| Background: Ovarian malignant tumor has high mortality and poor prognosis, which is a serious threat to women's life and health. Epithelial malignant tumors accounted for 85%~90%. The serous ovarian cancer is one of the most common malignant epithelial ovarian tumor, prognosis and clinical stage, pathological type, cell differentiation, tumor size and tumor cell sensitivity to the residual cancer after operation for the chemotherapy of ovarian cancer. Theory of the pathogenesis of epithelial ovarian cancerdualism, has been widely accepted and recognized, according to the theory of dualism, the serous ovarian cancer is divided into the differentiation degree of I type and II type. The degree of differentiation of type I ovarian carcinoma s high, and the degree of malignancy is low. It is mainly derived from the ovarian borderline tumors and the endometriosis, common mirror Benignborderline- cancer transition, Mainly include: low grade serous carcinoma, low grade endometrial carcinoma, clear cell carcinoma and mucinous carcinoma. Type II epithelial ovarian cancer, low degree of differentiation, a high degree of malignancy, multi-source in the fallopian tube epithelium, easy to early metastasis, mainly including: high-grade serous carcinomas, previously reported poorly differentiated endometrioid carcinoma, undifferentiated carcinoma and sarcomatoid carcinoma and so on. Early diagnosis of ovarian cancer is critical to its prognosis, so it is the most important task for the treatment of ovarian cancer to find a specific diagnostic index or an effective treatment plan. Transcription factor is a kind of protein molecules with special structure, which can drive the function of gene expression. SP1/Kr(?)ppel like transcription factor(Sp1-like and Kr(?)ppel-like transcription factors, SP1/KLFs) participated in cell proliferation and differentiation. SP1 is a transcription factor that first cloned in the Sp/KLF family, it is widely expressed in mammalian cells. There has a lot of current research on the SP1, SP1 has been known as a cancer promoting proteins, but its role during the development of cancer is not very clear, its expression in serous ovarian cancer remains to be further studied. Kr(?)pple like zinc finger transcription factor(Kr(?)ppel-like transcription factors, KLFs) is a subfamily of SPl/Kruppel like transcription factor family. KLFs has different affinity to the GT box of different gene promoter. Therefore, KLFs is not only used as a transcriptional activator in different tissues, but also can be used as a transcriptional inhibitors. KLFs plays an important role in cell proliferation, differentiation and apoptosis. KLF4 is widely expressed in human tissues, in the end of the zinc finger C- is highly homologous to SP1, studies have confirmed the expression of KLF4 and Sp1 in pancreatic cancer and gastric cancer was negatively correlated, but in the majority of tumor cells KLF4 as tumor suppressor genes, such as cervical cancer, hepatocellular carcinoma, skin cancer, and so on, however in breast cancer and oral cancer it as the cancer gene, but its role in ovarian cancer is unclear. P21 is the transcription product of P53 gene of downstream target genes, is the first to be found in the family of CDKIs(cyclin dependent kinase inhibitor). The low expression of P21 is closely related to the occurrence of many tumors. SP1 is a must for P21 transcription, the regulation of SP1 on P21 is likely to related to c-myc, so as to promote cell proliferation. At present about the role of P21 in ovarian cancer is not very clear, studies have shown that its role as a tumor suppressor gene. In this paper, we mainly studied the expression of the three in different levels of serous ovarian cancer, further research in ovarian serous carcinoma dualism theory, looking for ovarian cancer diagnosis and prognosis evaluation index, to provide a better theoretical basis for early diagnosis and treatment of ovarian cancer, to improve the different levels of ovarian cancer patients survival rate.Objective: Study the expression of SP1, KLF4 and P21 in high grade ovarian serous adenocarcinoma, low grade serous adenocarcinoma, normal fallopian tubes and normal ovarian tissues. Analysis the relationship of the expression of SP1, KLF4 and P21 with the pathological grade, surgical pathologic staging and prognosis of ovarian cancer. Analysis of the correlation between SP1 and KLF4, P21, and further explore the role of SP1, KLF4 and P21 in the occurrence and development of ovarian serous adenocarcinoma.Research methods: Collect the clinical data that from January 2006 to January 2011 of surgical treatment of Obstetrics and Gynecology of the second hospital of Hebei Medical University were complete, the pathological confirmed ovarian serous adenocarcinoma specimens in 65 cases, 42 cases of high level, low level in 23 cases, and the other to take the normal tubal tissue 15 cases, normal ovarian tissue 11 cases as control. According to the dualism, low grade adenocarcinoma with normal ovaries as control, advanced adenocarcinoma originated from the fallopian tube, select the fallopian tube epithelium as control. Using Immune Histochemistry(S-P method) was used to detect ovarian different levels of serous carcinoma in SP1, KLF4 and p21 protein expression. The experimental procedure was strictly in accordance with the immunohistochemical(S-P method) test kit operation steps, positive control to select the known positive pathological sections, phosphate buffer(PBS) instead of one anti as negative control. 44 cases of ovarian serous adenocarcinoma patients with complete follow-up records were followed up, including 13 cases of low-grade serous adenocarcinoma, 31 cases of high-grade serous adenocarcinoma. Using statistical analysis to calculate the 3 and 5 year survival rate, analysis the relationship of SP1, KLF4, P21 protein expression and surgical pathologic staging, pathological grading, postoperative chemotherapy, postoperative residual tumor size and prognosis of patients. Statistical analysis using SPSS13.0 statistical software, count data using x2 test or Fisher's exact probability test, SP1, KLF4 and p21 three indicators between the correlation analysis using Spearman rank correlation. The results to P < 0.05 for had significant difference.Result: 1 The expression of SP1, KLF4 and P21 protein in ovarian low grade serous adenocarcinoma 1.1 The expression results of SP1 protein The positive rates of SP1 protein expression in the normal ovarian tissues and low grade serous adenocarcinoma were 9.1% and 65.2%, Statistical results showed that the positive rate of SP1 protein expression was significantly higher in the low grade adenocarcinoma group than in the normal ovarian group, and there was significant difference between the two groups(P<0.05). 1.2 The expression results of KLF4 protein The positive rates of KLF4 protein expression in the normal ovarian tissues and low grade serous adenocarcinoma were 72.7% and 34.8%, Statistical results showed that the positive rate of KLF4 protein expression was significantly lower than that in the normal ovarian group, and there was significant difference between the two groups(P<0.05). 1.3 The expression results of P21 protein The positive rates of P21 protein expression in the normal ovarian tissues and low grade serous adenocarcinoma were 72.7% and 26.1%. Statistical results showed that the positive rate of P21 protein expression was significantly lower than that in the normal ovarian group, and there was significant difference between the two groups(P<0.05). 2 The expression of SP1, KLF4 and P21 protein in ovarian high-grade serous carcinomas 2.1 The expression results of SP1 protein In normal fallopian tube tissue and ovarian high-grade serous carcinomas, the strong positive expression rates of SP1 were 6.7% and 73.8%. Statistical results show that: high-grade prostate cancer group Sp1 protein expression and the strong positive rate was significantly higher than that in normal fallopian tube group, in comparison with a significant difference(P < 0.05). 2.2 The expression results of KLF4 protein In normal fallopian tube tissue and ovarian high-grade serous carcinoma, the strong positive expression rates of KLF4 were 86.7% and 16.7%. Statistical results show that: high-grade prostate cancer group KLF4 protein expression and the strong positive rate was significantly lower than that of normal fallopian tube group, in comparison with a significant difference(P < 0.05). 2.3 The expression results of P21 protein In normal fallopian tube tissue and ovarian high-grade serous carcinoma, the strong positive expression rates of P21 were 66.7% and 11.9%. Statistical results show that: high-grade prostate cancer group P21 protein expression and the strong positive rate was significantly lower than that of normal fallopian tube group, in comparison with a significant difference(P < 0.05). 3 Comparison of SP1, KLF4 and P21 protein expression in serous adenocarcinoma of the ovary at different levels 3.1 The expression of SP1 protein in different levels of ovarian serous adenocarcinoma The strong positive expression rates of SP1 protein were 65.2% and 73.8% in low-grade adenocarcinoma and high-grade adenocarcinoma. Statistical analysis showed that there was no significant difference in the positive expression rate of SP1 protein between the low-grade and high-grade groups.(P > 0.05). 3.2 The expression of KLF4 protein of different levels of ovarian serous adenocarcinoma The strong positive expression rates of KLF4 protein were 34.8% and 16.7% in low-grade adenocarcinoma and high-grade adenocarcinoma. Statistical analysis showed that there was no significant difference in the positive expression rate of KLF4 protein between the low-grade and high-grade groups(P > 0.05). 3.3 The expression of P21 protein of different levels of ovarian serous adenocarcinoma The strong positive expression rates of P21 protein were 26.1% and 11.9% in low-grade adenocarcinoma and high-grade adenocarcinoma. Statistical analysis showed that there was no significant difference in the positive expression rate of P21 protein between the low-grade and high-grade groups(P > 0.05). 4 The expression of SP1, KLF4 and P21 protein and the prognosis of patients with different levels of ovarian serous adenocarcinoma 4.1 Comparison of survival rate of serous ovarian cancer at different levels of ovary The 3 year and 5 year survival rate of ovarian tumors of low grade adenocarcinoma group were 69.2% and 30.8%, ovarian high-grade adenocarcinoma group 3 and 5 year survival rates were 35.5% and 9.7%. Statistical analysis showed that the low level group and high level group of 3 years survival rate and 5-year survival rate were significantly different.(P < 0.05) 4.2 The expression of SP1 protein and its relationship with the prognosis of serous ovarian cancer at different levels of ovary In ovarian tumors of low grade adenocarcinoma group, SP1 strong positive group and Sp1 negative or weakly positive group compared to the of the 3 year survival rate(42.9%, 100.0%) and the 5 year survival rate(0.00%, 66.7%), the differences were statistically significant(P < 0.05). In ovarian high-grade adenocarcinoma group, SP1 strong positive group and SP1 negative or weak positive group compared to the 3 years survival rate(22.7%, 66.7%) and 5 years survival rate(0.00%, 33.3%) were significantly different(P < 0.05). 4.3 The expression of KLF4 protein and its relationship with the prognosis of serous ovarian cancer at different levels of ovary In ovarian tumors of low grade adenocarcinoma group, KLF4 strong positive group and KLF4 negative or weakly positive group compared to the 3 years(75.0%, 66.7%) and the 5 year survival rate(50.0%, 22.2%) had no significant difference(P > 0.05). In ovarian high-grade adenocarcinoma group, KLF4 strong positive group and KLF4 negative or weak positive group compared to the 3 years(85.7%, 20.8%) and the 5 year survival rate(42.9%, 0.00%) had significant difference(P < 0.05). 4.4 The expression of P21 protein and its relationship with the prognosis of serous ovarian cancer at different levels of ovary In ovarian tumors of low grade adenocarcinoma group, p21 positive group and p21 negative or weakly positive group compared to the 3 years(100%, 60.0%) and the 5 year survival rate(66.7%, 20.0%) had no significant difference(P > 0.05). In ovarian high-grade adenocarcinoma group, p21 positive group and p21 negative or weak positive group compared to the 3 years(100.0%, 25.9%) and the 5 year survival rate(50.0%, 3.7%) had significant difference(P < 0.05). 5 Correlation analysis of expression of SP1, KLF4 and P21 in ovarian serous adenocarcinoma at different levels In lower serous ovarian cancer, there was no significant correlation between high expression of SP1 and low expression of P21 and KLF4(P>0.05). There was no significant difference between the low expression of KLF4 and low expression of P21(P>0.05); In advanced ovarian serous adenocarcinoma, the expression of SP1 and KLF4, P21 was significantly negatively correlated(P<0.05), the expression of KLF4 and P21 was positively correlated(P<0.05). 6 COX multivariate survival analysis of ovarian low grade and high grade serous adenocarcinoma To further determine the prognostic factors of ovarian serous adenocarcinoma, Kaplan-Meier univariate survival analysis of prognostic factors selected: high expression of SP1 and low expression of KLF4 and low expression of P21, surgical pathologic staging, postoperative chemotherapy and postoperative residual tumor size into COX regression model for multivariate survival analysis. The results show that: in the low level of ovary no serous cancer, high expression of SP1 is an independent prognostic influence of low-grade ovarian serous carcinoma(P=0.016); the factors in high grade ovarian serousadenocarcinoma, SP1 and clinical pathological stage into the COX proportional hazard regression model, so as the two independent factors affecting high grade ovarian serousadenocarcinoma prognosis(P=0.001, P=0.012).Conclusion: 1 In the ovary low-grade and high-grade serous carcinomas, the expression of SP1 was increased, but the expression of KLF4 and P21 was decreased, which indicated that the three were involved in the occurrence of ovarian high-grade and low-grade serous carcinoma. 2 SP1, KLF4 and P21 showed no significant difference in the expression of ovarian low grade and high grade serous adenocarcinoma, which indicated that the occurrence of ovarian low grade and high-grade serous adenocarcinoma was regulated by many factors, there may be a common molecular basis. 3 In the ovary high-grade serous carcinomas, the expression of SP1, KLF4 and P21 were significantly correlated, but there was no significant correlation between the expression of the three in the in the ovary low-grade serous carcinomas. 4 In the ovary high-grade serous carcinomas, all of the high expression of SP1 and low expression of P21 and KLF4 are the factors influencing the prognosis of patients, in the ovary low-grade serous carcinomas only the high expression of SP1 is a risk factor affecting the prognosis of the patients. Multivariate survival analysis showed that the high expression of SP1 may be an independent factor affecting the prognosis of the ovary low-grade and high-grade serous carcinomas. |
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