Search

Background High-risk HPV is clearly associated with cervical cancer. Integration of HPV DNA into the host genome is considered a key event in driving cervical carcinogenesis. However, the mechanism on how HR-HPV integration influences the host genome structure has remained enigmatic. Methods In our study, 25 DNA samples including 11 from fresh-frozen cervical carcinomas and 14 from fresh-frozen high-grade squamous intraepithelial lesion (HSILs) were detected using the method of HPV capture combined with next generation sequencing. Results We calculated the frequency in each viral gene or region and found that breakpoints were prone to occur in L1 and L2 instead of E2 in the cervical cancer (P = 0.0004 and P = 5.15×10− 40) and HSIL group (P = 2.1×10− 32 and P = 7.06×10− 13). The results revealed that HPV16 showed a strong tendency towards intronic region (P = 5.02×10–64) but a subtle tendency towards intergenic region (P = 0.04). The most frequent integration site was in the MACROD2 gene (introns 2, 4, 5, 6, 8 and 9), which in MACROD2 functional domain. Conclusion Our results revealed that MACROD2 is HPV hot spot integration site in cervical lesions, and its deficiency alter DNA repair and sensitivity to DNA damage thought impaired PARP1 activity resulting in chromosome instability.

High-risk HPV is clearly associated with cervical cancer. Integration of HPV DNA into the host genome is considered a key event in driving cervical carcinogenesis. However, the mechanism on how HR-HPV integration influences the host genome structure has remained enigmatic.In our study, 25 DNA samples including 11 from fresh-frozen cervical carcinomas and 14 from fresh-frozen high-grade squamous intraepithelial lesion (HSILs) were detected using the method of HPV capture combined with next generation sequencing.We calculated the frequency in each viral gene or region and found that breakpoints were prone to occur in L1 and L2 instead of E2 in the cervical cancer (P = 0.0004 and P = 5.15 × 10Our results revealed that MACROD2 is HPV hot spot integration site in cervical lesions, and its deficiency alter DNA repair and sensitivity to DNA damage thought impaired PARP1 activity resulting in chromosome instability.

Background The efficacy of therapy for cervical cancer is related to the alteration of multiple molecular events and signaling networks during treatment. The aim of this study was to evaluate gene expression alterations in advanced cervical cancers before- and after-trans-uterine arterial chemoembolization- (TUACE). Methods Gene expression patterns in three squamous cell cervical cancers before- and after-TUACE were determined using microarray technique. Changes in AKAP12 and CA9 genes following TUACE were validated by quantitative real-time PCR. Results Unsupervised cluster analysis revealed that the after-TUACE samples clustered together, which were separated from the before-TUACE samples. Using a 2-fold threshold, we identified 1131 differentially expressed genes that clearly discriminate after-TUACE tumors from before-TUACE tumors, including 209 up-regulated genes and 922 down-regulated genes. Pathway analysis suggests these genes represent diverse functional categories. Results from real-time PCR confirmed the expression changes detected by microarray. Conclusions Gene expression signature significantly changes during TUACE therapy of cervical cancer. Theses alterations provide useful information for the development of novel treatment strategies for cervical cancers on the molecular level.

This study aimed to determine the in vitro and in vivo properties of sixteen frequently used endometrial cancer (EC) cell lines, including the cell proliferation rate, morphology, hormone receptor expression patterns, PTEN, hMLH1 expression, p53 mutation, karyotype, and tumorigenicity in mouse xenograt model.Twelve type I (AN3, ECC-1, EN, EN-1, EN-11, HEC-1A, HEC1B, Ishikawa, KLE, MFE-280, MFE-296, MFE-319) and four type II (ARK1, ARK2, HEC-155/180, SPEC-2) endometrial cancer cell lines were studied. Cell proliferation and morphology were determined using cell growth curves and light microscopy, respectively. Real-time PCR was performed to measure the mRNA levels of target genes. Denaturing High Performance Chromatography (DHPLC) screening and PCR/sequencing were performed to identify p53 mutations. G-banding was applied for karyotyping. Tumorigenicity was evaluated using mouse xenograft.The population doubling time of the cell lines ranged between 19 and 41 h. Ishikawa, ECC-1, and MFE-280 have high while AN3 and EN1 have low expression of ER-α and ER-β. Expression of total PR and PR-B uniformly decreased in all type II cell lines and several type I cell lines (AN3, HEC-1A, HEC1B, KLE, EN-1). Regression analyses revealed significant correlations between PR-B and total PR (p .001), between isoforms ER-α and ER-β (p .001), and between total PR and ER (p .001), mRNA levels in type I cell lines. p53 mutations were detected in exons 5-8 of seven out of twelve type I and one out of four type II cell lines. PTEN expression was more uniformly suppressed in type II than type I cells, while hMLH1 did not show this pattern. All the five cell lines tested contained severe karyotype abnormalities. Mouse xenograft results indicated that HEC-1A, HEC-1B and EN-1 type I as well as ARK1 and ARK2 type II cell lines had potent tumorigenic activities. Low PR-B and ER-α expression in type I cell lines were associated with high tumorigenic activity.This study provides resource information on EC cell lines commonly used in laboratories, which could be used for choosing cell lines suitable for specific research purposes. The results of karyotype analysis and p53 mutation together with hormone receptor expression pattern and morphology comparison strongly suggested an independent nature of these cell lines, excluding the possibility of cross-contamination between cell lines. Additionally, this information suggests potential directions for future studies on the pathogenic mechanisms of endometrial cancer.

This study investigates the effects of trastuzumab on the proliferation and apoptosis of ovarian cancer cells. Epithelial ovarian cancer tissues were collected from 60 patients, benign ovarian tissues from 45 patients and normal ovarian tissues from 30 patients. Human epidermal growth factor receptor 2 (HER2) protein expression was measured by immunohistochemistry and mRNA expression by quantitative real-time polymerase chain reaction (RT-PCR). Proliferation and apoptosis of SKOV3 cells were then measured by MTS assay and flow cytometry and cleaved caspase-3 expression was detected by Western blot. Our results established that HER2 protein is expressed in tumor tissues, benign tissues and normal tissues and its positive expression rate in tumor tissues is significantly higher than in benign tissues and normal tissues (p

Additional file 1: Supplementary Table 1. The efficacy analysis of patients with high-grade serous cancer. ORR, objective response rate; DCR, disease control rate; a Twelve patients receiving less than 2 cycles of PLD and 4 patients without efficacy assessments after 2 cycles of PLD were excluded. Moreover, 1 patient had a postbaseline efficacy assessment that could not be confirmed and was thus excluded; b Including patients with complete and partial responses; c Including patients with complete and partial responses and stable disease.

Additional file 2:Supplementary Table 2. Predictive impact of factors on efficacy evaluated by the RECIST or the GCIG criteria. ECOG, Eastern Cooperative Oncology Group; FIGO, International Federation of Gynecology and Obstetrics; RECIST, Response Evaluation Criteria in Solid Tumors version 1.1; GCIG, Gynecologic Cancer InterGroup.

Additional file 3:Supplementary Table 3. Predictive impact of a CA125 decrease after the first cycle on efficacy evaluated by the RECIST or the GCIG criteria. ORR, objective response rate; DCR, disease control rate; a chi-square test; b Including patients with complete and partial responses; c Including patients with complete and partial responses and stable disease. RECIST, Response Evaluation Criteria in Solid Tumors version 1.1; GCIG, Gynecologic Cancer InterGroup.

The present review aims at reviewing the role of metformin in the treatment of endometrial cancer (EC). According to the literature, excessive estrogen levels and insulin resistance are established risk factors of EC. As a traditional insulin sensitizer and newly discovered anticancer agent, metformin directly and indirectly inhibits the development of EC. The direct mechanisms of metformin include inhibition of the LKB1-AMP-activated protein kinase-mTOR, PI3K-Akt and insulin-like growth factor 1-related signaling pathways, which reduces the proliferation and promotes the apoptosis of EC cells. In the indirect mechanism, metformin increases the insulin sensitivity of body tissues and decreases circulating insulin levels. Decreased levels of insulin increase the blood levels of sex hormone binding globulin, which leads to reductions in circulating estrogen and androgens. The aforementioned findings suggest that metformin serves an important role in the treatment of EC. Increased understanding of the mechanism of metformin in EC may provide novel insights into the treatment of this malignancy.

Objective To evaluate the efficacy and safety of PLD in treating of in patients who experience epithelial ovarian, fallopian tubal, and peritoneal cancer progression within 12 months after the first-line platinum-based therapy. Methods This was an open-label, single-arm and multicenter clinical trial. The ORR was the interim primary objective, and the DCR, AEs and QOL were the secondary objectives. The impact of factors on efficacy outcomes, the change trend of CA125 and the artificial platinum-free interval were exploratory endpoints. Results Totally, 115 patients were enrolled in this study and included in the ITT population. Moreover, 101 patients were included in the safety population. The median follow-up time was 4 months (IQR 2–6). In the ITT population, the confirmed ORR was 37.4% (95% CI, 28.4–46.4%), and the DCR was 65.2% (95% CI, 56.4–74.1%). The previous response status to platinum-based chemotherapy and baseline CA125 levels were significantly correlated with the ORR. The ORR was significantly higher in patients with a CA125 decrease after the first cycle than in the patients with a CA125 increase. The most common grade 3 or higher AE was hand-foot syndrome (3 [3.0%] of 101 patients). No statistically significant differences existed between the baseline and the postbaseline questionnaires. Conclusions For patients who experience platinum-resistant and platinum-refractory relapse, the use of PLD may be acceptable because of the associated satisfactory efficacy, low frequency of AEs and high patient QOL. Moreover, a low CA125 level at baseline and a reduction in CA125 after the first cycle are predictive factors for satisfactory efficacy.

Background Paclitaxel is a first-line chemotherapy drug for pancreatic, ovarian, endometrial cancers and other malignancies. However, its efficacy is often compromised by decreased cell sensitivity or the development of resistance. Human epididymis protein 4 (HE4) is highly expressed in gynecologic and pancreatic cancer tissues, and its serum levels are used for patient triage and assistant diagnosis of gynecologic cancers. Previous studies have shown that HE4 overexpression could promote cancer cell proliferation and the growth of tumor xenografts, which suggests its potential involvement in cancer chemosensitivity. Methods Two pancreatic cancer cell lines, Capan-1 and Suit-2, were transiently transfected with an HE4 overexpression plasmid, and transfected cells were treated with paclitaxel. S-phase cells were labeled using BrdU, and cell positivity rates were determined by counting BrdU-positive cells. Following HE4 overexpression and/or drug treatment, a western blotting analysis was performed to determine the protein alterations of PCNA and p21, two important cell cycle regulators. Results HE4 overexpression not only promoted the proliferation of the Capan-1 pancreatic cells, but also significantly decreased cell sensitivity to paclitaxel. Results from western blotting showed that paclitaxel inhibited cell proliferation by decreasing the expression of PCNA and increasing the expression of p21. Data analysis indicated interactive actions between HE4 function and paclitaxel effects, both converging to cell cycle regulation. Conclusion These findings suggest that HE4 could be a potential therapeutic target for the sensitization of pancreatic cancer cells to paclitaxel treatment. HE4 expression levels may be used to predict the sensitivity of pancreatic cancer patients to paclitaxel.

Endometrial cancer is a common gynecological malignancy in developed countries. Insulin has been identified as a risk factor for endometrial cancer. However, whether insulin levels are related to the risk of lymph node metastasis (LNM) in endometrial cancer is unknown. We conducted a prospective cohort study in a regional hospital to examine the relationships between insulin levels and risk of LNM in premenopausal and postmenopausal women. A total of 668 patients were recruited. Of these, 206 were premenopausal (mean age: 42.01 ± 10.17) and 462 were postmenopausal (mean age: 62.13 ± 13.85). The incidence of LNM in both premenopausal and postmenopausal groups was comparable at 7% and 8%, respectively. In premenopausal women, multivariate logistic regression demonstrated that insulin levels (OR: 2.11, 95% CI: 1.48–2.85, P

// Xiuli Wang 1, 2, * , Zenghui Li 2, * , Beihua Kong 1 , Chen Song 3 , Jianglin Cong 2 , Jianqing Hou 2 and Shaoguang Wang 2 1 Department of Gynecology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China 2 The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, 264000, P.R. China 3 Department of Gynecology, Zhucheng Maternal and Child Health Hospital, Zhucheng, Shandong 262200, P.R. China * These authors have contributed equally to this work Correspondence to: Beihua Kong, email: jiangshuzhongxu@gmail.com Keywords: m 6 A RNA methylation; cervical cancer; cancer Received: May 04, 2017 Accepted: October 02, 2017 Published: October 24, 2017 ABSTRACT The m 6 A mRNA methylation involves in mRNA splicing, degradation and translation. Recent studies have revealed that reduced m 6 A mRNA methylation might promote cancer development. However, the role of m 6 A mRNA methylation in cervical cancer development remains unknown. Therefore, we investigated the role of m 6 A methylation in cervical cancer in the current study. We first evaluated the m 6 A mRNA methylation level in 286 pairs of cervical cancer samples and their adjacent normal tissues by dot blot assay. Then the role of m 6 A on patient survival rates and cervical cancer progression were assessed. The m 6 A level was significantly reduced in the cervical cancer when comparing with the adjacent normal tissue. The m 6 A level reduction was significantly correlated with the FIGO stage, tumor size, differentiation, lymph invasion and cancer recurrence. It was also shown to be an independent prognostic indicator of disease-free survival and overall survival for patients with cervical cancer. Reducing m 6 A level via manipulating the m 6 A regulators expression promoted cervical cancer cell proliferation. And increasing m 6 A level significantly suppressed tumor development both in vitro and in vivo . Our results showed that the reduced m 6 A level is tightly associated with cervical cancer development and m 6 A mRNA methylation might be a potential therapeutic target in cervical cancer.

To observe the clinical efficacy and safety of bevacizumab (BEV) combined with paclitaxel on recurrent ovarian cancer.A total of 164 patients with recurrent ovarian cancer were selected and randomly divided into two groups: experimental group (n=82, BEV + paclitaxel + carboplatin) and control group (n=82, paclitaxel + carboplatin). The clinical therapeutic effects including objective response rate (ORR), complete response (CR) rate, partial response (PR) rate, stable disease (SD), progressive disease (PD), progression free survival (PFS) and overall survival (OS) were evaluated, together with the adverse clinical reactions and improvement of quality of life (QoL). Immunohistochemistry was used to detect the expression of phosphate and tension homology deleted on chromosome ten (PTEN).The PFS, OS and ORR of patients in the experimental group were significantly higher than those in the control group (p0.05). In addition, the incidence rates of allergy, gastrointestinal reactions and leukopenia were significantly lower in the experimental group compared with those in the control group (p0.05). There was no significant difference in QoL score between the two groups before treatment (p0.05). However, after treatment, the QoL score in the experimental group was increased significantly compared with the control group (p0.05). Moreover, the expression of PTEN in PR, SD and PD patients was lower, with significant difference between the two groups (p0.05).The clinical therapeutic effect of BEV combined with paclitaxel in patients with recurrent ovarian cancer was improved, suggesting it might be beneficial for the treatment of ovarian cancer.

AIM Subjects with germline BRCA1/2 mutations (gBRCAm) have an increased risk of developing breast cancer and ovarian cancer. At present, knowledge of BRCA1/2 mutation frequency in Chinese patients with ovarian cancer is still insufficient, and the detailed clinical information of these patients is poorly understood. METHODS A total of 547 unselected ovarian cancer patients were enrolled, and their gBRCAm status was detected. Clinical characteristics including age, personal and family history, histopathologic diagnosis, carbohydrate antigen 125 (CA-125) level, ascites, Federation International of Gynecology and Obstetrics (FIGO) stage, residual lesions, platinum sensitivity, recurrence interval and survival information were collected. Accurate assessments of disease response were based on the RECIST standard or CA-125 level. RESULTS In 547 patients with ovarian cancer, we detected 129 (23.6%) patients with pathogenic mutations, 84 patients with BRCA1 mutations (15.4%) and 45 patients with BRCA2 mutations (8.2%). Twenty-five novel mutations were identified, and the mutation of BRCA1, c.5470_5477del8, was the most common mutation in this study. BRCA1/2 mutations were significantly associated with age; personal and family history; FIGO stage; secondary recurrence interval; sensitivity to platinum in 1st, 2nd and 3rd line treatment; and response to doxorubicin liposomes. Patients with BRCA1/2 mutations showed significant advantages in 3- and 5-year survival rates but no advantage in long-term survival. CONCLUSION BRCA1/2 mutation prevalence in Chinese ovarian cancer patients is higher than the international rate. We recommend BRCA1/2 testing for patients with family histories and personal histories of malignancy and genetic counseling for cancer in healthy people with high-risk family histories.

Background Our study aimed to investigate the role of lncRNA PVT1 in cervical squamous cell carcinoma. Materials and methods A total of 156 patients with cervical squamous cell carcinoma were enrolled in this study and human papillomavirus (HPV) infection was detected by highly sensitive PCR techniques. Serum levels of PVT1 in patients infected with different HPVs and healthy controls was detected by qRT-PCR and compared. Serum levels of PVT1 were also compared among patients with different sizes of tumor. ROC curve analysis was performed to evaluate the diagnostic values of serum for cervical squamous cell carcinoma. Survival curves were plotted by Kaplan–Meier method and compared to evaluate the prognostic values of serum PVT1 for this disease. Effects of PVT1 siRNA silencing and overexpression on proliferation of cervical squamous cell carcinoma cells were explored by CCK-8 assay. Western blot was performed to detect the expression of TGF-β1 after PVT1 siRNA silencing and overexpression. Results No significant differences in serum levels of PVT1 were detected among patients infected with different HPVs and HPV-negative patients. However, serum levels of PVT1 were significantly higher in all patient groups than in healthy control group. Serum level of PVT1 increased with the increased sizes of primary tumor. Serum PVT1 accurately predicted the disease and its prognosis. PVT1 siRNA silencing inhibited the proliferation of cancer cells and reduced the expression of TGF-β1, while PVT1 overexpression played an opposite role. Conclusion LncRNA PVT1 promotes the growth HPV positive and negative cervical squamous cell carcinoma by inhibiting TGF-β1.

Accumulating data indicate that insulin resistance and unopposed estrogen are important risk factors of endometrial cancer (EC). Medroxyprogesterone 17‑acetate (MPA) has been used in the treatment of EC for many years. However, the therapeutic effect of this agent on EC has not been satisfactory. 36 arMetformin was recently reported to be a promising agent for the treatment of malignant diseases including EC. However, information on the synergistic effect of the two agents in EC is limited. With the aim to evaluate the synergistic effect of metformin and MPA, we conducted the present study in vitro and in vivo. We found that the combined application of metformin and MPA significantly inhibited the proliferation of the Ishikawa cells and arrested the cells in the G0/G1 phase. Furthermore, the apoptosis rate of the Ishikawa cells was significantly increased. In the animal study, the development of the xenograft tumors was significantly suppressed by the combined application of the two agents. Further investigation revealed that the synergistic inhibitory effect of the two agents on EC can be at least partly, explained by the decreased expression of cyclin D1 and cyclin E. The results of the current study provide novel insights into the treatment of EC.

Background Chronic activation of macrophage-mediated inflammatory signals in insulin-sensitive metabolic tissues is thought to be one of the causes of insulin resistance-one of the hallmarks of the metabolic syndrome. Insulin resistance is a feature of polycystic ovary syndrome (PCOS) and is related to mitochondrial and endothelial function. Methods In the present study, we investigated the phosphorylation level of FoxO 1, which is suppressed by the action of AKT, triggers the TLR4 inflammatory signaling pathway in the macrophages, from polycystic ovary syndrome patients or normal subjects. Then we investigated the influence of phosphorylation level of FoxO 1FoxO 1 on the induction of proinflammatory cytokines in the macrophages and the influence by FoxO FoxO 1 knockdown on the insulin-induced glucose uptake in PCOS macrophages. Results Our results demonstrated that the significantly high level of FoxO 1FoxO 1 phosphorylation correlated with the production of proinflammatory cytokines, such as IL-6, IL-1β, and TNF-α in the macrophages from PCOS patients. The high level of FoxO 1FoxO 1 phosphorylation enhanced the TLR-4 signaling in response to LPS, and the FoxO FoxO 1 knockdown inhibited the insulin-induced glucose uptake in PCOS macrophages. Conclusions The findings of this paper suggest an intriguing regulatory transcriptional/signaling loop in macrophages that may contribute to maintain and exacerbate inflammation and insulin resistance in PCOS macrophages.

The aim of the article was to evaluate the important role played by insulin in the development of endometrial cancer (EC) among Chinese premenopausal women. In this study, 128 endometrial cancer patients and 294 controls who were all premenopausal were included. Baseline characteristics data were collected and serum insulin, C-peptide, sex hormone-binding globulin, C-reaction protein, interleukin-6, and tumor necrosis factor-α levels were measured. Paired t test, χ(2) test, Spearman correlation coefficients, and univariate and multivariate logistic regression models were used in data analysis. Furthermore, insulin levels were categorized into quartiles, and likelihood ratio was calculated for the four categories. Blood insulin levels of the patients were significantly higher than those of the controls (P