Publications by authors named "Suping Han"

26 Publications

  • Page 1 of 1

Simultaneous detection of dual biomarkers using hierarchical MoS nanostructuring and nano-signal amplification-based electrochemical aptasensor toward accurate diagnosis of prostate cancer.

Biosens Bioelectron 2021 Nov 16;197:113797. Epub 2021 Nov 16.

College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, 201620, China.

Accurate and reliable quantification of tumor biomarkers in clinical samples is of vital importance for early stage diagnosis and treatment of cancer. However, a poor specificity of prostate specific antigen (PSA) testing alone fostering overdetection and overtreatment, remains a great controversy in prostate cancer (PCa) screening. Here we report an electrochemical aptasensor using hierarchical MoS nanostructuring and SiO nano-signal amplification for simultaneous detection of dual PCa biomarkers, PSA and sarcosine, to enhance the diagnostic performance of PCa. In this strategy, hierarchical flower-like MoS nanostructures as functional interface accelerated intermolecular accessibility and improved DNA hybridization efficiency. Moreover, the spherical SiO nanoprobe that conjugated with both electroactive tags and DNA probes, allowed effective electrochemical signal amplification. By deliberately designing different hybridization modes, we individually implemented the optimization of PSA and sarcosine sensing system. Based on this, simultaneous determination of PSA and sarcosine was achieved, with limit of detection (LOD) down to 2.5 fg/mL and 14.4 fg/mL, respectively, as well as excellent selectivity. More importantly, using this approach, we could directly differentiate cancer patients with healthy ones for clinical serum samples. The ultrasensitive biosensor provides single-step analysis with simple operation and a small sample volume (∼12 μL), shedding new light on accurate diagnosis and early-detection of cancer in clinical applications.
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http://dx.doi.org/10.1016/j.bios.2021.113797DOI Listing
November 2021

Research progress on intervention effect and mechanism of protocatechuic acid on nonalcoholic fatty liver disease.

Crit Rev Food Sci Nutr 2021 Jun 18:1-23. Epub 2021 Jun 18.

College of Food Science and Nutritional Engineering, Beijing Key Laboratory of Viticulture and Enology, China Agricultural University, Beijing, China.

Nonalcoholic fatty liver disease (NAFLD) has become a surge burden worldwide due to its high prevalence, with complicated deterioration symptoms such as liver fibrosis and cancer. No effective drugs are available for NALFD so far. The rapid growth of clinical demand has prompted the treatment of NAFLD to become a research hotspot. Protocatechuic acid (PCA) is a natural secondary metabolite commonly found in fruits, vegetables, grains, and herbal medicine. It is also the major internal metabolites of anthocyanins and other polyphenols. In the present manuscript, food sources, metabolic absorption, and efficacy of PCA were summarized while analyzing its role in improving NAFLD, as well as the mechanism involved. The results indicated that PCA could ameliorate NAFLD by regulating glucose and lipid metabolism, oxidative stress and inflammation, gut microbiota and metabolites. It was proposed for the first time that PCA might reduce NAFLD by enhancing the energy consumption of brown adipose tissue (BAT). However, the PCA administration mode and dose for NAFLD remain inconclusive. Fresh insights into the specific molecular mechanisms are required, while clinical trials are essential in the future. This review provides new targets and reasoning for the clinical application of PCA in the prevention and treatment of NAFLD.
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http://dx.doi.org/10.1080/10408398.2021.1939265DOI Listing
June 2021

Construction of Bio-Nano Interfaces on Nanozymes for Bioanalysis.

ACS Appl Mater Interfaces 2021 May 29;13(18):21040-21050. Epub 2021 Apr 29.

College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China.

Nanomaterials with enzyme-like activity (nanozymes) have been of great interest in broad applications ranging from biosensing to biomedical applications. Despite that much effort has been devoted to the development of the synthesis and applications of nanozymes, it is essential to understand the interactions between nanozymes and most commonly used biomolecules, i.e., avidin, streptavidin (SA), bovine serum albumin (BSA), immunoglobulin G (IgG), and glutathione (GSH), yet they have been rarely explored. Here, a series of bio-nano interfaces were constructed through direct immobilization of proteins on a variety of iron oxide and carbon-based nanozymes with different dimensions, including FeO nanoparticles (NPs, 0D), [email protected] NPs (0D), [email protected] nanowires (NWs, 1D), and graphene oxide nanosheets (GO NSs, 2D). Such interfaces enabled the modulation of the catalytic activities of the nanozymes with varying degrees, which allowed a good identification of multiplex proteins with high accuracy. Given the maximum inhibition on [email protected] NP by BSA, we established molecular switches based on aptamer and toehold DNA, as well as Boolean logic gates (AND and NOR) in response to both DNA and proteins. Also importantly, we developed an on-particle reaction strategy for colorimetric detection of GSH with ultrahigh sensitivity and good specificity. The proposed sensor achieved a broad dynamic range spanning 7 orders of magnitude with a detection limit down to 200 pg mL, which was better than that of an in-solution reaction-based biosensor by 2 orders of magnitude. Furthermore, we explored the mechanisms of the interactions at bio-nano interfaces by studying the interfacial factors, including surface coverage, salt concentration, and the curvature of the nanozyme. This study offered new opportunities in the elaborate design and better utilization of nanozymes for bioanalysis in clinical diagnosis and in vivo detection.
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http://dx.doi.org/10.1021/acsami.1c04241DOI Listing
May 2021

LBX2-AS1 promotes ovarian cancer progression by facilitating E2F2 gene expression via miR-455-5p and miR-491-5p sponging.

J Cell Mol Med 2021 01 20;25(2):1178-1189. Epub 2020 Dec 20.

Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

LBX2-AS1 is a long non-coding RNA that facilitates the development of gastrointestinal cancers and lung cancer, but its participation in ovarian cancer development remained uninvestigated. Clinical data retrieved from TCGA ovarian cancer database and the clinography of 60 ovarian cancer patients who received anti-cancer treatment in our facility were analysed. The overall cell growth, colony formation, migration, invasion, apoptosis and tumour formation on nude mice of ovarian cancer cells were evaluated before and after lentiviral-based LBX2-AS1 knockdown. ENCORI platform was used to explore LBX2-AS1-interacting microRNAs and target genes of the candidate microRNAs. Luciferase reporter gene assay and RNA pulldown assay were used to verify the putative miRNA-RNA interactions. Ovarian cancer tissue specimens showed significant higher LBX2-AS1 expression levels that non-cancerous counterparts. High expression level of LBX2-AS1 was significantly associated with reduced overall survival of patients. LBX2-AS1 knockdown significantly down-regulated the cell growth, colony formation, migration, invasion and tumour formation capacity of ovarian cancer cells and increased their apoptosis in vitro. LBX2-AS1 interacts with and thus inhibits the function of miR-455-5p and miR-491-5p, both of which restrained the expression of E2F2 gene in ovarian cancer cells via mRNA targeting. Transfection of miRNA inhibitors of these two miRNAs or forced expression of E2F2 counteracted the effect of LBX2-AS1 knockdown on ovarian cancer cells. LBX2-AS1 was a novel cancer-promoting lncRNA in ovarian cancer. This lncRNA increased the cell growth, survival, migration, invasion and tumour formation of ovarian cancer cells by inhibiting miR-455-5p and miR-491-5p, thus liberating the expression of E2F2 cancer-promoting gene.
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http://dx.doi.org/10.1111/jcmm.16185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812289PMC
January 2021

Pathogenic Heteroplasmic Somatic Mitochondrial DNA Mutation Confers Platinum-Resistance and Recurrence of High-Grade Serous Ovarian Cancer.

Cancer Manag Res 2020 2;12:11085-11093. Epub 2020 Nov 2.

Department of Pathology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, People's Republic of China.

Purpose: Platinum resistance is a primary barrier to improving the survival rate of ovarian cancer. The relationship between mtDNA somatic mutations and response to platinum-based chemotherapy in ovarian cancer has not been well clarified.

Patients And Methods: Here, we employed the next-generation sequencing (NGS) platform to identify mtDNA mutations of the unrelated high-grade serous ovarian cancer (HGSOC) patients.

Results: We identified 569 germline variants and 28 mtDNA somatic mutations, and found the platinum-sensitive relapsed HGSOC patients had more synonymous mutations while the platinum-resistant relapsed HGSOC patients had more missense mutations in the mtDNA somatic mutations. Meanwhile, we found that the HGSOC patients who harbored heteroplasmic pathogenic mtDNA somatic mutations had significantly higher prevalence of both platinum-resistance and relapse than those without (80.0% versus 16.7%, p=0.035). Additionally, we observed that the tumor tissues had significantly higher lactate-to-pyruvate (L/P) ratio than the paired nontumor tissues (p<0.001), and L/P ratio of tumors with any heteroplasmic pathogenic mtDNA mutations was significantly higher than that of the tumors free of pathogenic mtDNA mutations (p=0.025).

Conclusion: Our findings indicate that these heteroplasmic pathogenic mtDNA somatic mutations may cause decreased respiratory chain activity and lead to the metabolism remodeling that seem to be beneficial for progression of both platinum-based chemotherapy resistance and relapse.
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http://dx.doi.org/10.2147/CMAR.S277724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646460PMC
November 2020

Upregulation of bromodomain PHD finger transcription factor in ovarian cancer and its critical role for cancer cell proliferation and survival.

Biochem Cell Biol 2021 06 27;99(3):304-312. Epub 2020 Sep 27.

Department of Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.

Bromodomain PHD finger transcription factor (BPTF) is a core subunit of the nucleosome-remodeling factor (NURF) complex, which plays an important role in the development of several cancers. However, it is unknown whether BPTF regulates the progression of ovarian cancer (OC). To investigate this, we measured the relative expression levels of BPTF in OC cell lines and tissues using Western blot and immunohistochemistry, respectively, and the results were analyzed using the χ test. We also examined the effects from BPTF knockdown on the proliferation, migration, invasiveness, and apoptosis of OC cell lines. Mechanistic studies revealed that these effects were achieved through simultaneous modulation of multiple signaling pathways. We found that BPTF was highly expressed in OC cell lines and tissues compared with a normal human ovarian epithelial cell line and non-cancerous tissues ( < 0.05). These results are also supported by the public RNA-seq data. BPTF overexpression was correlated with a poor prognosis for OC patient survival ( < 0.05). In vitro experiments revealed that the downregulation of BPTF inhibited OC cell proliferation, colony formation, migration, and invasiveness, and induced apoptosis. BPTF knockdown also affected the epithelial-mesenchymal transition (EMT) signaling pathways and induced the cleavage of apoptosis-related proteins. Consequently, BPTF plays a critical role in OC cell survival, and functions as a potential therapeutic target for OC.
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http://dx.doi.org/10.1139/bcb-2020-0227DOI Listing
June 2021

Malignant ascite-derived extracellular vesicles inhibit T cell activity by upregulating Siglec-10 expression.

Cancer Manag Res 2019 29;11:7123-7134. Epub 2019 Jul 29.

Department of Obstetrics and Gynecology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China.

To evade immune defense, cancer cells can employ extracellular vesicles (EVs) to inhibit the anti-tumor activity of lymphocytes in the tumor microenvironment. However, the mechanisms and key molecules that mediate the effects of EVs on lymphocytes are unclear. We used Quantibody Human Cytokine Antibody Array 440 to determine the tumor immunity-related cytokine profile of peripheral blood lymphocytes (PBLs) stimulated with EVs derived from peritoneal washes or malignant ascites. We detected 21 upregulated and 27 downregulated proteins, including the immunosuppressive receptors Siglec-10, SLAM, PD-1, and TIM-3. Flow cytometry analysis of PBLs or ovarian cancer ascites suggested that Siglec-10 expression on CD3+ T cells was higher in ovarian cancer patients than in healthy controls and in the malignant ascites of ovarian cancer patients than in their blood. Moreover, the expression of CD24, the Siglec-10 ligand, was associated with tumor stage and cancer cell metastasis. Finally, compared to the benign peritoneal wash-derived EVs, the malignant EVs significantly upregulated Siglec-10 expression on Jurkat T cells, inhibited the protein kinase C activity induced by phorbol 12-myristate 13-acetate and ionomycin, and impaired the phosphorylation of the tyrosine kinase ZAP-70 activated by crosslinking with an anti-CD3 antibody. The EVs secreted by malignant ovarian cells upregulated Siglec-10 expression on T cells and impaired T cell activation in the tumor microenvironment. We believe that a comprehensive understanding of the regulation of Siglec-10 and CD24 by malignant EVs has clinical importance, as it will aid in the development of better immunotherapeutic strategies for ovarian cancer.
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http://dx.doi.org/10.2147/CMAR.S210568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6681125PMC
July 2019

Telomere length in cervical exfoliated cells, interaction with HPV genotype, and cervical cancer occurrence among high-risk HPV-positive women.

Cancer Med 2019 08 26;8(10):4845-4851. Epub 2019 Jun 26.

National Office for Cancer Prevention and Control, Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, China.

Background: Although high-risk human papillomavirus (HR-HPV) infection is recognized as the main cause of cervical cancer, only a minority of HPV-infected women develop this malignancy. Increasing evidence suggests that alterations of telomere length might be implicated in carcinogenesis. However, the association between cervical cancer and telomere length remains unknown.

Methods: This case-control study included 591 cervical cancer patients and 373 cancer-free controls, all of whom were infected with HR-HPV. Relative telomere length (RTL) in cervical cancer exfoliated cells was measured by quantitative PCR. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis.

Results: HPV16, 18, 52, and 58 were common in both case and control groups. The proportion of HPV16 infection tended to increase across the quartiles of RTL (P  < 0.001). There was no statistically significant association of RTL with tumor differentiation, histological type, and FIGO stage. After adjustment for age and HPV types, the lowest quartile of RTL presented a 49% lower risk (OR = 0.51, 95% CI: 0.35, 0.76; P < 0.001) than those with the highest quartile of RTL. There was also a dose-response relationship of shorter RTL on lower risk of cervical cancer (P  < 0.001).

Conclusion: Shortened telomere length in cervical exfoliated cells was related to the lower risk of cervical cancer among HR-HPV-positive women, which might help to improve cervical cancer screening and surveillance. Further prospective studies with large sample should be designed to validate our preliminary findings, and evaluate the potential efficacy of telomere length for cervical cancer screening.
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http://dx.doi.org/10.1002/cam4.2246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712472PMC
August 2019

miR-146a promotes cervical cancer cell viability via targeting IRAK1 and TRAF6.

Oncol Rep 2018 Jun 23;39(6):3015-3024. Epub 2018 Apr 23.

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210036, P.R. China.

Cervical cancer is the third most common type of cancer in women, and microRNAs play an important role in this type of cancer. The elevated expression of miR-146a is involved in the pathogenesis of cancers generally, but its role in cervical cancer has not been fully elucidated. In the present study, we assessed the expression of miR-146a in G>C polymorphisms and confirmed that the overexpression of miR-146a promoted cervical cancer cell viability. The recombinant expression plasmids pre-miR-146a-G or pre-miR-146a-C including single nucleotide polymorphisms (SNP) were successfully constructed. Pre-miR-146a-G or pre-miR-146a-C was transfected into cervical cancer cells or immortalized non-tumorigenic cells and the expression of miR-146a was evaluated by real-time PCR. The cell viability, cell-cycle analysis and apoptosis were assessed using Cell Counting Kit-8 assay (CCK-8), flow cytometry and cleaved caspase-3 protein expression, respectively. The expression of interleukin 1 receptor associated kinase 1 (IRAK1), TNF receptor-associated factor 6 (TRAF6) and cyclin D1 was assessed following the transfection with a miR-146a mimic or a negative control. The cell viability and the number of S-phase cells increased after transfection with miR-146a mimic or an IRAK1 or TRAF6 interference fragment. After transfection, IRAK1 and TRAF6 protein expression was downregulated and the expression of cyclin D1 was upregulated, however apoptosis and cleaved caspase-3 were not affected. Polymorphisms in miR-146a precursor may be linked to the expression of miR-146a and may be a potential target for cervical cancer therapy.
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http://dx.doi.org/10.3892/or.2018.6391DOI Listing
June 2018

Cytochrome P450 1A1 gene polymorphisms and cervical cancer risk: A systematic review and meta-analysis.

Medicine (Baltimore) 2018 Mar;97(13):e0210

Department of Gynecology and Obstetrics, Zhongda Hospital, School of Medicine, Southeast University Department of Gynecology and Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Objective: This meta-analysis aims to examine whether the MspI and Ile462Val polymorphisms of cytochrome P450 1A1 (CYP1A1) are associated with cervical cancer risk.

Methods: Eligible case-control studies were identified dated until July 2017. Pooled odds ratios (ORs) were used to assess the strength of the association between the two variants and cervical cancer risk.

Results: Thirteen studies were eligible (2148 cases and 2252 controls) concerning MspI polymorphism and 8 studies were eligible (1466 cases and 1690 controls) for Ile462Val polymorphism. MspI polymorphism seemed to result in cervical cancer risk in any genetic model (C allele vs T allele: OR = 1.44, 95% confidence interval [CI] = 1.16-1.79; heterozygous model: OR = 1.40, 95% CI = 1.08-1.82; homozygous model: OR = 2.22, 95% CI = 1.48-3.33, dominant model: OR = 1.50, 95% CI = 1.14-1.98 and recessive model: OR = 1.80, 95% CI = 1.35-2.41); similar significantly increased risk was found among Caucasians and Asians. Ile462Val polymorphism was associated with elevated cervical cancer risk (Val allele vs Ile allele: OR = 1.85, 95% CI = 1.27-2.67; heterozygous model: OR = 1.42, 95% CI = 1.28-1.61; homozygous model: OR = 2.94, 95% CI = 1.15-7.54; dominant model: OR = 2.00, 95% CI = 1.33-3.00); this finding was replicated upon Caucasian population.

Conclusion: This meta-analysis demonstrated that polymorphisms in MspI and Ile462Val of CYP1A1 were risk factors for developing cervical cancer.
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http://dx.doi.org/10.1097/MD.0000000000010210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895380PMC
March 2018

Potential Significance of Peptidome in Human Ovarian Cancer for Patients With Ascites.

Int J Gynecol Cancer 2018 02;28(2):355-362

Objective: Ovarian cancer (OC) is one of the lethal gynecological malignancies. Most women affected by OC with malignant ascites will relapse. Peptidomics, as an emerging branch of proteomics, is more applied in screening of disease biomarkers, diagnosis, treatment, and monitoring. However, there is still little in-depth analysis about peptidomics study in OC with malignant ascites.

Methods: A comparative peptidomic profiling of ascites fluid between 6 OC patients and 6 benign gynecological conditions using liquid chromatography-tandem mass spectrometry was analyzed. Afterward, the Ingenuity Pathway Analysis was performed to reveal the potential function of peptide-protein precursors.

Results: A total of 4388 nonredundant peptides were identified, 104 of which were significantly differentially expressed in the ascites fluid of OC and benign gynecological conditions (>2-fold changes and P < 0.05): 52 peptides were upregulated while 52 peptides were downregulated. These peptides were imported into the Ingenuity Pathway Analysis and identified putative roles in OC.

Conclusions: We identified the peptidome patterns of patients with OC and benign gynecological conditions, and these differentially expressed that peptides might play an important role during occurrence and development of OC and will be in hope to explore bioactive peptides in the pathogenesis of OC.
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http://dx.doi.org/10.1097/IGC.0000000000001166DOI Listing
February 2018

Knockdown of JARID2 inhibits the proliferation and invasion of ovarian cancer through the PI3K/Akt signaling pathway.

Mol Med Rep 2017 Sep 17;16(3):3600-3605. Epub 2017 Jul 17.

Nanjing Maternal and Child Health Institute, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210004, P.R. China.

Protein Jumonji (JARID2), a member of the family of JmjC domain-containing proteins, has been reported to serve an important role in tumor growth and metastasis. However, the expression pattern and role of JARID2 in ovarian cancer remains unclear. Therefore, in the present study, the role of JARID2 in ovarian cancer was investigated, as well as the underlying mechanisms. The results of the present study demonstrated that the expression of JARID2 is upregulated in human ovarian cancer cell lines. Furthermore, downregulation of JARID2 significantly suppressed proliferation, migration, invasion and epithelial‑mesenchymal transition in human ovarian cancer cells. Mechanistically, downregulation of JARID2 decreased the protein expression levels of phosphorylated phosphoinositide 3‑kinase (PI3K) and protein kinase B (Akt) in ovarian cancer cells. In conclusion the observations suggested that knockdown of JARID2 inhibited proliferation, migration and invasion in vitro through the inactivation of the PI3K/Akt signaling pathway. Therefore, JARID2 may represent a potential therapeutic target for the treatment of ovarian cancer.
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http://dx.doi.org/10.3892/mmr.2017.7024DOI Listing
September 2017

Comparative Gene Expression Analysis of Lymphocytes Treated with Exosomes Derived from Ovarian Cancer and Ovarian Cysts.

Front Immunol 2017 1;8:607. Epub 2017 Jun 1.

Nanjing First Hospital, Nanjing Medical University, Nanjing, China.

Cancer cells employ many strategies to evade immune defense and to facilitate tumor growth and angiogenesis. As a novel mode of intercellular communication, cancer-derived exosomes contribute to the recruitment and mediation of lymphocytes within the tumor environment. However, the mechanisms and key molecules mediating the effect of exosomes on lymphocytes are unclear. We treated healthy peripheral blood lymphocytes with exosomes from ovarian cancer and ovarian cysts and screened for differentially expressed genes using the RT Profiler Cancer Inflammation and Immunity Crosstalk PCR Array. A total of 26 upregulated genes (mainly pro-inflammatory genes and immunostimulatory and immunosuppressive factor) and two downregulated genes (antigen presentation HLA-A/B) were identified. Western blotting using lymphocytes from malignant ascites and peritoneal washings of benign ovarian cysts suggested that the interferon and NF-κB signaling pathway were involved in the immune regulation of malignant exosomes. Out of 28 differentially expressed genes detected using the array, 11 were validated by real-time PCR using lymphocytes within ovarian cancer ( = 27) and ovarian cyst ( = 9) environments. In conclusion, our findings indicate that malignant cells secrete exosomes in the tumor microenvironment to recruit lymphocytes in order to suppress antitumor immunity (IL10, Foxp3, and HLA-A/B) and enhance tumor invasion, angiogenesis, and dissemination of proinflammatory cytokines (such as IL6 and VEGFA) the interferon and NF-κB signaling pathways. These results clarify lymphocyte-cancer cell cross talk exosomes and may facilitate the development of effective immunotherapeutic strategies for ovarian cancer.
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http://dx.doi.org/10.3389/fimmu.2017.00607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451634PMC
June 2017

All-trans retinoic acid suppresses topoisomerase IIα through the proteasomal pathway.

Anticancer Drugs 2015 Aug;26(7):737-46

aDepartment of Nutrition and Food Safety, Nanjing Medical University bDepartment of Gynecology of the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Topoisomerase IIα is a nuclear enzyme that alters DNA topology. It is a well-known anticancer target and related to cell differentiation status. All-trans retinoic acid (ATRA), an important active metabolite of vitamin A, is a promising anticancer agent in numerous malignancies. However, there are little data on the effect of retinoids on topoisomerase IIα regulation. In the present study, we investigated the relationship between ATRA and topoisomerase IIα, and the potential mechanisms of ATRA on topoisomerase IIα regulation. In several human carcinoma cell lines, ATRA was shown to suppress topoisomerase IIα protein, but not mRNA expression. ATRA induced the degradation of topoisomerase IIα through the proteasome pathway, but not the lysosome pathway. Ubiquitination was involved in this degradation. Western blot and immunocytochemistry proved that ATRA-induced topoisomerase IIα repression occurred only in the cell nuclei. ATRA not only influenced the cycle procession but also reduced the expression of cyclin D1. Cyclin D1, which is involved in cell differentiation, was regulated by topoisomerase IIα. Similar to cyclin D1, knockdown of topoisomerase IIα resulted in the increased differentiation of the cells, which was in contrast to the overexpression of topoisomerase IIα in the cells. Taken together, these data suggested that ATRA could target topoisomerase IIα and exert potential beneficial effects on cell differentiation.
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http://dx.doi.org/10.1097/CAD.0000000000000241DOI Listing
August 2015

Polymorphisms of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) and endometriosis risk: a meta-analysis.

Eur J Obstet Gynecol Reprod Biol 2014 Dec 30;183:114-20. Epub 2014 Oct 30.

Department of Gynecology and Obstetrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210029, China.

Published data on the association between the glutathione S-transferases (GSTs) gene polymorphisms and endometriosis risk are inconclusive. We performed a meta-analysis to clarify the association of GSTM1 and GSTT1 polymorphisms and endometriosis risk. A comprehensive search was conducted to examine all the eligible studies of GSTM1 and GSTT1 polymorphisms and endometriosis risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. A total of 18 case-control studies were included in the meta-analysis of GSTM1 (2593 cases and 2732 controls) and GSTT1 (2520 cases and 2508 controls) genotypes. The overall results showed that the GSTM1 null genotype was related to an increased risk of endometriosis (OR=1.55, 95% CI=1.38-1.73). Similarly, for GSTT1 null polymorphism, moderate significantly increased risk was found (OR=1.30, 95% CI=1.13-1.50). In the subgroup analysis by ethnicity, significantly increased risks were also found among Caucasians and Asians for null GSTM1 genotype, and Asians for null GSTT1 genotype, but no correlation was noted in Caucasian populations for GSTT1 polymorphism. This meta-analysis provides strong evidence that the GSTM1 and GSTT1 polymorphisms are associated with the development of endometriosis.
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http://dx.doi.org/10.1016/j.ejogrb.2014.10.032DOI Listing
December 2014

Genetic variant in APE1 gene promoter contributes to cervical cancer risk.

Am J Obstet Gynecol 2013 Oct 16;209(4):360.e1-7. Epub 2013 Jul 16.

Institute of Toxicology, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China; Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention, and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.

Objective: Apurinic/apyrimidinic endonuclease 1 (APE1) is an essential enzyme in the base excision repair pathway, which plays an important role in repairing DNA damage caused by oxidation and alkylation. However, the exact mechanism of APE1 associated with cervical cancer risk is still unknown. In this study, we explored whether the APE1 -656T>G polymorphism contributed to the risk of cervical cancer.

Study Design: In the hospital-based case-control study, 306 cervical cancer cases and 306 cancer-free controls were genotyped for the APE1 -656T>G polymorphism using the polymerase chain reaction restriction fragment length polymorphism method. Luciferase reporter assay and electrophoretic mobility shift assay were used to evaluate the APE1 transcriptional activity and the binding ability of transcriptional factors to the APE1 promoter, respectively.

Results: Logistic regression analysis showed that individuals with the APE1 -656 TG/GG genotypes had a significantly reduced risk of cervical cancer compared with the TT genotype (adjusted odds ratio, 0.61; 95% confidence interval, 0.42-0.89). The luciferase assays in 3 cell lines showed that the APE1 -656T>G substitution can increase the expression of APE1, which was consistent with the finding of association study. Electrophoretic mobility shift assay further indicated that the APE1 -656T>G polymorphism enhanced the binding affinity of transcriptional factors to the promoter region.

Conclusion: These findings suggested that the APE1 -656T>G polymorphism was associated with cervical cancer risk in a Chinese population by affecting the binding affinity of transcriptional factors to the promoter, leading to an increased expression level of APE1.
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http://dx.doi.org/10.1016/j.ajog.2013.07.010DOI Listing
October 2013

Tumor necrosis factor α -308 G>A polymorphisms and cervical cancer risk: a meta-analysis.

Int J Gynecol Cancer 2012 Feb;22(2):213-9

Department of Gynecology and Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Objective: Tumor necrosis factor α (TNF-α), secreted mainly by activated macrophages, is recently involved in fighting against tumorigenesis. Tumor necrosis factor α -308 G>A, the common polymorphism in the promoter of TNF-α, has been implicated to alter the risk of cervical cancer, yet the results of relative studies are inconclusive or controversial. To derive a more precise estimation of the relationship, we performed a meta-analysis based on 8 studies.

Methods: A comprehensive search was conducted to examine all the eligible studies of TNF-α -308 G>A polymorphism and cervical cancer risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association.

Results: Eight studies regarding TNF-α -308 G>A polymorphism status including 2298 cases and 1903 controls were collected. Overall, significantly elevated cervical cancer risk was found for A allele versus G allele (OR, 1.25; 95% CI, 1.10-1.42), for GA versus GG (OR, 1.33; 95% CI, 1.14-1.54), and for GA/AA versus GG (OR, 1.31; 95% CI, 1.14-1.52). In the subgroup analysis by ethnicity, significantly increased risks were also found among whites (for A allele vs G allele: OR, 1.16; 95% CI, 1.00-1.34; for GA vs GG: OR, 1.24; 95% CI, 1.05-1.48; and for GA/AA vs GG: OR, 1.22; 95% CI, 1.03-1.44) and Asians (for A allele vs G allele: OR, 2.36; 95% CI, 1.60-3.50; AA vs GG: OR, 3.85; 95% CI, 1.30-11.37; for GA vs GG: OR, 2.06; 95% CI, 1.30-3.27; GA/AA vs GG: OR, 2.29; 95% CI, 1.49-3.52; and for AA vs

Ga/gg: OR, 3.70; 95% CI, 1.25-10.81). However, no significant associations were found among Africans for all genetic models.

Conclusions: The natural genetic polymorphism in TNF-α -308 G>A is a risk factor for developing cervical cancer, especially for Asians and whites.
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http://dx.doi.org/10.1097/IGC.0b013e3182375aedDOI Listing
February 2012

Polymorphism of the pre-miR-146a is associated with risk of cervical cancer in a Chinese population.

Gynecol Oncol 2011 Jul 29;122(1):33-7. Epub 2011 Apr 29.

Department of Gynecology and Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.

Objective: MicroRNAs are tiny non-coding RNAs that reportedly play an important role in numerous physiological processes. A G>C polymorphism (rs2910164) is located on the passenger strand of the precursor of miR-146a, which could alter mature miR-146a expression. We hypothesized that a possible association exists between miR-146a gene polymorphisms and cervical cancer risk in a population-based control study of female residents in Jiangsu Province.

Methods: The subjects included 447 cervical cancer cases and 443 cancer-free controls with frequency matched by age. We genotyped the functional polymorphism of miR-146a (rs2910164) by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, and used a sample of 24 cervical cancer tissue to test the expression of miR-146a by real-time quantitative reverse transcription.

Results: Our study indicated that the subjects carrying GG homozygote had a 1.496-fold increased risk than those carrying CG/CC genotypes (95% CI=1.068-2.095). Moreover, miR-146a quantification showed that the carriers of GG genotype had obviously more reduced miR-146a expression level compared with the carriers of CC genotype.

Conclusion: Our study suggests that the risk of cervical cancer in a Chinese population partly results from miRNA-146a expression deviation in vivo, being caused by common polymorphism in miR-146a. This is an initial study to indicate that miR-146a (rs2910164) might contribute to cervical cancer susceptibility.
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http://dx.doi.org/10.1016/j.ygyno.2011.03.032DOI Listing
July 2011

CCND1 G870A polymorphism and cervical cancer risk: a case-control study and meta-analysis.

J Cancer Res Clin Oncol 2011 Mar 15;137(3):489-94. Epub 2010 May 15.

Department of Gynecology and Obstetrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.

Purpose: Cyclin D1 (CCND1) is a key regulatory protein in the G1/S checkpoint of the cell cycle. We hypothesized that the G870A polymorphism of CCND1 is associated with the risk for cervical cancer and performed a meta-analysis of eligible studies to evaluate this relationship.

Methods: In a case-control study of 300 patients with newly diagnosed cervical cancer and 312 cancer-free controls who were frequency-matched by age, we genotyped the G870A polymorphism of CCND1 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A meta-analysis was performed using five case-control studies, including our results.

Results: No significant association was observed between the G870A polymorphism of CCND1 and cervical cancer risk. Further, in our meta-analysis, there was no significant risk of cervical cancer that correlated with the G870A polymorphism of CCND1. In the stratified analysis by race, however, individuals who harbored the AA or AA/AG genotypes were at significantly greater risk compared with GG carriers in the Asian population.

Conclusion: The G870A polymorphism in CCND1 may not contribute to the etiology of cervical cancer in Chinese populations.
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http://dx.doi.org/10.1007/s00432-010-0904-xDOI Listing
March 2011

Polymorphisms involved in the miR-218-LAMB3 pathway and susceptibility of cervical cancer, a case-control study in Chinese women.

Gynecol Oncol 2010 May 16;117(2):287-90. Epub 2010 Feb 16.

Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.

Objective: Laminin-5 is required in RAS and NF-kappaB blockade induced tumorigenesis of human squamous cell carcinoma and a marker of invasiveness in cervical lesions. MicroRNA-218 (miR-218) can target laminin-5 beta3 (LAMB3), but suppressed by HPV-16 E6 protein. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in pri-miR-218 and LAMB3 may individually and/or jointly contribute to cervical cancer carcinogenesis.

Methods: We identified one SNP rs11134527 located in pri-miR-218 sequence and one SNP rs2566 in 3'UTR of LAMB3 and genotyped these two SNPs in a case-control study of 703 cervical cancer cases and 713 cancer-free controls in Chinese women.

Results: Logistic regression analyses showed that the pri-miR-218 rs11134527 variant homozygote GG was associated with a decreased risk of cervical cancer compared with the AA genotype (adjusted OR=0.72, 95% CI=0.52-0.99), while the LAMB3 rs2566 variant CT/TT genotypes were associated with a significantly increased risk of cervical cancer (adjusted OR=1.57, 95% CI=1.25-1.96), compared with the wild type CC genotype. A significant dose-response effect was observed between the number of risk alleles, rs11134527A and rs2566 T, and the risk of cervical cancer (P for trend=0.0006).

Conclusion: These findings indicate that pri-miR-218 rs11134527 and LAMB3 rs2566 may contribute to cervical cancer carcinogenesis, and further validations in diverse populations and functional characterizations are warranted.
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http://dx.doi.org/10.1016/j.ygyno.2010.01.020DOI Listing
May 2010

The remedial effect of soluble interleukin-1 receptor type II on endometriosis in the nude mouse model.

J Biomed Res 2010 Jan;24(1):43-50

Center of Clinical Reproductive Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029 ; Suzhou Municipal Hospital & Suzhou Medical Center for Maternal and Child Health, Suzhou 215002, China.

Objective: Recent studies have shown that the local expression of soluble interleukin (IL) -1 receptor type II (sIL-1 RII) in endometrial tissue of women with endometriosis is decreased, and the depression of IL-1 RII was more significant in infertile women than that in fertile women with endometriosis. In this research, we investigated the remedial effect of sIL-1-RII administration on endometriosis in the nude mouse model.

Methods: NINETEEN NUDE MODEL MICE WITH ENDOMETRIOSIS WERE RANDOMLY DIVIDED INTO THREE GROUPS: group A was treated by intraperitoneal administration with only sIL-1 RII for two weeks, group B was similarly treated with only IL-1, and group C (control) was administered saline . After 2 weeks, the size of the ectopic endometrial lesions was calculated, and the expression of vascular endothelial growth factor (VEGF) and B-cell lymphoma leukemia-2 (Bcl-2) were detected by immunohistochemistry. The IL-8 and VEGF levels in the peritoneal fluid (PF) and serum were also measured by enzyme-linked immunosorbent assay (ELISA).

Results: The mean size of ectopic endometrial lesion did not differ between the three groups (P > 0.05). Compared with the control, the expression of VEGF and Bcl-2 was significantly lower in group A, and higher in group B. In the three groups, the levels of IL-8 in the PF and serum were highest in group A, and lowest in group B.

Conclusion: sIL-1 RII may suppresse hyperplasia of ectopic endometriosis, perhaps by reducing the expression of certain cytokines, such as VEGF, IL-8, and Bcl-2, which could provide a new clinical strategy for the treatment of endometriosis.
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http://dx.doi.org/10.1016/S1674-8301(10)60007-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3596534PMC
January 2010

Circulating IL-1beta levels, polymorphisms of IL-1B, and risk of cervical cancer in Chinese women.

J Cancer Res Clin Oncol 2010 May 11;136(5):709-16. Epub 2009 Nov 11.

Nanjing Medical University, China.

Purpose: Long-term human papillomavirus (HPV) infection is a prerequisite for cervical cancer. IL-1beta and IL-1Ra expression levels play an important role in cervical carcinogenesis. Several functional genetic variants in IL1B and IL-RN have been reported to be associated with IL-1beta expression and cancer susceptibility. In the current study, we hypothesized that plasma IL-1beta levels, IL-1B and IL-RN polymorphisms were candidate biomarkers for cervical cancer.

Methods: We measured plasma IL-1beta levels and genotyped IL-1B and IL-RN polymorphisms in a case-control study of 404 cervical cancer cases and 404 controls in Chinese women.

Results: The mean plasma IL-1beta levels in cervical cancer cases (42.19 +/- 31.55 pg/ml) was significantly higher than those in controls (34.86 +/- 22.68 pg/ml, P = 0.0002), and plasma IL-1beta levels above the 75% quartiles in controls (IL-1beta > or = 46.94 pg/ml) were associated with a 1.74-fold significantly increased risk of cervical cancer [95% confidence interval (CI), 1.28-2.36], compared with those of lowest quartile. Multivariate logistic regression analyses revealed that the variant genotypes, IL-1B T-31C TC/CC and C-511T CT/TT, were associated with a significantly increased risk of cervical cancer [adjusted odds ratio (OR), 1.60; 95% CI, 1.16-2.21 for -31TC/CC, and adjusted OR, 1.52; 95% CI, 1.10-2.09 for -511CT/TT, respectively), especially among subjects having higher levels of IL-1beta. However, IL-RN VNTR polymorphism was not associated with cervical cancer risk in the current study. Furthermore, the significant differences of IL-1beta concentration between cervical cancer cases and controls were observed only among subjects carrying T-31C or C-511T variant genotypes.

Conclusion: Functional IL-1B genotypes may modify plasma IL-1beta concentrations to contribute to the etiology of cervical cancer in Chinese women; however, further perspective studies are warranted to test the causal effects of IL-1beta concentration in cervical carcinogenesis.
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http://dx.doi.org/10.1007/s00432-009-0710-5DOI Listing
May 2010

Polymorphisms in HPV E6/E7 protein interacted genes and risk of cervical cancer in Chinese women: a case-control analysis.

Gynecol Oncol 2009 Aug 31;114(2):327-31. Epub 2009 May 31.

Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.

Objective: Accumulating studies indicate that HPV E6/E7 oncoproteins interacting genes, TP53, BRCA1 and BARD1, play a critical role in cervical carcinogenesis. We hypothesized that potentially functional polymorphisms in TP53, BRCA1 and BRAD1 may individually and/or jointly contribute to cervical cancer risk.

Methods: We genotyped 4 single nucleotide polymorphisms (SNPs) with amino acid changes, TP53 Pro72Arg (rs1042522), BRCA1 Pro871Leu (rs799917), BARD1 Pro24Ser (rs1048108) and Arg378Ser (rs2229571), in a case-control study of 404 cervical cancer cases and 404 cancer-free controls in Chinese women.

Results: Logistic regression analysis showed that the BRCA1 variant rs799917 TT genotype was associated with a significantly decreased risk of cervical cancer in a recessive genetic model (adjusted OR=0.62, 95% CI=0.40-0.95), compared with the genotypes CT/CC. However, no significant associations with cervical cancer were observed for other 3 SNPs (adjusted OR=1.01, 95% CI=0.68-1.50 for rs1048108 TT vs CT/CC; adjusted OR=1.04, 95% CI=0.67-1.64 for rs2229571 CC vs GG/GC; adjusted OR=0.84, 95% CI=0.59-1.20 for rs1042522 CC vs GG/GC).

Conclusion: These findings indicate that BRCA1 rs799917 polymorphism may contribute to the risk of cervical cancer in this Chinese population, and further validation in other populations are warranted.
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http://dx.doi.org/10.1016/j.ygyno.2009.05.011DOI Listing
August 2009

FAS promoter polymorphisms and cancer risk: a meta-analysis based on 34 case-control studies.

Carcinogenesis 2009 Mar 23;30(3):487-93. Epub 2009 Jan 23.

Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

FAS is a cell surface receptor involved in apoptotic signal transmission and plays important roles in the etiology of cancer. The -1377G>A and -670A>G polymorphisms of the FAS gene influence the FAS transcription and have been implicated in cancer risk. However, the results from the published studies on the association between these two FAS polymorphisms and cancer risk are conflicting. To derive a more precise estimation of association between the FAS polymorphisms and risk of cancer, we performed a meta-analysis of 11 461 cancer cases and 12 708 controls from 34 published case-control studies for these two polymorphisms. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. Overall, individuals with the -1377AA genotype were associated with higher cancer risk than those with the -1377GG (OR = 1.21, 95% CI: 1.08-1.36, P(heterogeneity) = 0.062) or GA/GG (OR = 1.23, 95% CI: 1.10-1.36, P(heterogeneity) = 0.060) genotypes, whereas the -670GG genotype had no effects on overall cancer risk. In the stratified analyses for the -1377G>A polymorphism, there was a significantly increased risk of breast cancer but a significantly decreased risk of melanoma in a dominant model. Moreover, a significantly increased risk was observed among smokers in a recessive model (OR = 1.96, 95% CI: 1.55-2.49; P(heterogeneity) = 0.528). Although some modest bias could not be eliminated, this meta-analysis suggested that the FAS -1377A allele is a low-penetrant risk factor for cancer development, particularly among smokers.
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http://dx.doi.org/10.1093/carcin/bgp016DOI Listing
March 2009

Interactions of IL-12A and IL-12B polymorphisms on the risk of cervical cancer in Chinese women.

Clin Cancer Res 2009 Jan;15(1):400-5

Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.

Purpose: Accumulative evidence suggests that interleukin-12 (IL-12) plays a central role in the Th1 responses and thus participates in the carcinogenesis of human papillomavirus-related cervical cancer. We hypothesized that potentially functional polymorphisms in IL12A and IL12B may individually and jointly contribute to cervical cancer risk.

Experimental Design: We genotyped IL12A rs568408 [3' untranslated region (UTR) G>A] and rs2243115 (5'UTR T>G) and IL12B rs3212227 (3'UTR A>C) in a hospital-based study of 404 cervical cancer cases and 404 cancer-free controls.

Results: The IL12A rs568408 GA/AA and IL12B rs3212227 AC/CC variant genotypes were associated with a significantly increased risk of cervical cancer [adjusted odds ratio, 1.43; 95% confidence interval (CI), 1.06-1.93; and adjusted odds ratio, 1.30; 95% CI, 0.97-1.75, respectively], compared with their corresponding wild-type homozygotes. Moreover, a significant gene-gene interaction of these 2 loci were evident in the risk of cervical cancer, and subjects carrying variant genotypes of both loci had a 1.82-fold (95% CI, 1.28-2.57) increased risk of cervical cancer. In the stratified analyses, the combined genetic effect was more pronounced in patients who had early-stage tumors or more parities. Subjects carrying rs568408 AG/AA and rs3212227 AC/CC genotypes and having >2 parities showed a 6.00-fold (95% CI, 2.86-12.56) elevated cervical cancer risk (P for multiplicative interaction = 0.046).

Conclusion: These findings suggest that IL12A rs568408 and IL12B rs3212227 may individually and jointly contribute to the risk of cervical cancer and may modify cervical cancer risk associated with parity, but these data need further validation.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-1829DOI Listing
January 2009

Effect of bisphenol A on steroid hormone production in rat ovarian theca-interstitial and granulosa cells.

Mol Cell Endocrinol 2008 Feb 25;283(1-2):12-8. Epub 2007 Oct 25.

Center of Clinical Reproductive Medicine, The First Affiliated Hospital of Nanjing Medical University, PR China.

Many studies have shown that 2,2-bis 4-hydroxyphenyl propane (BPA), an estrogenic chemical, affects the reproductive health of wildlife and possibly of humans. In this study, we investigated the effects of BPA on steroid hormone production in rat ovarian theca-interstitial cells (T-I cells) and granulosa cells. In T-I cells, BPA increased testosterone synthesis and mRNA expression of 17-alpha hydroxylase (P450c17), cholesterol side chain cleavage enzyme (P450scc) and steroidogenic acute regulatory protein (StAR) at concentrations of 10(-7) to 10(-4)M after a 72 h incubation period. Treatment of granulosa cells with BPA at concentrations of 10(-7) to 10(-5)M caused an increase in progesterone levels and P450scc mRNA expression, with an unexpected decrease at 10(-4)M. BPA (10(-7) to 10(-5)M) tended to elevate the expression of StAR mRNA with a significant increase at 10(-4)M concentration. A significant concentration-dependent inhibitory effect of BPA (10(-6) to 10(-4)M) on estradiol levels and the expression of P450arom mRNA was observed. These results suggest that BPA may interrupt ovarian steroidogenesis by altering the steroidogenic enzymes.
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http://dx.doi.org/10.1016/j.mce.2007.10.010DOI Listing
February 2008
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