| [Background]: Ovarian cancer is one the three major female genital malignant tumor, of which the mortality rate is the first one and sources of malignant epithelium accounts for 85-90%. The effect of combined treatment such as surgery and chemotherapy is satisfied to early period (â… -â…¡period) of ovarian cancer, of which 5-year survival rate up to about 90%. While the ovary is located in the deep pelvics, the majority of patients are late when they are to be treated. A comprehensive treatment such as surgery, chemotherapy, radiotherapyor biological treatment has greatly improved the remission rate of ovarian cancer, but the 5-year survival rate is still hovering at 25% - 30%, and this has become an urgent problems to be solved by gynecologist. Therefore, it is especially important to explore means of early diagnosis of ovarian cancer and the prognosis target.Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a relatively recently discovered member of the EGF growth factor family. It is initially synthesized as a transmembrane protein (proHB-EGF) in human body, which can be cleaved on the cell surface to yield a soluble growth factor(sHB-EGF) and be released in the extracellular environment by matrix metalloproteinases(MMP). Both proHB-EGF and sHB-EGF could be taken as the biological activity of EGF receptor ligand, which can activate tyrosine kinase, induce cell phenotype changes, accelerat rate of cell growth and activation cyclin D promoter through juxtacrine or paracrine / autocrine signal transmission channels. ProHB-EGF can enhance cell-cell and cell-matrix interaction and promote cell growth, while sHB-EGF can weaken cells and cell-matrix interaction, exerts a potent oncogenic potential, promote the vascular growth factor (VEGF) expression and participate in tumor metastasis. It has been demonstrated that HB-EGF can be up-regulated by oncogene and oncogene mutant cells in vitro and in vivo experiments and has been found widely expressed in tumor cells, such as colon cancer, breast cancer, pancreatic cancer, but there are few clinical studies about its expression in ovarian cancer.C-erbB-2 protein is a oncogene encoding glycoprotein with activity and function of amino acid kinase receptor and the epidermal growth factor receptor. There is a small amount of C-erbB-2 protein expression in normal human epithelial tissue concerned with cytothesis. The amplification and overexpression of C-erbB-2 oncogene result in activation of oncogenes, involve cell growth regulation and promote cancer cell growth and proliferation. At present, many researches have shown that the amplification and over-expression of C-erbB-2 oncogene exist in a variety of human malignant tumors. The study of oncogene showed the oncogene expression incidence and intensity of expression in ovarian cancer are higher than benign epithelial ovarian and are closely related to the development of ovarian cancer. Yet there isn't joint detection of C-erbB-2 protein and HB-EGF in ovarian cancer research. We examinaed the expression of proHB-EGF and C-erbB-2 protein in ovarian cancer in order to study whether there is synergistic effect or not. And this may provide experimental basis whether proHB-EGF and C-erbB-2 protein could be ovarian cancer diagnosis and prognosis target. At the same time, we detected sHB-EGF in the serum and ascites of ovarian cancer patients to provide experimental basis whether sHB-EGF could be one of the factors of ovarian cancer detection.[Objective]: To reveal the association and the possible mechanism between HB-EGF , C-erbB-2 protein and progression of disease of ovarian cancer by detecting the expression of proHB-EGF and C-erbB-2 protein in ovarian cancer tissue and the content of sHB-EGF in the serum and ascites of patients with ovarian cancer, in order to provide experimental basis for diagnosis and treatment to ovarian cancer.[Method]: To detect the positive cells number(/104 tumor cells) and mean fluorescence intensity of proHB-EGF and C-erbB-2 protein in ovarian tumor tissue by flow cytometry. To detect the sHB-EGF level in serum and supernatant of ascites of patients with ovarian tumors by ELISA method. The serum CA125 data from the results of our hospital over the same preoperative period.[Results]:1. The comparison of the proHB-EGF positive cell rate and the mean fluorescence intensity in ovarian tumor: The proHB-EGF positive cell rate of ovarian cancer tissue was significantly higher than the groups of borderline ovarian tumors and benign ovarian tumors (P<0.01); the proHB-EGF-positive cell rate of borderline ovarian tumor tissue was significantly higher than that of benign ovarian tumor tissue (P<0.01). Among groups classed according to ovarian cancer clinical pathological characteristics, the proHB-EGF positive cell rate of III-IV ovarian cancer patients was significantly higher than the I-II patients (P<0.05), there were no difference between age groups, different cell differentiation, different histological types and amount of ascites(P>0.05). The mean fluorescence intensity of proHB-EGF in ovarian cancer tissues had no significant correlation with classification of ovarian tumor and clinicopathologic factors(P>0.05).2. The comparison of the C-erbB-2 protein positive cell rate and the mean fluorescence intensity in ovarian tumor: The C-erbB-2 protein positive cell rate of ovarian cancer tissue was significantly higher than the borderline ovarian tumor and benign ovarian tumors (P<0.05); the C-erbB-2 protein positive cell rate of borderline ovarian tumor tissue was not significantly higher than benign ovarian tumor tissue (P>0.05). Among groups classed according to ovarian cancer clinical pathological characteristics, the C-erbB-2 protein positive cell rate of III-IV ovarian cancer patients was significantly higher than the I-II patients(P<0.05), there were no difference between age groups, different cell differentiation, different histological types and amount of ascites(P> 0.05).The mean fluorescence intensity of proHB-EGF in ovarian cancer tissues had no significant correlation with classification of ovarian tumor and clinicopathologic factors(P> 0.05).3. The proHB-EGF and C-erbB-2 protein positive cell rate had a linear correlation in ovarian tumor tissues (Linear regression equation Y? = 2.26+0.88X, correlation coefficient r =0.94). The mean fluorescence intensity of proHB-EGF and C-erbB-2 protein in ovarian tumor was relevant(rs = 0.349, P<0.01).4. The comparison of the sHB-EGF level in the supernatant of ascite of the ovarian tumor patients: The sHB-EGF level in the supernatant of ascites of the ovarian cancer group was significantly higher than that in benign ovarian tumor group(P <0.05). There was no significant difference between ovarian cancer group and chronic pelvic inflammatory disease group(P> 0.05), as well as the ovarian benign tumor and chronic pelvic inflammatory disease group(P> 0.05). The sHB-EGF level in the supernatant of the ascite of ovarian cancer patients whose ascites was above 500ml was significantly higher than that of less than 500ml ascites group(P <0.05). There were no difference between age groups, difference disease stages, different histological types and different pathological types(P>0.05).5. The comparison of the sHB-EGF level in the serum of the ovarian tumor patients: The sHB-EGF level in the serum of the ovarian cancer group was significantly higher than that in normal control group and benign ovarian tumor group(P<0.05). Therewasno significantly difference between normal control group and benign ovarian tumor group(P>0.05). The sHB-EGF level in the serum of borderline ovarian tumor group had no significant difference with other groups(P>0.05). There were no difference between age groups, difference disease stage, different histological types, different pathological types and the amount of ascites(P> 0.05).6. The comparison of levels of sHB-EGF in the supernatant of ascites and serum between groups of ovarian cancer and benign ovarian tumors group patients: The sHB-EGF level in the supernatant of ascite of the ovarian cancer group was significantly higher than that in serum(P <0.05), while the sHB-EGF level in the supernatant of ascite of the benign ovarian tumor group was significantly lower than that in serum(P <0.05).7. The comparison of ovarian cancer diagnostic significance among sHB-EGF in Serum, sHB-EGF in the supernatant of ascites and CA125 in serum: The sensitivity and specificity of CA125 in Serum in the diagnosis of ovarian cancer are as follows: 76%, 83.33%. in Serum are 56% 83.33%, and are 64% and 91.67% in the supernatant of ascites. When the three methods were put together, the diagnosis sensitivity and specificity of ovarian cancer were improved upto 88%, 91.67%.[Conclusion]:1. The expression of proHB-EGF, C-erbB-2 protein in ovarian tumor tissue could be a target to identify benign and malignant ovarian, and be related to the severity of ovarian cancer. That proHB-EGF, C-erbB-2 protein have a coordinate expression in ovarian tumor tissue may play an important role in the development of ovarian cancer and be related to the prognosis of ovarian patients. United detection of them could reflect the ovarian cancer patient's condition more accurately. If both of them become gene therapy treatment goals, it will be significant to individuated oncotherapy.2. The sHB-EGF level in serum and supernatant of ascites of patients with ovarian tumors is significant to identify benign and malignant ovarian tumors. It also can be used as one of the tumor marker of ovarian cancer. To the patients with ascites, that multiindex detecting will be beneficial to improve the rate of preoperative diagnosis of ovarian cancer besides the inspection of exfoliated cells in ascites, especially in cases negative exfoliated cells. Joint monitoring of the sHB-EGF level in serum and supernatant of ascites and CA125 in serum of patients with ovarian cancer will improve diagnostic sensitivity and specificity. sHB-EGF involved in tumor local invasion, metastasis and ascites formation of ovarian cancer and are related to the severity of the pathogenetic condition. It also may play a pivotal role in the progression of ovarian cancer. If sHB-EGF is inhibited effectively, the ovarian cancer patients'pathogenetic condition will be significantly reduced , meanwhile their life quality will be improved. The sHB-EGF content in ascites supernatant may be an effective indicator of chemotherapy.3. Flow cytometry has the advantages of rapid measuring speed and multi-parameter measurement simultaneously. It can not only quantize antigen presentation and avoid the subjective assessment of immunohistochemistry, but also evade the damage of cell antigen caused during the process of immunohistochemistry. So Flow cytometry could be one of the detection methods of ovarian cancer. But we need more experiments on the application of the flow cytometry in tumor diagnosis, prognosis and other aspects.
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