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TGF-β-regulated different iron metabolism processes in the development and cisplatin resistance of ovarian cancer

Oncology Research 2024年第2期32卷 373-391页

作者： JIANFA WU QIANYI LIAO LI ZHANG SUQIN WU ZHOU LIU Department of Gynecology Shanghai University of Medicine&Health Sciences Affiliated Zhoupu HospitalShanghaiChina Department of Gynecology Shanghai University of Medicine&Health SciencesShanghaiChina Department of Gynecology Gongshan People’s HospitalNujiang Lisu Autonomous PrefectureChina

The impact of different iron metabolism processes(DIMP)on ovarian cancer remains unclear.In this study,we employed various gene chips and databases to investigate the role of DIMP in the initiation and development of ovarian cancer.cBioPortal was used to determine mutations in DIMP-associated genes in ovarian cancer.Kaplan-Meier plotter was used to examine the influence of DIMP on the prognosis of ovarian cancer.By analyzing 1669 serous ovarian cancer cases,we identified a range of mutations in iron metabolism genes,notably in those coding for the transferrin receptor(19%),melanotransferrin(19%),and ceruloplasmin(10%)in the iron import process,and glucose-6-phosphate isomerase(9%),hepcidin antimicrobial peptide(9%),metal regulatory transcription factor 1(8%),and bone morphogenetic protein 6(8%)in the iron regulation process.Compared to the unaltered group,the group with gene alterations exhibited a higher tumor mutation burden count(43 vs.54)and more advanced histologic grade(78.19%vs.87.90%).Compared to the normal ovarian counterparts,a reduction in expression was observed in 9 out of the 14 genes involved in iron utilization and 4 out of the 5 genes involved in iron export in ovarian cancer;in contrast,an increase in expression was observed in 2 out of the 3 genes involved in iron storage in ovarian cancer.Furthermore,in cisplatin-resistant cells compared to cisplatin-sensitive ones,the expression of all genes in iron storage and 13 out of 14 genes in iron import was decreased,while that of 8 out of the 10 genes in iron utilization was increased.In addition,survival curve analysis indicated that a higher expression in the majority of genes in the iron import process(12/21),or a reduced expression in most genes in the iron export process(4/5)correlated with poor progression-free survival.Additionally,TGF-βcould regulate the expression of most iron metabolism-associated genes;particularly,expression of genes involved in the iron storage process(2/2)was inhibited after TGF-β1 or TGF-β2 treatment.In conclusion,DIMP

关键词： Chemoresistance Cisplatin Iron ovarian neoplasms TGF-β

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Immune pathway through endometriosis to ovarian cancer

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World Journal of Clinical Oncology 2024年第4期15卷 496-522页

作者： Mariana Santos Calmon Fabian Fellipe Bueno Lemos Marcel Silva Luz Samuel Luca Rocha Pinheiro Luis Guilherme de Oliveira Silva Gabriel Lima Correa Santos Gabriel Reis Rocha Fabrício Freire de Melo Instituto Multidisciplinar em Saúde Universidade Federal da BahiaVitória da Conquista 45029-094BahiaBrazil

Endometriosis is an estrogen-dependent inflammatory disease,defined by the presence of functional endometrial tissue outside of the uterine cavity.This disease is one of the main gynecological diseases,affecting around 10%-15%women and girls of reproductive age,being a common gynecologic disorder.Although endometriosis is a benign disease,it shares several characteristics with invasive cancer.Studies support that it has been linked with an increased chance of developing endometrial ovarian cancer,representing an earlier stage of neoplastic processes.This is particularly true for women with clear cell carcinoma,low-grade serous carcinoma and endometrioid.However,the carcinogenic pathways between both pathologies remain poorly understood.Current studies suggest a connection between endometriosis and endometriosis-associated ovarian cancers(EAOCs)via pathways associated with oxidative stress,inflammation,and hyperestrogenism.This article aims to review current data on the molecular events linked to the development of EAOCs from endometriosis,specifically focusing on the complex relationship between the immune response to endometriosis and cancer,including the molecular mechanisms and their ramifications.Examining recent developments in immunotherapy and their potential to boost the effectiveness of future treatments.

关键词： ovarian neoplasms Endometriosis Endometriosis-associated ovarian cancers Immune response Immunotherapy

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EZH2 Contributes to Anoikis Resistance and Promotes Epithelial ovarian Cancer Peritoneal Metastasis by Regulating m6A

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当代医学科学(英文) 2023年第4期43卷 794-802页

作者： Shao-hai WANG Lin LIU Ke-yong BAO Yi-fan ZHANG Wen-wen WANG Shi DU Na-er JIA Suo SUO Jing CAI Jian-feng GUO Gang LV Department of Obstetrics and Gynecology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China Department of Obstetrics and Gynecology Affiliated Hospital of Inner Mongolia University for The NationalitiesTongliao 028000China Department of Obstetrics and Gynecology Bozhou Branch of Union HospitalBozhou 833400China Department of Obstetrics and Gynecology Bozhou People's HospitalBozhou 833400China

Objective:Histone modification has a significant effect on gene expression.Enhancer of zeste homolog 2(EZH2)contributes to the epigenetic silencing of target chromatin through its roles as a histone-lysine N-methyltransferase enzyme.The development of anoikis resistance in tumor cells is considered to be a critical step in the metastatic process of primary malignant tumors.The purpose of this study was to investigate the effect and mechanism of anoikis resistance in ovarian adenocarcinoma peritoneal metastasis.Methods:In addition to examining EZH2 protein expression in ovarian cancer omental metastatic tissues,we established a model of ovarian cancer cell anoikis and a xenograft tumor model in nude mice.Anoikis resistance and ovarian cancer progression were tested after EZH2 and N6-methyladenosine(m6A)levels were modified.Results:EZH2 expression was significantly higher in ovarian cancer omental metastatic tissues than in normal ovarian tissues.Reducing the level of EZH2 decreased the level of m6A and ovarian cancer cell anoikis resistance in vitro and inhibited ovarian cancer progression in vivo.M6a regulation altered the effect of EZH2 on anoikis resistance.Conclusion:Our results indicate that EZH2 contributes to anoikis resistance and promotes ovarian adenocarcinoma abdominal metastasis by m6A modification.Our findings imply the potential of the clinical application of m6A and EZH2 for patients with ovarian cancer.

关键词： anoikis heterografts N6-methyladenosine enhancer of zeste homolog 2 ovarian neoplasms

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Overexpression of catalytic subunit M2 in patients with ovarian cancer

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Chinese Medical Journal 2012年第12期125卷 2151-2156页

作者： WANG Li-ming LU Fei-fei ZHANG Shao-yan YAO Ru-yong XING Xiao-ming WEI Zhi-min Department of Obstetrics and Gynecology Department of Central Laboratory AffiliatedHospital of Medical College of Qingdao University QingdaoShandong 266003 China Department of Pathology AffiliatedHospital of Medical College of Qingdao University QingdaoShandong 266003 China

Background The formation and growth of tumors are related to the synthesis of the DNA. The enzyme ribonucleotide reductase （RR） is an enzyme that regulates the total rate of DNA synthesis and thus plays a pivotal role in cell growth. Catalytic subunit M2 （RRM2） is the main unit modulating the ribonucleotide reductase enzymatic activity. This study aimed to investigate the expression of RRM2 mRNA and protein in patients with ovarian cancer and its relevance to diagnosis and clinical outcome of the patients. Methods RRM2 mRNA levels and protein expression were detected in 98 ovarian specimens with immunohistochemistry and real-time quantitative polymerase chain reaction （PCR）. Expression of the RRM2 protein and correlation of the RRM2 gene expression with clinical pathological features were analyzed. The Kaplan-Meier test was used for evaluating RRM2 expression and time to progression and survival. The Cox proportional model was used to analyze the risk factors in prognosis of patients. Results Positive RRM2 immunostaining was found in 43 of 62 （69.4%） patients with epithelial ovarian cancer, 10 of 15 （66.7%） patients with borderline neoplasm, 4 of 15 （26.7%） patients with benign growths, and none of the normal group. The RRM2 mRNA levels were significantly over expressed in epithelial ovarian cancer （1.722＋0.639） and borderline ovarian neoplasms （1.365＋0.615）, compared to the normal group （0.678＋0.446） and benign group （0.828_＋0.545）. Patients with ovarian caner in clinical FIGO-stages Ill-IV presented higher RRM2 gene expression than those in clinical FIGO-stages I-I1. Furthermore, the survival of patients with low RRM2 mRNA level was significantly better than patients with high levels （P 〈0.05）. By Cox proportional risk model analysis, the risk of mortality of patients with high level expression of RRM2 mRNA was 2.553 times greater than those with low expression. Conclusion RRM2 expression closely correlates with the development of ovarian tumor and may serve as a novel predictive marker for diagnosis and progno

关键词： ovarian neoplasms ribonucleotide reductase M2 real-time quantitative polymerase chain reaction immunohistochemistry diagnosis prognosis

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Effects of an Engineered Anti-HER2 Antibody chA21 on Invasion of Human ovarian Carcinoma Cell In Vitro

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Chinese Journal of Cancer Research 2011年第2期23卷 147-152页

作者： Yi Gao Qiang Wu Zheng-sheng Wu Gui-hong Zhang An-li Zhang Department of Pathology Anhui Medical University Hefei 230032 China

Objective： HER-2 plays an important role in the development and progression of ovarian carcinoma. A number of monoclonal antibodies （MAbs） and engineered antibody fragments （such as scFvs） against the subdomain II or IV of HER-2 extracellular domain （ECD） have been developed. We investigated the effect of chA21, an engineered anti-HER-2 antibody that bind primarily to subdomain I, on ovarian carcinoma cell invasion in vitro, and explored its possible mechanisms. Methods： Growth inhibition of SK-OV-3 cells was assessed using a Methyl thiazolyl tetrazolium （MTT） assay. The invasion ability of SK-OV-3 was determined by a Transwell invasion assay. The expression of matrix metalloproteinase-2 （MMP-2） and its tissue inhibitors （TIMP-2） was detected by immunocytochemical staining, and the expression of p38 and the phosphorylation of p38 were assayed by both immunocytochemistry and Western blot. Results： After treatment with chA21, the invasion of human ovarian cancer SK-OV-3 cells was inhibited in dose- and time-dependent manners. Simultaneously the expression of p38, phospho-p38, MMP-2 and the MMP-2/TIMP-2 ratio decreased, while TIMP-2 expression increased. Additionally, the decrease in phospho-p38 was much greater than that of p38. Conclusion： chA21 may inhibit SK-OV-3 cell invasion via the signal transduction pathway involving MMP-2, TIMP-2, p38 and the activation of p38MAPK.

关键词： HER-2 ovarian neoplasms Invasion p38 mitogen-activated protein kinase Matrix metalloproteinase-2 Tissue inhibitor of matrix metalloproteinase-2

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Effect of retroperitoneal lymphadenectomy on prognosis of patients with epithelial ovarian cancer

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Chinese Medical Journal 2003年第4期116卷 588-592页

作者：王泽华熊宙芳王世宣 Department of Obstetrics and Gynecology Union HospitalTongji Medical CollegeHuazhong University of Science and Technology

To evaluate prognostic factors which have an influence on overall survival and to assess the rational application of retroperitoneal lymphadenectomy in patients with epithelial ovarian cancer Methods The data of 131 patients treated between January 1990 and December 1998 in Union Hospital and Tongji Hospital were analyzed retrospectively Survival was calculated using the Kaplan-Meier method and comparisons were performed using Log-rank test Independent prognostic factors were identified by the Cox proportional hazards regression model Results Univariate analysis showed that age, general conditions, menopausal status, stage, pathological types, location of the tumor, residual tumor and retroperitoneal lymphadenectomy were prognostic factors Multivariate analysis showed that age, stage, residual tumor, retroperitoneal lymphadenectomy and the number of courses of chemotherapy were the most important prognostic factors The survival rate could not be improved through retroperitoneal lymphadenectomy in the patients in early stage, advanced stage with residual tumor >2 cm or those with mucinous adenocarcinoma (P>0 05) Among patients in advanced stage cancer with a residual tumor ≤2 cm, 5-year survival was 65% and 30% for patients who did and did not undergo lymphadenectomy, respectively (Povarian cancer may be influenced by age, stage, residual tumor, retroperitoneal lymphadenectomy and the number of courses of chemotherapy Although retroperitoneal lymphadenectomy could improve the survival rate, it should be carried out selectively

关键词： ovarian neoplasms prognosis retroperito neal lymphadenectomy

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Expression of seprase in effusions from patients with epithelial ovarian carcinoma

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Chinese Medical Journal 2007年第8期120卷 663-668页

作者： ZHANG Meng-zhen QIAO Yu-huan Jahn M Nesland SUO Zhen-he Department of Obstetrics and Gynecology First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 China Department of Pathology Norwegian Radium Hospital Oslo N-0310 Norway

Background Seprase plays an important role in malignant cell invasion and metastasis by degrading the extracellular matrix. However, its clinical significance remains largely unknown. The objective of the current study was to evaluate the expression of seprase in effusions from patients with epithelial ovarian carcinoma and its clinical values. Methods Immunohistochemistry was used to examine the expression of seprase protein in a series of 74 malignant peritoneal （n=64） and pleural （n=10） effusions from Norwegian patients with epithelial ovarian carcinoma. Additionally, 34 effusions were evaluated using the Western blotting. Nine reactive effusions, obtained from patients with benign lesions, served as a control group. Statistical analyses were carried out by Chi-square test and Kaplan-Meier method. Results In the 74 malignant effusion specimens, 57 （77.02%） were positive for seprase, while only 2 （22.22%） of the control group were positively stained （P=-0.001）. In the malignant effusions, 17 （22.97%）, 22 （29.73%）, 22 （29.73%）, 13 （17.57%） had negative, weak, moderate and strong seprase protein expression, respectively. The expression of seprase protein was predominant in cytoplasm of carcinoma cells. Increased seprase protein was negatively associated with the overall survival rate of the patients （P=0.03）. However, there was no significant correlation between protein expression and FIGO stage, age, histology, and histological grade. By Western blotting, 27 of the 34 effusions showed the presence of both 170-kD dimeric form and 97-KD monomeric form of seprase while only 1 of the 34 had 170-KD dimeric form, which was consistent with the results of immunohistochemistry （P=0.05）. Conclusions Seprase may be involved in the development of ovarian cancer, and is a potential predictive marker for the disease.

关键词： seprase ovarian neoplasms effusion

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ovarian juvenile granulosa cell tumor associated with Maffucci’s syndrome: case report

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Chinese Medical Journal 2004年第10期117卷 1592-1594页

作者：袁键群林小娜许敬尧祝佳郑伟良 Departments of Pathology Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 China Gynecology Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 China Radiology Sir Run Run Shaw Hospital School of Medicine Zhejiang University Hangzhou 310016 China

Granulosa cell tumors (GCTs) are the most common ovarian sex-cord stromal tumors. Two histopathologically well defined patterns of GCTs are known: adult granulosa cell tumor (AGCT) and juvenile granulosa cell tumor (JGCT). JGCTs are rare and those associated with enchondromatosis are much rarer. A review of the literature revealed four previous cases of JGCT were associated with Maffucci ' s syndrome (MS),1-4 and nine with Ollier ' s disease (OD). This report describes ovarian JGCT with MS in a 21-year-old woman, and reviews the clinicopathological causes of both disorders.

关键词： ovarian neoplasms granulosa cell tumors Maffucci’s syndrome enchondromatosis

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Expression of aFGF, bFGF, and FGFR_1 in ovarian epithelialneoplasm

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Chinese Medical Journal 2004年第4期117卷 601-603页

作者：张颐郭科军尚海王亚军孙黎光 Department of Gynecology Department of Surgery Department of Biochemistry

ovarian epithelial cancer is a common malignant ovarian neoplasm with a high mortality. The factors that regulate the rapid growth of ovarian epithelial cancers are still largely unknown. There are some evidences indicating that oncogene can confer growth factor automatically onto cancer cells. The autocrine secretion hypothesis proposes that, as a result of oncogene activation, neoplastic cells can escape growth-restraining mechanism by independently producing and responding to their own growth factors. In recent years, attention has focused on fibroblast growth factor (FGF), as well as acidic fibroblast growth factor (aFGF) and basic fibroblast growth factor (bFGF), because it is a polypeptide growth factor with a widespread biological activity. In order to explore the factors responsible for the rapid growth and proliferation of human ovarian cancer, we investigated the possible role of aFGF and bFGF and their receptors (FGFR1).

关键词： fibroblast growth factor gene expression ovarian neoplasms

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Cloning of WWOX Gene and Its Growth-inhibiting Effects on ovarian Cancer Cells

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2010年第3期30卷 365-369页

作者：熊宙芳胡沙王泽华 Department of Obstetrics and Gynecology Union HospitalTongji Medical CollegeHuazhong University of Science and Technology

The growth-inhibiting and apoptosis-inducing effects of WW domain-containing oxidoreductase(WWOX) gene on ovarian cancer cell line A2780 were investigated.The full length cDNA of human WWOX gene was amplified from normal human ovary tissues.The correct cDNA of full length WWOX was subcloned into eukaryocytic expression vector pCMV.After introduction of WWOX gene into cancer cells with liposome,the WWOX mRNA and protein level in the cancer cells were detected by reverse transcription polymerase chain reaction(RT-PCR) and immunoblotting.The growth activities of cancer cells were detected by Trypan blue staining.The clone formation assay in soft agar was employed to observe the proliferation of the cancer cells.Apoptosis was examined by DNA ladder and acridine orange-ethidium bromide fluorescent staining.The results showed that 72 h after WWOX gene transfection,the WWOX expression was increased significantly(Povarian cancer cells was decreased by 16.41% to 38.49%(Povarian cancer cells,which might be potentially useful in the gene therapy of ovarian cancers.

关键词： gene expression ovarian neoplasms WW domain-containing oxidoreductase apoptosis

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