esophageal Squamous Carcinoma And Its Significance

Background and objectiveThe malignant tumor is one of the heavy diseases that seriously threaten mankind's health. Nearly years, in China or in the world, the malignant tumor presents up-trend. According to the WHO expert's prediction, the tumor will become the first cutthroat for mankind in 21 century. The research expresses that the process of occurrence, development, and differentiation of malignant tumor experiences many steps from atypical hyperplasia tissues to carcinoma in situ and infiltration carcinoma, there are many changes on the level of molecule, including growth factor/receptor gene etc, and its expression has become an important reason of cancerization. It is very urgent that looks for a kind of new tumor marker and clarifies the relation between the tumor marker and biological characteristic of malignant tumor and provides theory foundation for early diagnoses and therapy of malignant tumor.In rencent years, many varieties of genes have cloned that is relative to occurring, development, infiltration, metastasis of tumor one after another, among these, Midkine(MK)is a newly founded heparin-binging growth factor that was origionally discovered as the product of a retinoic acid-responsive gene during the differentiation of embryonal carcinoma cells. But it was distinct from other heparin-binding growth factor. Compared with normal tissues it was over expressed in many types of human carcinomas such as breast, gastric, lung, liver, ovary, urinary, colon carcinomas,neuroblastomas and willms' tumors. Over-expression was also detected in premalignant stages and early stages in human carcinoma. Many research confirmed that Midkine was related to tumor growth, differentiation, angiogenesis, infiltration, metastasis and prognosis.To achieve their infiltration and metastasis, the cancer cells must break through a tissue barrier which is consist of basement membrane (BM) and extracellular matrix (ECM). Heparan sulfate (HS) is biological macromolecules of extracellular matrix (ECM) and cell surface. It is a main element of basement membrane (BM). Heparanase is a kind of endoglycosidase, it can degrade the glycosidic bond between the side-line of heparan sulfate and core protein, damage the ECM and BM directly.Recently studies show that heparanase (Hpa) can not only specifically degrades heparin sulfate proteoglycan (HSPG), the main constituent of the barrier, but also synergize many factors to directly or indirectly enhance tumor infiltration and metastasis via multiple methods. Thus recently it has become a hot research area for the mechanism and solution of cancer metastasis.China has the first morbidity and mortality of eophageal carcinoma in the world, Morbidity and mortality of eophageal carcinoma of Henan province are both the first, the most cases that caused the death of esophageal carcinoma are its infiltration and metastasis. So exploring the mechanism of the occurrence, development, infiltration and metastasis of esophageal carcinoma has become a focus. To date, in despite of there have been a lot of reports about the relationship between the midkine or heparanase and the occurence, development, infiltration and metastasis of tumor, there was rarely fewer report about the relationship between the midkine and heparanase and infiltration and metastasis of esophageal carcinoma. In order to explore farther relation between the expression of midkine and heparanase and the infiltration and metastasis of esophageal carcinoma, to find the early defective markers of infiltration and metastasis of esophageal carcinoma and to research the useful ways to repress the infiltration and metastasis of esophageal carcinoma and extend survival time of esophageal carcinoma patients,cut down mortality rate. Our research adopts immunohistochemistry sp method, observing the expressions of midkine and heparanase protein in esophageal carcinoma tissues of 49 cases,adjacent atypical hyperplasia tissues of 20 cases and normal mucosa tissues of 49cases, Detecting unitedly illuminates furtherly the mechanisms of infiltration and metastasis of esophageal carcinoma and provides theory foundation for blocking infiltration and metastasis of esophageal carcinoma.Methods1. Using the technology of immunohistochemistry SP to detect the expression of midkine and heparanase in the 49 cases of esophageal squamous cell carcinoma, 20 cases of atypical hyperplasia tissues of tumor-adjacent and 49 cases of normal mucosa of esophageal carcinoma respectively.2. Statistical analysis: All the dates were analyzed by SPSS 11.0 statistical package, the count information calculated the positive rate, The comparison of positive rates uses the Chi-square or Fisher's exact test; The relation of two variable are analyzed by the spearman level correlation analysis.The level of significant difference isα=0.05.Results1. Immunohistochemical results indicated: the positive expression rate of midkine protein in normal mucosa of esophagus is 0.00%(0/49); The positive expression rate of midkine protein in atypical hyperplasia tissues is 50.00% (10/20); The positive expression rate of midkine protein in the carcinoma tissues is 79.59%(39/49), the positive expression rate of midkine protein in the carcinoma tissues is compared with that in the atypical hyperplasia tissues and normal mucosa tissues from each other, There is statistical significance( P <0.05).2. Immunohistochemical results indicated: The positive expression rate of heparanase protein in normal mucosa of esophagus is 0.00%(0/49). The positive expression rate of heparanase protein in atypical hyperplasia tissues is 55.00%(11/20) ; The positive expression rate of heparanase protein in the carcinoma tissues is 65.31%(32/49), the positive expression rate of heparanase protein in the carcinoma tissues is compared with that in the atypical hyperplasia tissues, there is no significant difference (P>0.05).3. In the 21 cases of metastatic group, the positive rates of expression of midkine protein in the tumor tissues are 95.24 %( 20/21); in the 28 cases of non-metastatic group, they are 67.86% (19/28). There is significant difference between the two groups (P<0.05).4. In the 21 cases of metastatic group, the positive rates of expression of heparanase protein in the tumor tissues are 100 %( 21/21); in the 28 cases of non-metastatic group, they are 39.29% (11/28). There is significant difference between the two groups (P<0.05).5. In the tissues of esophageal squamous cell carcinoma, the positive rate of expression of midkine protein in the no infiltration,low-muscle infiltrated,deep-muscle infiltrated and outer lay infiltrated is 40% (2/5),57.14% (4/7),77.78 % (14/18) and 100 % (19/19) respectively. The expression of midkine protein in the carcinoma tissues with the outer lay infiltrated is higher than that in the tissue with no infiltration,low-muscle infiltrated and deep-muscle infiltrated. There was significant difference among the groups. (P<0.05). Thus the expression of midkine protein in the carcinoma tissues with deep-muscle infiltrated is compared with that with low-muscle infiltrated, there is no significant difference (P>0.05).6. In the tissues of esophageal squamous cell carcinoma, the positive radio of expression of heparanas protein in the no infiltration,low-muscle infiltrated,deep-muscle infiltrated and outer lay infiltrated is 20% (1/5),42.86% (3/7),50.00 % (9/18) and 100 % (19/19) respectively. The expression of heparanas protein in the carcinoma tissues with the outer lay infiltrated is higher than that in the tissue with no infiltration,low-muscle infiltrated and deep-muscle infiltrated. There was significant difference among the groups. (P<0.05). Thus the expression of heparanas protein in the carcinoma tissues with deep-muscle infiltrated is compared with that with low-muscle infiltrated, there is no significant difference (P>0.05).7. The relativity of the expression of midkine and heparanas was analysized by statistics, Results showed that the both are positive correlation.Conclusions1. The positive rates of the expression of midkine protein in squamous carcinoma tissues of esophagus, atypical hyperplasia tissues of the tumor-adjacent and normal mucosa tissues were depressed in turn; the comparison of the three groups has statistical signicance. It indicaed that midkine participated in occurrence and development of squamous carcinoma of esophagus.2. There was no expression of heparanase protein in normal esophagus mucosa tissues. There was no statistical significance between the expression of heparanase protein in esophageal squamous cell carcinoma tissues and that in atypical hyperplasia tissues of the tumour-adjacent. It prompted that there was no correlation between the expression of the heparanase protein and angiogenesis, progression of esophageal squamous cell carcinoma.3. The positive rates of the expression of midkine and heparanas protein in carcinomas tissues were increased gradually accompany with the infiltration depth increasing , and the positive rates which infiltrate outer lay were higher than that infiltrate low-muscle lay and deep-muscle lay and no infiltration; the expression of midkine and heparanas in esophageal squamous cell carcinoma tissues with lymphnode metastasis were higher than that without lymphnode metastasis, It indicated that there was correlation between the expression of midkine and heparanas protein and infiltration and lymphnode metastasis of esophageal squamous cell carcinoma.4. The relativity of the expression of midkine and heparanas protein was analysized by statistics, Results showed relative and they played synergistic effect during the process of occurrence, development, infiltration and metastasis of squamous carcinoma of esophagus.