Jinke Li

The prognostic value of vascular endothelial growth factor in ovarian cancer: A systematic review and meta-analysis

OBJECTIVE The prognostic role of vascular endothelial growth factor (VEGF) in ovarian cancer remains inconclusive. This meta-analysis aimed to explore the association between VEGF overexpression and survival outcomes in ovarian cancer patients. METHODS Studies were identified from PubMed and EMBASE searches performed on January 2nd, 2011. After careful review, survival data were extracted from eligible studies. A meta-analysis was performed to generate combined hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS) in serum and tumor tissue studies. RESULTS Sixteen studies with 1111 patients were analyzed. Elevated serum VEGF was significantly associated with poor PFS [HR 2.46, 95% CI (1.84, 3.29)] and OS [HR 2.21, 95% CI (1.57, 3.13)]. No significant heterogeneity existed in serum studies. Similarly, tissue VEGF overexpression was associated with poor PFS [HR 1.63, 95% CI (1.09, 2.42)] and OS [HR 1.70, 95% CI (1.01, 2.87)]. However, significant heterogeneity was found in tissue studies, with I(2) of 44% for PFS and 64% for OS. Studies were stratified into subgroups by International Federation of Gynecology and Obstetrics (FIGO) stages. Subgroup analyses showed that high tissue VEGF was significantly associated with shorter PFS [HR 5.34, 95% CI (1.95, 14.59)] and OS [HR 6.13, 95% CI (2.47, 15.26)] in studies where predominantly early-stage patients were included, but not in studies with a majority of advanced-stage patients. Subgroup analysis was not performed in serum studies because all those studies enrolled more patients in advanced stages than early stages. CONCLUSIONS Overexpression of VEGF in primary tumor and serum associates with poor PFS and OS for patients with ovarian cancer. The association between high tissue VEGF level and poor prognosis exists in early stage patients, but not in advanced stage patients.

Association of constitutive nuclear factor-kappaB activation with aggressive aspects and poor prognosis in cervical cancer.

Introduction: Although nuclear factor-&kgr;B (NF-&kgr;B) is generally believed to be involved in carcinogenesis, the relationship between NF-&kgr;B activation and progression of cervical cancer in clinical settings has not been reported. In this study, we investigated the association of NF-&kgr;B activation with aggressive aspects and prognosis in cervical cancer. Methods: Nuclear factor-&kgr;B subunits p65 and p50 were detected in 159 paraffin tissues including normal cervical, precancerous (squamous intraepithelial lesions), and cervical carcinoma tissues by immunohistochemistry. Nuclear factor-&kgr;B nuclear translocation and DNA-binding activity in precancerous or carcinoma tissues were examined by Western blot and electrophoretic mobility shift assay, respectively. Results: A gradual NF-&kgr;B activation from normal cervical epithelial cells to precancerous and carcinoma cells was detected by immunohistochemistry (nuclear expression of p65 and p50, P < 0.001), Western blot (NF-&kgr;B nuclear translocation), and electrophoretic mobility shift assay (enhanced DNA-binding activity). In 79 cancer tissues, increased nuclear p65, an active NF-&kgr;B form, was correlated with poor tumor grade, lymphatic metastasis, interstitial invasion, and larger tumor size (P < 0.05). Similarly, increased nuclear p50 was correlated with poor tumor grade, interstitial invasion, and larger tumor size (P < 0.05). Moreover, increased nuclear p65 was associated with lower survival rate in patients with cancer (P < 0.05). Conclusions: Constitutive NF-&kgr;B activation is correlated to tumor progression, aggressive behaviors, and poor prognosis in cervical cancer, suggesting that NF-&kgr;B is a tumor promoter, a prognostic indicator, and a possible therapeutic target for this malignant disease.

Human papillomavirus type-specific prevalence in women with cervical intraepithelial neoplasm in western China

ABSTRACT Human papillomavirus (HPV) type-specific prevalence was studied in 600 cases of cervical intraepithelial neoplasm in western China by GenoArray test. HPV-16 and -58 were the most prevalent types, with prevalences of 37.8% and 21.8%, respectively. HPV-18 and -45 were uncommon types. The results show different type distributions from that of other regions, which is important evidence for the selection of future genotypes in HPV vaccines in western China.

Overexpression of cystic fibrosis transmembrane conductance regulator (CFTR) is associated with human cervical cancer malignancy, progression and prognosis

OBJECTIVE To investigate the correlation of cystic fibrosis transmembrane conductance regulator (CFTR) to cervical cancer progression and prognosis by examining CFTR expression levels in different cervical tissues and cell lines. METHODS Paraffin-embedded cervical tissue samples (n=192) were collected for immunohistochemistry (IHC), while fresh cervical tissue samples (n=165) and human cervical cell lines were collected for protein and mRNA detection by quantitative real-time PCR and western blot, respectively. Correlations between CFTR expression levels to cancer clinicopathologic features and prognosis were statistically analyzed. RESULTS Both CFTR mRNA and protein expression gradually increased from normal to precancerous (LSIL, HSIL) and cervical cancer tissues (p<0.05). Furthermore, CFTR expression level was well-correlated to tumor stage (p<0.001), histological grades (p<0.001), lymphatic metastasis (p<0.001), vascular invasion (p<0.05), interstitial invasive depth (p<0.05), tumor size (p<0.05) and HPV infection (p<0.05). In vitro, CFTR mRNA and protein were expressed strongly both in SiHa and HeLa, but little was seen in Caski and H8 (p<0.05). More importantly, overexpression of CFTR conferred significantly poorer survival in cervical carcinoma (Log rank p=0.028), although it was not an independent predictor for prognosis according to multivariate analysis (p>0.05). CONCLUSIONS These results suggest that higher CFTR expression is closely associated with cervical cancer progression, aggressive behaviors and poorer prognosis, indicating that CFTR may function as a novel tumor marker, a prospective prognostic indicator and a potential therapeutic target for cervical cancer.

Constitutive activation of nuclear factor κB contributes to cystic fibrosis transmembrane conductance regulator expression and promotes human cervical cancer progression and poor prognosis.

Objective Cystic fibrosis transmembrane conductance regulator (CFTR) and nuclear factor κB (NF-κB) have been known to play important roles in the development and progression of many types of cancer including cervical cancer. The study aimed to verify the relevance and significance of CFTR and NF-κB expressions in cervical cancer tissues and cell lines. Methods The expressions of CFTR and NF-κB p65 were analyzed respectively by immunohistochemistry in total of 135 cervical tissue samples. The correlation to clinicopathologic characteristics and prognostic value was evaluated. The coexpression of CFTR and NF-κB was detected in cervical cancer cell lines. Nuclear factor κB signaling was inhibited by siRNA for NF-κB p65 and activated by stimulation of cells with interleukin β or tumor necrosis factor &agr;. Results We found both the membrane expression of CFTR and nuclear translocation of NF-κB p65 were progressively increased from normal cervical tissue, cervical intraepithelial neoplasm, to cervical cancer (overall R2 = 0.74, P < 0.001). Cystic fibrosis transmembrane conductance regulator expression and NF-κB activation were also positively associated with stage, histological grade, lymph node metastasis, and invasive interstitial depth. Multivariate analysis showed that coexpression of CFTR and NF-κB was an independent prognostic factor for survival (relative risk, 5.16; P = 0.003). Dual-immunofluorescence analysis showed CFTR and NF-κB were coexpressed in cervical cancer. Studies in vitro revealed that the expression levels of CFTR mRNA and protein were positively related to NF-κB activation. Conclusions Cystic fibrosis transmembrane conductance regulator and NF-κB were coexpressed in cervical cancer, and the activation of NF-κB mediated the expression of CFTR. Multivariate analysis revealed that coexpression of CFTR and NF-κB was associated with poor prognosis in patients with cervical cancer.

Prevalence and genotype distribution of human papillomavirus in women with cervical cancer or high-grade precancerous lesions in Chengdu, western China

To study the prevalence and genotype distribution of human papillomavirus (HPV) among women with cervical cancer or high‐grade squamous intraepithelial lesions (HSIL) in western China.

Correlation of inhibitor of differentiation 1 expression to tumor progression, poor differentiation and aggressive behaviors in cervical carcinoma

OBJECTIVE To study the correlation of inhibitor of differentiation 1 (Id-1) to tumor invasion and metastasis by examining Id-1 expression levels in different stages of cervical carcinogenesis. METHODS Id-1 mRNA and protein expression was detected in total of 171 cervical samples including precancerous and cancerous tissues by quantitative RT-PCR (qRT-PCR) and immunohistochemistry (IHC), respectively. Twenty-five normal cervical tissues were used as a normal control. Correlation between Id-1 positive rates and expression levels to cancer progression and clinicopathologic features was statistically analyzed. RESULTS A gradual increase of Id-1 protein expression associated with cervical cancer progression was detected (4%, 16%, 50% and 75.9% in normal, low squamous intraepithelial lesion (LSIL), high squamous intraepithelial lesion (HSIL) and cancer tissue, respectively, p<0.001). A similar trend of Id-1 mRNA expression was also observed (1.3, 3.4 and 10.4 fold higher than normal tissues in LSIL, HSIL and cancer tissue, respectively, p<0.001). Furthermore, the Id-1 expression level was correlated to tumor grade (p=0.005), lymph node metastasis (p=0.001), interstitial invasive (p<0.001) and tumor size (p<0.001). These results suggest that high Id-1 expression is associated with tumor growth, invasion and metastasis. CONCLUSION Id-1 expression is correlated to progression and aggressive behaviors in cervical cancer, suggesting a tumor-promoting role for Id-1 in progression of this malignancy.

High expressions of bcl-2 and survivin, and decreased apoptosis in uterine cervical carcinosarcoma compared to cervical squamous cell carcinoma.

PurposesUterine cervical carcinosarcoma (CS) is very rare. To date, only 40 cases have been reported. It seems to have a more aggressive clinical behavior than does cervical squamous cell carcinoma (SCC). The purposes of our study were to characterize the clinicopathologic characteristics and human papillomavirus (HPV) status of the rare tumor and to analyze the molecular features in cervical CS that may account for its aggressive behavior.MethodsThree patients were diagnosed with uterine cervical CS at West China Second Hospital of Sichuan University between 1995 and 2009. Data were retrospectively analyzed from available charts and pathological reports. Twelve patients with FIGO stage Ib–IIa cervical SCC were enrolled as the controls, and the expression profiling of p53, Ki-67, bcl-2, survivin and apoptosis index between cervical CS and SCC was compared. Immunohistochemical and apoptosis results were scored separately for the carcinomatous and sarcomatous components.ResultsAll three patients were shown to be negative for HPV infection by Hybribio HPV genoarray assay. Expression of p53 was observed in one patient in both carcinomatous and sarcomatous components in a similar proportion; in contrast, the Ki67, bcl-2 and survivin expressions were higher in carcinomatous components than in sarcomatous components in all three cases. Compared to cervical SCC, stronger immunostaining for bcl-2, survivin and lower apoptosis was observed in cervical CS.ConclusionsCervical CS is a peculiar tumor with many different clinicopathologic characteristics from cervical SCC. Dysregulation of apoptosis may confer tumor cells of cervical CS with survival and growth advantages, and thereby facilitate the aggressive behavior of cervical CS.

Concurrent blockade of the NF-κB and Akt pathways potently sensitizes cancer cells to chemotherapeutic-induced cytotoxicity

Nuclear factor-kappaB (NF-kappaB) and Akt are two major cell survival pathways that are often constitutively activated and can be further stimulated by chemotherpeutics in cancer cells. Although individually targeting the NF-kappaB or Akt has been reported to sensitize caner therapy, the effectiveness of concurrent blocking these two pathways for chemosensitizing of cancer cells to genotoxic therapeutics has not been investigated. In the present study, we investigate the activation of the NF-kappaB and Akt pathways by two frontline anticancer drugs cisplatin and etopside in a variety of cancer cell lines. The effects of blocking these two survival pathways individually or concurrently on cisplatin- or etopside-induced cytotoxicity were detected. The results show that cisplatin and etopside activate both NF-kappaB and Akt in cancer cells. Blockade of either of these pathways with chemical inhibitors or siRNA moderately sensitized cancer cells to cisplatin- or etopside-induced cytotoxicity. Strikingly, much more effective potentiation of cytotoxicity to these anticancer drugs was achieved when NF-kappaB and Akt were concurrently blocked. These data suggest that NF-kappaB and Akt cooperatively attenuate therapeutic-induced cytotoxicity and concurrently blocking these pathways is an effective strategy for improving the anticancer efficacy of therapeutics.

Association of inhibitor of differentiation 1 expression with human papillomaviruses infections in cervical carcinoma.

Background: Our recent study has shown that inhibitor of differentiation 1 (Id-1) is overexpressed in cervical carcinoma. However, the relationship between Id-1 expression and human papillomavirus (HPV) infection has not been elucidated. In this study, we investigate the association of Id-1 protein expression and HPV infection in cervical carcinoma tissues. Methods: A total of 56 paraffin-embedded and 12 fresh cervical carcinoma tissues were collected for Id-1 and HPV detection. The Id-1 protein was detected by immunohistochemistry and Western blot in paraffin-embedded and fresh carcinoma tissues. Human papillomavirus DNA was detected and genotyped by using an oligonucleotide microarray and polymerase chain reaction. Results: The overall HPV prevalence was 82.1%, whereas that of HPV type 16 (HPV-16) was 62.5% in cervical carcinoma. The HPV-positive samples showed higher Id-1 expression levels than the HPV-negative ones (Cochran-Mantel-Haenszel &khgr;2 test [&khgr;2 CMH] = 4.39, P < 0.05). The HPV-16-infected samples had higher Id-1 expression levels than the samples with infection of other single HPV genotypes (&khgr;2 CMH = 6.42, P < 0.02). The results of Western blot were correlated to the immunohistochemistry results, showing a higher Id-1 expression level in HPV-infected especially HPV-16-infected carcinoma tissues. Conclusions: Inhibitor of differentiation 1 expression is correlated to HPV infection in cervical carcinoma, suggesting that Id-1 plays a role in HPV-related cervical carcinogenesis.