CircUBE2D2 regulates HMGB1 through miR-885-5p to promote ovarian cancer malignancy.

BACKGROUND: The newly discovered CircUBE2D2 has been shown to abnormally upregulate and promote cancer progression in a variety of cancers. The present study explored circUBE2D2 (hsa_circ_0005728) in Ovarian Cancer (OC) progression. METHODS: CircUBE2D2, miR-885-5p, and HMGB1 were examined by RT-qPCR or WB. SKOV-3 cell functions (including cell viability, apoptosis, migration, and invasion) were validated using the CCK-8, flow cytometry, scratch assay, and transwell assay, respectively. The direct relationship between miR-885-5p and circUBE2D2 or HMGB1 was confirmed by a dual-luciferase reporter and RNA pull-down analysis. circUBE2D2's role in vivo tumor xenograft experiment was further probed. RESULTS: OC tissue and cell lines had higher circUBE2D2 and HMGB1 and lower miR-885-5p. Mechanically, CircUBE2D2 shared a binding relation with miR-885-5p, while miR-885-5p can directly target HMGB1. Eliminating circUBE2D2 or miR-885-5p induction inhibited OC cell activities. However, these functions were relieved by down-regulating miR-885-5p or HMGB1 induction. Furthermore, circUBE2D2 knockout reduced tumor growth. CONCLUSION: CircUBE2D2 regulates the expression of HMGB1 by acting as a sponge of ceRNA as miR-885-5p, thereby promoting the control of OC cell proliferation and migration and inhibiting cell apoptosis. Targeting CircUBE2D2 could serve as a new potential treatment strategy for OC.

Machine learning-assisted analysis of epithelial mesenchymal transition pathway for prognostic stratification and immune infiltration assessment in ovarian cancer.

Background: Ovarian cancer is the most lethal gynaecological malignancy, and serous ovarian cancer (SOC) is one of the more important pathological subtypes. Previous studies have reported a significant association of epithelial tomesenchymal transition (EMT) with invasive metastasis and immune modulation of SOC, however, there is a lack of prognostic and immune infiltration biomarkers reported for SOC based on EMT. Methods: Gene expression data for ovarian cancer and corresponding patient clinical data were collected from the TCGA database and the GEO database, and cell type annotation and spatial expression analysis were performed on single cell sequencing data from the GEO database. To understand the cell type distribution of EMT-related genes in SOC single-cell data and the enrichment relationships of biological pathways and tumour functions. In addition, GO functional annotation analysis and KEGG pathway enrichment analysis were performed on mRNAs predominantly expressed with EMT to predict the biological function of EMT in ovarian cancer. The major differential genes of EMT were screened to construct a prognostic risk prediction model for SOC patients. Data from 173 SOC patient samples obtained from the GSE53963 database were used to validate the prognostic risk prediction model for ovarian cancer. Here we also analysed the direct association between SOC immune infiltration and immune cell modulation and EMT risk score. and calculate drug sensitivity scores in the GDSC database.In addition, we assessed the specific relationship between GAS1 gene and SOC cell lines. Results: Single cell transcriptome analysis in the GEO database annotated the major cell types of SOC samples, including: T cell, Myeloid, Epithelial cell, Fibroblast, Endothelial cell, and Bcell. cellchat revealed several cell type interactions that were shown to be associated with EMT-mediated SOC invasion and metastasis. A prognostic stratification model for SOC was constructed based on EMT-related differential genes, and the Kapan-Meier test showed that this biomarker had significant prognostic stratification value for several independent SOC databases. The EMT risk score has good stratification and identification properties for drug sensitivity in the GDSC database. Conclusions: This study constructed a prognostic stratification biomarker based on EMT-related risk genes for immune infiltration mechanisms and drug sensitivity analysis studies in SOC. This lays the foundation for in-depth clinical studies on the role of EMT in immune regulation and related pathway alterations in SOC. It is also hoped to provide effective potential solutions for early diagnosis and clinical treatment of ovarian cancer.

Comprehensive Analysis of CRIP1 in Patients with Ovarian Cancer, including ceRNA Network, Immune-Infiltration Pattern, and Clinical Benefit.

BACKGROUND: With the development of sequencing technology, an increasing number of biomarkers have been identified in ovarian cancer (OC). However, there have been few comprehensive analyses of CRIP1 in patients with OC. METHODS: Logistic regression analysis was conducted to analyze the correlations between clinical characteristics and CRIP1 expression. Kaplan-Meier survival analysis was used to explore the difference in survival in each clinical subgroup. In addition, univariate and multivariate Cox regression analyses were further used to confirm the independent prognostic values of CRIP1. We further constructed ceRNA network based on the difference analysis. Subsequently, we used the ssGSEA algorithm to excavate the correlation between CRIP1 and tumor-infiltrating immune cells. Moreover, the potential biological functions of CRIP1 were investigated by gene function annotation. Finally, we knocked down CRIP1 gene for preliminary biological function verification in A2780 and SKOV-3 cell lines. RESULTS: The overexpression of CRIP1 was confirmed in The Cancer Genome Atlas (TCGA) cohort, immunohistochemistry, and OC cell lines. CRIP1 overexpression was correlated with the FIGO stage according to a logistic regression analysis that used the median of CRIP1 expression as a categorization of the dependent variable. Survival analysis revealed that CRIP1 was associated with a poor prognosis in most clinical subgroups and acts as an independent prognostic marker in OC patients. In immuno-bioinformatics analysis, CRIP1 is associated to majority of immune cells. This is noteworthy given that we identified that the ceRNA network based on CRIP1 may regulate progression in OC. In addition, gene enrichment analysis suggested CRIP1 may be involved in the JAK-STAT signaling pathway, etc. Finally, we found that knockdown CRIP1 could inhibit the proliferation of OC cells. CONCLUSION: We provided robust evidences that CRIP1 is an indicator of poor prognosis and a potential target for immunotherapy in patients with OC.

Long Noncoding RNA RMRP Contributes to Paclitaxel Sensitivity of Ovarian Cancer by Regulating miR-580-3p/MICU1 Signaling.

Ovarian cancer is a prevalent female malignancy affecting the health and life of an increasing population of women around the world. Paclitaxel (PTX) resistance is a significant clinical problem in the treatment of ovarian cancer. However, the regulation mechanism of PTX resistance remains unclear. In this investigation, we reported an innovative function of the long noncoding RNA RMRP in promoting PTX resistance and glycolysis of ovarian cancer cells. We observed that RMRP was highly expressed in the ovarian cancer samples, in which the expression of RMRP was elevated in the PTX-resistant patients compared with the PTX-sensitive patients. Meanwhile, RMRP was upregulated in PTX-resistant ovarian cancer cell lines. Functionally, we found that the silencing of RMRP by siRNA significantly enhanced the PTX sensitivity of PTX-resistant ovarian cancer cells, in which the IC50 of PTX was reduced by RMRP depletion. The RMRP knockdown reduced cell viabilities and enhanced cell apoptosis of PTX-resistant ovarian cancer cells. Moreover, we observed that glucose uptake was enhanced in PTX-resistant ovarian cancer cells. The depletion of RMRP decreased glucose uptake, lactate product, and ATP production in PTX-resistant ovarian cancer cells. About the mechanism, we identified that RMRP was able to sponge miR-580-3p to enhance mitochondrial calcium uptake 1 (MICU1) expression in PTX-resistant ovarian cancer cells. MICU1 overexpression and miR-580-3p repression could reverse the RMRP-inhibited proliferation of PTX-resistant ovarian cancer cells in vitro. Thus, we concluded that RMRP contributes to PTX resistance and glycolysis of ovarian cancer by enhancing MICU1 expression through sponging miR-580-3p. Targeting RMRP may serve as a potential therapeutic strategy for the treatment of PTX-resistant ovarian cancer patients.

Independent effect of main components in particulate matter on DNA methylation and DNA methyltransferase: A molecular epidemiology study.

BACKGROUND: There is a paucity of mechanistic information on the DNA methylation and particulate matter (PM) exposure. This study aimed to investigate the association of PM and its component with DNA methylation, and the roles of DNA methyltransferase (DNMTs). METHODS: There were 240 high-exposed, 318 low-exposed and 210 non-exposed participants in this study. Individual concentrations of PM, polycyclic aromatic hydrocarbons (PAHs) and metals were identified by the monitoring data in their workplaces. Urinary 1-OHP and metals were determined as exposure markers. The global DNA methylation (% 5mC) and the mRNA expression of DNMT1, DNMT3A and DNMT3B were measured. We used mediation analysis to evaluate the role of DNMTs expression on DNA methylation alteration induced by PAHs and metals components. RESULTS: The decreasing trend of % 5mC was associated with increment of PM exposure in all subjects. We found that one IQR increase in total PAHs (3.82 µg/m3) and urinary 1-OHP (1.06 µmol/mol creatinine) were associated with a separate 6.08% and 7.26% decrease in % 5mC (P = 0.009, P < 0.001), and one IQR increase in urinary Ni (27.75 µmol/mol creatinine) was associated with a 3.29% decrease in % 5mC (P = 0.03). The interaction of urinary 1-OHP with Ni on global DNA methylation (%5mC) was not found (P interaction = 0.89). PM exposure was significantly associated with decreased mRNA level of DNMT3B, but the mediated effect of the PAHs and Ni levels on % 5mC through the DNMT3B pathway was not observed. CONCLUSIONS: We found the decrement of global DNA methylation and DNMT3B expression with elevated PM levels in population. The independent mode of action on DNA hypomethylation was found from PAHs and metal components. Global DNA hypomethylation might be a potential biomarker for evaluation of adverse health effects in response to PM exposure.

Spatial analysis on hepatitis C virus infection in mainland China: from 2005 to 2011.

BACKGROUND: The burden of Hepatitis C virus (HCV) has become more and more considerable in China. A macroscopic spatial analysis of HCV infection that can provide scientific information for further intervention and disease control is lacking. METHODS: All geo-referenced HCV cases that had been recorded by the China Information System for Disease Control and Prevention (CISDCP) during 2005-2011 were included in the study. In order to learn about the changes of demographic characteristics and geographic distribution, trend test and spatial analysis were conducted to reflect the changing pattern of HCV infection. RESULTS: Over 770,000 identified HCV infection cases had specific geographic information during the study period (2005-2011). Ratios of gender (Male/Female, Z-value  = -18.53, P<0.001), age group (≤30 years old/≥31 years old, Z-value  = -51.03, P<0.001) and diagnosis type (Clinical diagnosis/Laboratory diagnosis, Z-value  = -130.47, P<0.001) declined. HCV infection was not distributed randomly. Provinces Henan, Guangdong, Guangxi, Xinjiang, and Jilin reported more than 40,000 HCV infections during 2005 to 2011, accounting for 43.91% of all cases. The strength of cluster of disease was increasing in China during the study period. Overall, 11 provinces had once been detected as hotspots during 7 years, most of which were located in the central or border parts of China. Tibet, Qinghai, Jiangxi were the regions that had coldspots. CONCLUSIONS: The number of clustering of HCV infection among older adults increased in recent years. Specific interventions and prevention programs targeting at main HCV epidemic areas are urgently in need in mainland China.

[Epidemiological characteristics of hepatitis C in China, 1997-2011].

OBJECTIVE: To analyze the epidemiological characteristics and changing trend as well as the related affecting factors of hepatitis C in China. METHODS: Data analysis was performed based on the case-reporting data of hepatitis C from 1997 to 2011, using SPSS 19.0. RESULTS: The number of reported cases and incidence of hepatitis C had been increasing annually since 1997, especially in 2004. The hepatitis C reported incidence increased from 3.03 per 100 000 in 2004, to 12.97 per 100 000 in 2011. The 15 to 49 age group accounted for more than 50% of all the reported cases, seen in every year. The number and proportion of hepatitis C reported cases among those over 50 year-olds had an annually increase. From 2005 to 2011, the number of cases in both urban areas and rural areas increased annually, while the urban-rural ratio decreased from 1.47 in 2005 to 0.99 in 2011. There appeared an increasing trend of hepatitis C reported incidence in China, with most of the high reported incidence of hepatitis C fell in the northern parts of China. 74.8% of the HCV/HIV co-infected cases had histories of intravenous drug use, plasma donation, blood transfusion or surgical operation. CONCLUSION: The reported number and incidence of HCV infection had been increasing annually. To develop a more realistic control measures for hepatitis C, it is necessary to strengthen the monitoring program and carrying out specific epidemiological study among target groups and key areas.

Prevalence and risk factors of hepatitis C and B virus infections in hemodialysis patients and their spouses: a multicenter study in Beijing, China.

Hemodialysis patients are at risk for hepatitis C and B virus infections. This study investigated the prevalences and risk factors of HCV and HBV infection and the distribution of HCV genotypes among hemodialysis patients and their spouses. From August to November 2011, a cross-sectional study was conducted on 20 hemodialysis units in Beijing to investigate prevalences and risk factors for markers of HCV and HBV among 2,120 patients and 409 spouses. In hemodialysis patients, prevalences of anti-HCV, HCV RNA, and hepatitis B surface antigen (HBsAg) were 6.1%, 4.6%, and 7.0%, respectively. The prevalence of HCV antibodies among spouses was 0.5%, of HCV RNA was 0.2%, and of HBsAg was 4.2%. Risk factors for HCV infection were dialysis duration, blood transfusion, and attending more than one dialysis unit. HBV infection was independently associated with age, family member with hepatitis infection, gender, and surgery. The predominant HCV genotypes were 1b (89.0%) and 2a (7.7%), and genotypes 3a, 3b, and 6a were each 1.1%. A significant decrease in HCV and HBV prevalences in Chinese dialysis units showed that infection control measures were effective. However, because nosocomial transmissions persist, strict adherence to infection control measures should be emphasized to reduce the risk of transmission.

[HIV prevalence among populations at risk, using sentinel surveillance data from 1995 to 2009 in China].

OBJECTIVE: To effectively monitor the time trend of HIV prevalence and epidemic among injecting drug users (IDUs), female sex workers (FSWs), sexually transmitted disease (STD) clinic attendants, men who have sex with men (MSM) and pregnant women etc., to provide information for evaluation on strategies regarding comprehensive HIV prevention and effectiveness of intervention, in China. METHODS: Cross-sectional studies had been repeatedly conducted on sentinel surveillance program with uniformed questionnaire and collection of venous blood specimen among IDUs, FSWs, STD clinic attendants, MSM and pregnant women, from 1995 to 2009. RESULTS: HIV prevalence (median) among IDUs had been increasing rapidly since 1996, reaching the plateau (19.2%) in 1999-2000, then gradually decreasing in 2001-2003, and leveling off since 2004 in those relatively hard-hit epidemic provinces. HIV prevalence among drug users had increased a bit since 2001, achieving high level (2.9%) in 2004 before leveling off, showing a slight downward trend in the past two years among the medially-hit epidemic provinces, while it maintained at a low level in those low epidemic provinces. HIV prevalence (median) among FSWs had been slightly increasing, reaching a high level (1.5%) in 1999, then decreased and maintained at a low level in relatively hard-hit provinces. HIV prevalence among FSWs maintained at a low level in medially-hit and low epidemic provinces. HIV prevalence (median) among STD clinic attendants had been maintained at a lower level, lower than 0.7%. HIV prevalence among MSM had been consistently greater than 1%, and was increasing year by year, becoming one of the most important drivers of the HIV/AIDS epidemic over the past years. HIV prevalence (median) among pregnant women had slightly been increasing since 1997, then leveling off over the past years in those relatively hard-hit provinces (0.3%). HIV prevalence among pregnant women had maintained at a low level in the medial and low epidemic provinces. CONCLUSION: Data from sentinel surveillance programs showed a leveling-off situation on HIV prevalence rates among IDUs, FSWs, sexually transmitted infections clinic patients and pregnant women. However, HIV prevalence among MSM had increased significantly since 2005, indicating the high speed of transmission among this population. Epidemic among IDUs had still been concentrated in those relatively hard-hit epidemic provinces. As for FSWs and STD patients, the overall epidemic remained at low level, but the areas of epidemic kept expanding.

[Situations and trends of HIV and syphilis infections among drug users in China, 1995 - 2009].

OBJECTIVE: To understand the characteristics and trends of HIV and syphilis infections among drug users. METHODS: Information was collected regarding HIV and syphilis epidemics, as well as on high risk behaviors from the HIV/AIDS surveillance system. Source of information was from HIV/AIDS case-reporting, sentinel surveillance and trend estimation, related to the changes of distribution among HIV positive drug users prevalence rates on HIV and syphilis together with their high risk behaviors. RESULTS: Scale number on drug users remained stable in the past six year (from 2003 - 2009), while the proportion of drug users decreased from 44.2% in 2005 to 25.8% in 2009. Based on the information from HIV/AIDS case reporting system, HIV sentinel surveillance data showed that the HIV prevalence of drug users was quite different from those of Southwestern to Northeastern parts of China. The HIV prevalence in Southwestern China was much higher than that of the Northeastern areas. Sentinel surveillance data showed that the average positive rates were 6.2% and 3.7% on HIV and syphilis, among the drug users. As for injecting drug users (IDU), the average rates on HIV antibody syphilis and HCV were 9.2% and 4.0% respectively. Series surveillance data indicated that the HIV epidemic expanded quickly among drug users from 1995 - 1999 but became plateaued after 2000 among the IDUs. HIV antibody positive rate remained at 9.0% - 10.0% in the past three years while syphilis fluctuated between 3.5% - 4.5% in the past three years. CONCLUSION: Drug users and IDUs still remained an important driven factor for HIV/AIDS epidemic in China, suggesting more specific strategies and methods should be developed, based on the characteristics and trends of HIV epidemic, to optimize the allocation HIV prevention and control resources.

[HIV/AIDS epidemic situation and data analysis among young students from 2006-2009 in China].

OBJECTIVE: To analyze the HIV/AIDS epidemic situation and related behavioral components among young students in the last years and to provide information for integrated control and prevention programs. METHODS: Data on young students (15 - 24 years) through case reporting system was collected from 2006 to 2009 and continuous sentinel surveillance data regarding 6 national sentinel sites carried out from 2006 to 2009 was also collected. The sentinel sites would include universities, junior college and secondary vocational colleges registered students, using cluster sampling phases method. Self-administered questionnaire survey and blood (HIV antibody testing and syphilis antibody testing) tests were carried out, with the sample size was about 800 cases per site per year. RESULTS: The number of case report on HIV/AIDS among the young students of 15 - 24 years age group had been rising. Similar trend was also observed on the number of reported cases over the years, accounting for the proportions of the total number of reported cases, as 0.39%, 0.50%, 0.83% and 1.02% respectively from 2006 to 2009. Sexual contacts continued to be the major route of transmission, with the increasing proportion of homosexual transmission. In the 6 national sentinel sites of young students which continuous surveillance was conducted during the period from 2006 to 2009, data showed the following facts as: proportion (median) of objects who admitted to have had sex, were: 4.3%, 4.5% and 6.1%, proportions (median) of commercial sex occurred in the past year were: 0.3%, 0.2% and 0.3%; proportions (median) of MSM occurred in the past year were: 0.7%, 0.2% and 0.2%; median of HIV antibody positive rate and syphilis antibody positive rate were 0%; median of awareness rate on HIV/AIDS were: 49.0%, 75.0% and 80.5%; proportion (median) of monitor objects who received intervention services in the past year were: 44.2%, 54.3% and 50.2% respectively. CONCLUSION: In recent years, the HIV/AIDS number through case reporting system on the young students under 15 - 24 years age group, was increasing, but the HIV prevalence among young students was still relatively low, in general. The main transmission was sexual. Some young students had been engaged in commercial sex and MSM activities. Health education should be strengthened to increase the awareness of young students on AIDS/STD prevention. It is necessary to take more effective intervention measures to decrease new infection and control HIV/AIDS epidemic among young students.

[Data analysis of national HIV comprehensive surveillance sites among female sex workers from 2004 to 2008].

OBJECTIVE: To monitor the time trend of behaviors change related to HIV/AIDS epidemic and HIV prevalence, and to provide information and basis for comprehensive HIV prevention responses and evaluation of intervention effectiveness among female sex workers in China. METHODS: During the year of 2004 to 2008, a series of cross-sectional surveys were conducted among female sex workers in community recruited in both entertainment places and in street, during the defined timeframe, a face-to-face interview was conducted with uniformed questionnaire; while, the venous blood specimen was collected. The sample size was 400 per site per survey. RESULTS: In 15 continuous national HIV comprehensive surveillance sites among female sex workers from 2004 to 2008, the median of HIV prevalence was 0.0%; Prevalence (median) of syphilis respectively: 0.5%, 1.8%, 1.6%, 1.8% and 1.0%. The median of target subjects who used condom in the last commercial sex was: 81.8%, 80.5%, 84.6%, 87.0% and 88.9% respectively; the median of always used condom in commercial sex during the last month: 65.8%, 59.6%, 60.3%, 59.8% and 73.7%. The median of awareness rate on HIV/AIDS transmission of female sex workers was: 74.3%, 84.1%, 65.2%, 66.0% and 74.3%. The median of target subjects who attended HIV VCT services were: 12.4%, 20.4%, 25.8%, 25.3% and 31.7%. The median of the proportion of female sex workers who reached intervention in last year respectively: 46.4%, 76.1%, 72.1%, 95.0% and 90.8%. CONCLUSION: Condom use and HIV awareness rate need to enhance further among female sex workers. The proportion of female sex workers who attended VCT and knew their HIV testing result and the proportion of female sex workers who reached intervention in last year both increase. HIV prevalence rate among female sex workers is generally low, but high risk behaviors are still alarming. It is necessary to take more comprehensive and effective prevention measures and intervention.