Acta Medica Mediterranea, 2018, 34: 1091 CORRELATION BETWEEN SURVIVIN OVEREXPRESSION AND CLINICO-PATHOLOGICAL FEATURES OF INVASIVE CERVICAL CANCER: A META-ANALYSIS HUI-RONG LI 1, JI-LI BAI 2*, RUI XU 2, YAN KONG 1 1 Department of Obstetrics and Gynecology, Shandong Provincial Third Hospital, Jinan City, Shandong Province 250000, China - 2 Department of Obstetrics and Gynecology, the Third People s Hospital of Lixia District of Jinan City, Jinan city, Shandong Province 250100, China ABSTRACT Objective: To systematically evaluate the correlation between overexpression of survivin and clinicopathological features of invasive cervical cancer. Methods: EMBASE, Medline, PubMed, Wan Fang, and VIP databases from 2001 were searched for published case-control studies on invasive clinical pathologies associated with cervical cancer as they relate to the overexpression of survivin. The data were screened and collected independently by two reviewers, and thereafter subjected to meta-analysis using RevMan5.2 analysis software version after assessing risk of bias. Results: Meta-analysis of 21 included articles showed that the clinical pathology features of invasive cervical cancer were generally accompanied by survivin overexpression; the expression of survivin in lymph node metastasis tissue was higher than that in non-metastasis lymph tissue, and the depth of invasive infiltration was higher than that in superficial layer. Moreover, survivin expression was significantly higher in the cervical cancer group than in the CIN group, and also higher in clinical stage Ⅲ than in clinical stage Ⅱ. There was a positive correlation between survivin and the clinical features of symptoms [OR = 5.52, 95 % CI = 4.09, 7.46; p < 0.00001]. Conclusion: High expression of survivin is consistent with clinical pathology of invasive cervical cancer, and the intensity of expression is positively correlated with the degree of pathological features. Keywords: Survivin, Cervical cancer, Invasiveness, Clinical pathology, Meta-analysis. DOI: 10.19193/0393-6384_2018_4_167 Received December 30, 2017; Accepted February 20, 2018 Introduction Cervical cancer, one of the malignant tumors of the female reproductive system, has unclear clinical characteristics. Currently, cytology-based screening for cervical cancer is used to reduce its incidence considerably. Cervical cancer has a relatively poor prognosis, and is often accompanied by pelvic lymph node involvement, which is mainly associated with metastasis and invasiveness. As one of its clinical characteristics, invasiveness presents as direct infiltration and lymphatic metastasis. The infiltration process is relatively long and preventable, but the factors that influence it are poorly understood (1, 2). Therefore, it is very vital to elucidate the factors that are associated with the clinical characteristics of oophoroma invasiveness. Several studies have demonstrated that survivin expression is enhanced in the infiltration and lymphatic metastasis of cervical cancer tissues, and that cervical cancer patients with different degrees of pathological differentiation have significantly different levels of expressions of survivin protein (3, 4). These findings indicate that survivin may be involved in invasiveness of cervical cancer. Survivin, an apoptosisinhibiting factor, is a new member of the family of apoptosis-inhibiting proteins (AIPs), and it appears to exhibit the highest activity within AIP family (5).
1092 Hui-rong Li, Ji-li Bai et Al Studies have shown that survivin is relatively common in malignant tumors, but is rarely expressed in differentiated tissues and normal paracarcinoma tissues of adults (6, 7). Currently, there are many studies on the overexpression of survivin in cervical cancer tissues which involve multiple clinical characteristics. The present study was a systematic evaluation of the literature by means of meta-analysis to ascertain the correlation between survivin overexpression and the clinical characteristics of invasive cervical cancer. Materials and methods Inclusion and exclusion criteria Inclusion criteria: Published case-control studies on survivin protein expression in cervical cancer tissues, in literature appearing in Chinese and English, were included. The subjects were patients clinically diagnosed with cervical cancer, and the exposure factor was expression of survivin, while the outcome indicator was expression levels of survivin. Exclusion criteria: Publications with incomplete research data, and studies that did not involve clinical characteristics of invasiveness were excluded. In addition, studies which were not reported in Chinese or English language, as well as case reports, overviews, lectures and conferences, and repeated publications were excluded. Strategies for information retrieval Databases such as PubMed, EMBASE, Medline, CNKI, Wanfang, and VIP were searched. The English retrieval key words were: survivin, express, cervical cancer and clinical features, while the Chinese retrieval keywords (translated) were: cervical cancer, clinical characteristics and expression. The retrieval was performed by using the keywords in different possible combinations. Literature screening, material extraction and bias risk evaluation Two reviewers independently performed literature screening, material extraction and evaluation of risk of bias in the inclusion studies. Disagreements over decisions were resolved through discussions, or through the involvement of a third party. The materials were extracted using self-prepared material extraction form, and the extracted contents included basic information on the included studies such as title, author, year of publication, and source of original references; baseline characteristics of subjects and nodes of interest, including cases and sample sizes, clinical staging, lymphatic metastasis and depth of infiltration; control groups, and key elements in bias risk evaluation. The included biases were evaluated using Newcastle Ottawa Scale (NOS). Statistical analysis The data were analyzed using Review Manager 5.2 software. Enumeration data were expressed with odds ratio (OR) as the effect indicator, and measurement data were expressed with mean deviation (MD) as the effect indicator. Estimated value and the 95 % CI were assigned to each effect size. Inter-result heterogeneity was analyzed using chi-square test (α = 0.1). In addition, the size of heterogeneity was judged quantitatively in combination with I 2. Values of I 2 less than 50 % indicated absence of heterogeneity among studies. A meta-analysis was made by taking advantage of fixed effect model. If statistical heterogeneity existed among the study results, the source of heterogeneity was further analyzed. After factors that significantly influenced the clinical heterogeneity were ruled out, the random effect model was deployed to make a meta-analysis. The meta-analysis had a test size (α) of 0.05. Results Data retrieval A total of 427 studies were retrieved: PubMed (n = 154), EMBASE (n = 34), Medline (n = 56), Wanfang (n = 127) and VIP (n = 56). Through layer-to-layer screening, 21 case-control studies were finally included (8-28). The literature screening procedures and results are shown in Figure 1. Basic characteristics of included studies and evaluation of risk of bias The results of basic characteristics of included literature and bias risk evaluation are shown in Table 1. A total of 21 studies featured comparison between survivin oophoroma group and cervical intra-epithelial neoplasia (CIN) group, and between oophoroma group and CIN group; 16 studies included comparison between lymphatic metastasis group and non-metastasis group; 14 studies included com-
Correlation between survivin overexpression and clinico-pathological features of invasive cervical cancer:... 1093 parison between FIGO clinical stage I and clinical stage II; 13 studies involved comparison between FIGO clinical stage II and clinical stage III; while 4 studies included survivin protein expressions in different infiltration depths. Results of meta-analysis Comparison between oophoroma group and CIN group Table 2 shows that in the 21 included studies (8-24, 25-28), survivin expressions in oophoroma and CIN groups were reported; out of the 1152 patients in the oophoroma group, 881 cases (76.4%) had survivin enhanced expression; while out of the 994 patients in the CIN group, 379 cases (38.1%) had survivin enhanced expression. The results of meta-analysis of random effect model showed that patients in the oophoroma group had significantly higher survivin expression than those in the CIN group (OR = 5.52, 95% CI = 4.09, 7.46, p < 0.00001). Figure 1: Literature screening procedures and results. Table 2: Meta-analysis of survivin protein expression of patients in cervical cancer group and CIN group. Table 1: Basic characteristics of included literature. Comparison between lymphatic metastasis group and non-metastasis group (9, 10, 12-17, 19-23, 26 A total of 16 studies were included - 28). Out of 364 patients in the lymphatic metastasis group, 344 (94.5%) had enhanced survivin expression; and out of 591 patients in the non-metastasis group, 398 (67.3%) had enhanced survivin expression. The meta-analysis results of fixed effect model showed that patients in the lymphatic metastasis group had significantly higher survivin expression than those in non-metastasis group (OR = 9.60, 95% CI = 5.82, 15.84; p < 0.00001). These results are shown in Table 3.
1094 Hui-rong Li, Ji-li Bai et Al and out of 248 patients in stage III, 232 (93.5%) had enhanced survivin expression. The meta-analysis results of fixed effect model showed that patients in stage III had significantly more enhanced expression of survivin than those in stage II (OR = 4.53, 95% CI = 2.55, 8.05; p < 0.00001). Table 3: Meta-analysis of survivin protein expressions in cervical cancer patients with lymphatic metastasis, and non-metastasis cervical cancer patients. Comparison between FIGO clinical stage I and stage II (8-11, 13, 14, 16-18, 20, A total of 14 studies were included 21, 23-26). Out of the 353 patients in stage I, 223 (63.2%) had enhanced survivin expression, and out of 313 patients in stage II, 265 (84.7%) had enhanced survivin expression. Results of meta-analysis of fixed effect model showed that patients in stage II had significantly higher expression of survivin than those in stage I (OR = 4.00, 95% CI = 2.58, 6.19; p < 0.00001) (Table 4). Table 5: Meta-analysis of survivin protein expression of cervical cancer patients in clinical stage II and stage III. Expression of survivin protein in patients with different infiltration depths Table 6 shows that a total of 4 studies were included (19, 21, 27, 28). Out of 175 patients with deep infiltration, 164 (93.7%) had enhanced expression of survivin, and out of 120 patients in the superficial infiltration, 85 (70.8%) had enhanced survivin expression. Meta-analysis of fixed effect model showed that patients with deep infiltration had significantly higher expression of survivin than those with superficial infiltration (OR = 6.88, 95% CI = 3.07, 15.42; p < 0.00001) (Table 6). Table 4: Meta-analysis of survivin protein expression in cervical cancer patients in clinical stages I and II. Comparison between FIGO clinical stage II and stage III Table 5 reveals that a total of 13 studies were included (8, 11-13, 15, 19, 21-27). Out of the 401 patients in stage II, 302 (75.3%) had enhanced survivin expression, Table 6: Meta-analysis of survivin protein expressions of patients with cervical cancer of different infiltration depths. Publication basis The results of funnel plot of survivin in metastasis group and non-metastasis group (Figure 2) showed that the included studies were basically within 95% CI, but the distribution was asymmetric, indicating that this study was somewhat subject to the influence of publication basis. Thus, this study might be compromised by some bias.
Correlation between survivin overexpression and clinico-pathological features of invasive cervical cancer:... 1095 Figure 2: Survivin funnel plot for metastasis group and non-metastasis group. Discussion Survivin is an apoptosis-inhibiting factor with a unique structure different from the structures of other IAP family members: it has only one cysteine/histidine residue at the N terminal as the basic zinc finger (29). It exerts its apoptosis inhibitory effects by inhibiting the activity of caspase, thereby blocking endogenous and exogenous apoptosis routes. Survivin affects oophoroma development by inhibiting the tumor cell apoptosis and promoting tumor cell multiplication (30). It acts on the vascular endothelial growth factor (VEGF), and inhibits vascular endothelial apoptosis, which is of benefit to tumor growth due to enhanced growth of new vessels. Survivin is highly expressed in common tumor tissues such as hepatocarcinoma, pulmonary carcinoma, and prostatic carcinoma, and it is associated with poor prognosis (31). Given that survivin is expressed in all stages of tumor tissues, it can be reasonably assumed that it can serve as a reference indicator during clinical diagnosis and treatment of tumors. Survivin is not expressed in normal cells, but it is expressed strongly in cancer cells. According to meta-analysis results in the present study, patients in the oophoroma group had significantly higher survivin expression than those in the CIN group, which showed that survivin expression was associated with severity of the disease. This finding is consistent with the results of existing studies. Analysis of correlation between survivin expression and the presence or absence of lymphatic metastasis revealed that patients in the lymphatic metastasis group had higher survivin expression than those in the non-metastasis group, which implies that survivin increased the risk of metastasis through inhibition of cell apoptosis and promotion of cell multiplication. Cervical cancer staging is determined by the degree of infiltration. Cervical cancer cells at clinical stage III have infiltrated the pelvic wall. At stage II, infiltration has gone beyond the neck of the uterus, and at stage I, the infiltration is limited to uterine neck without affecting the pelvic wall. The results of analysis showed that patients in clinical stage III had more enhanced expression of survivin when compared to those in stage II, and patients in stage II had enhanced expression when compared to those in stage I. These results are consistent with evidence of clinical staging of oophoroma. Survivin expressions were enhanced in patients with deep infiltration and superficial infiltration. The results from lymphatic metastasis, clinical staging and infiltration depths indicate that survivin plays a role in the cell invasion of cervical cancer patients. A deeper infiltration which implies a rapid spread of the disease, is associated with a higher survivin expression. The analysis showed that enhanced expression of survivin promoted cell multiplication, and increased the capacity of cancer cell metastasis and invasiveness. Therefore, the intensity of survivin expression can serve as an indicator for the clinical invasiveness of cervical cancer. In other words, the appearance of invasiveness characteristics can be delayed by inhibiting the expression of survivin. Although many studies were included into this study, the funnel plot suggested the existence of some bias, indicating that a larger sample-based research is further needed to validate the results obtained. Conclusion The intensity of survivin is closely associated with the pathological characteristics of invasiveness of oophoroma and the magnitude of its expression is consistent with the severity of invasiveness. This shows that survivin plays an important role in inhibiting cell apoptosis and promoting cancer cell invasion into peripheral tissues. However, these findings need further validation due to the limitations in the present study such as sample size and treatment differences. References 1) Modepalli N, Venugopal SB. Clinicopathological study of surface epithelial tumours of the ovary: an institutional study. J Clin Diagn Res, 2016, 10 (10): EC01- EC04.
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Corresponding author JI-LI BAI Department of Obstetrics and Gynecology, the Third People s Hospital of Lixia District of Jinan City, Jinan city, Shandong Province 250100, China Email: ldaky1@163.com (China)