Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits t...Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits the high-est prevalence of TP53 mutations,present in>96%of cases.Despite intensive efforts to reactivate p53,no clinical drug has been approved to rescue p53 func-tion.In this study,our primary objective was to administer in vitro-transcribed(IVT)wild-type(WT)p53-mRNA to HGSOC cell lines,primary cells,and ortho-topic mouse models,with the aim of exploring its impact on inhibiting tumor growth and dissemination,both in vitro and in vivo.Methods:To restore the activity of p53,WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system.Moreover,IVT WT p53 mRNA was delivered into different HGSOC model systems(primary cells and patient-derived organoids)using liposomes and studied for proliferation,cell cycle progression,apoptosis,colony formation,and chromosomal instabil-ity.Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells,followed by ingenuity path-way analysis.In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.Results:Reactivation of the TP53 tumor suppressor gene was explored in differ-ent HGSOC model systems using newly designed IVT mRNA-based methods.The introduction of WT p53 mRNA triggered dose-dependent apoptosis,cell cycle arrest,and potent long-lasting inhibition of HGSOC cell proliferation.Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling,such as apoptosis,cell cycle regulation,and DNA damage.Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells,under-scoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress.Furthermore,in various mouse models,treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.Conclusions:The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC,providing valuable insights into the molecular mechanisms underlying p53 function and its relevance in ovarian cancer treatment.展开更多
Background:High-grade serous ovarian cancer(HGSOC)is the biggest cause of gynecological cancer-related mortality because of its extremely metastatic nature.This study aimed to explore and evaluate the characteristics ...Background:High-grade serous ovarian cancer(HGSOC)is the biggest cause of gynecological cancer-related mortality because of its extremely metastatic nature.This study aimed to explore and evaluate the characteristics of candidate factors associated with the metastasis and progression of HGSOC.Methods:Transcriptomic data of HGSOC patients’samples collected from primary tumors and matched omental metastatic tumors were obtained from three independent studies in the National Center for Biotechnology Information(NCBI)Gene Expression Omnibus(GEO)database.Differentially expressed genes(DEGs)were selected to evaluate the effects on the prognosis and progression of ovarian cancer using data from The Cancer Genome Atlas(TCGA)database.Hub genes’immune landscapes were estimated by the Tumor Immune Estimation Resource(TIMER)database.Finally,using 25 HGSOC patients'cancer tissues and 10 normal fallopian tube tissues,immunohistochemistry(IHC)was performed to quantify the expression levels of hub genes associated with International Federation of Gynecology and Obstetrics(FIGO)stages.Results:Fourteen DEGs,ADIPOQ,ALPK2,BARX1,CD37,CNR2,COL5A3,FABP4,FAP,GPR68,ITGBL1,MOXD1,PODNL1,SFRP2,and TRAF3IP3,were upregulated in metastatic tumors in every database while CADPS,GATA4,STAR,and TSPAN8 were downregulated.ALPK2,FAP,SFRP2,GATA4,STAR,and TSPAN8 were selected as hub genes significantly associated with survival and recurrence.All hub genes were correlated with tumor microenvironment infiltration,especially cancer-associated fibroblasts and natural killer(NK)cells.Furthermore,the expression of FAP and SFRP2 was positively correlated with the International Federation of Gynecology and Obstetrics(FIGO)stage,and their increased protein expression levels in metastatic samples compared with primary tumor samples and normal tissues were confirmed by IHC(P=0.0002 and P=0.0001,respectively).Conclusions:This study describes screening for DEGs in HGSOC primary tumors and matched metastasis tumors using integrated bioinformatics analyses.We identified six hub genes that were correlated with the progression of HGSOC,particularly FAP and SFRP2,which might provide effective targets to predict prognosis and provide novel insights into individual therapeutic strategies for HGSOC.展开更多
BACKGROUND Low grade serous carcinoma of the ovary(LGSOC)is a rare type of epithelial ovarian cancer with a low incidence rate.The origin of ovarian cancer has always been a hot topic in gynecological oncology researc...BACKGROUND Low grade serous carcinoma of the ovary(LGSOC)is a rare type of epithelial ovarian cancer with a low incidence rate.The origin of ovarian cancer has always been a hot topic in gynecological oncology research,and some scholars believe that the origin of ovarian malignant tumors is the fallopian tubes.Primary fallopian tube cancer is the lowest incidence of malignant tumors in the female reproductive system.There are only a few reports in the literature,but the mortality rate is very high.But in clinical practice,fallopian tube cancer is very common,but in most cases,it is classified as ovarian cancer.CASE SUMMARY We report a 54 years old postmenopausal woman who was hospitalized with a lower abdominal mass and underwent surgical treatment.The final pathological confirmation was low-grade serous carcinoma of the right ovary and low-grade serous carcinoma of the left fallopian tube.No special treatment was performed after the surgery,and the patient was instructed to undergo regular follow-up without any signs of disease progression.CONCLUSION The prognosis of LGSOC is relatively good,over 80%of patients still experience disease recurrence.展开更多
Junctional adhesion molecule-A(JAM-A),also known as the F11 receptor(F11R),is one of the tight junction components.JAM-A is a transmembrane glycoprotein that regulates many cellular processes,i.e.,angiogenesis,leukocy...Junctional adhesion molecule-A(JAM-A),also known as the F11 receptor(F11R),is one of the tight junction components.JAM-A is a transmembrane glycoprotein that regulates many cellular processes,i.e.,angiogenesis,leukocyte transendothelial migration,intercellular permeability,epithelial-to-mesenchymal transition,and platelet activation.Of note,it is involved in the pathogenesis of various cancer types,including gynecological cancers.Only a few studies are available about this cancer type.Observed aberrant JAM-A expression in gynecological cancers correlates with poor patient prognosis.To the best of our knowledge,conflicting JAM-A roles in various cancer types suggest that its involvement is complex and tumor-type specific.The underlying molecular mechanisms and pathways responsible for JAM-A functions were not fully elucidated and need to be identified.Finding appropriate novel molecular cancer biomarkers may reduce observed very high mortality rates and could contribute to personalized treatment development.The main aim of the present viewpoint article is to report the current knowledge about JAM-A participation in gynecological malignancies.展开更多
Background Oncofetal protein high-mobility-group AT-hook protein 2 （HMGA2） is reactivated in serous ovarian cancer （SOC） and its overexpression correlates with poor prognosis.To explore the mechanism,we investigat...Background Oncofetal protein high-mobility-group AT-hook protein 2 （HMGA2） is reactivated in serous ovarian cancer （SOC） and its overexpression correlates with poor prognosis.To explore the mechanism,we investigated whether HMGA2 could avoid microRNA regulation due to gene truncation or 3＇ UTR shortening by alternative polyadenylation.Methods Real-time reverse transcription polymerase chain reaction （RT-PCR） was used to evaluate the abundance of different regions of HMGA2 mRNA in 46 SOC samples.Rapid amplification of cDNA 3＇ ends （3＇ RACE） and Southern blotting were used to confirm the shortening of 3＇ untranslated region （UTR）.5＇ RACE and Southern blotting were used to prove the mRNA decay.Results No significant difference in the ratio of the stable coding region to the fragile region was observed between SOC and control normal fallopian tubes,indicating that the HMGA2 gene is not truncated in SOC.Varying degrees of 3＇ UTR shortening in SOC samples were observed by comparing the abundance of the proximal region and distal region of the HMGA2 3＇ UTR.The ratio of the proximal to the distal region of the 3＇ UTR correlated significantly with expression of the HMGA2 coding region in SOC （r=0.579,P ＜0.01）.Moreover,although the abundance of the HMGA2 coding region varied,all samples,including the very low expressed samples,exhibit relatively high levels of the proximal 3＇ UTR region,suggesting a dynamic decay of HMGA2 mRNA from the 5＇ end.The shortening of 3＇ UTR and the decay from the 5＇ end were confirmed by 3＇ RACE,5＇ RACE and subsequent Southern blotting.Conclusion Heterogeneous 3＇ UTR lengths render HMGA2 susceptible to different levels of negative regulation by microRNAs,which represents an important mechanism of HMGA2 reactivation in SOC.展开更多
Background： Ovarian cancer is the most common cause of gynecological cancer-associated death. Iatrogenic menopause might adversely affect the quality of life and health outcomes in young female cancer survivors. We e...Background： Ovarian cancer is the most common cause of gynecological cancer-associated death. Iatrogenic menopause might adversely affect the quality of life and health outcomes in young female cancer survivors. We evaluated whether postoperative hormone replacement therapy （HRT） had a negative influence on the progression-free survival （PFS） of patients with papillary serous ovarian cancer （SOC）. Methods： We retrospectively reviewed the medical records of patients with papillary SOC, treated from January 1980 to December 2009, who suffered from menopause with or without HRT. Clinical characteristics of patients were compared between the two groups （HRT and non-HRT）. Blood samples were collected from all the participants to detect serum cancer antigen （CA） 125. Hazard ratios with 95% confidential intervals for each variable were calculated by univariable and multivariable conditional Logistic regression analyses. Results： Among 112 identified patients, 31 were HRT users and 81 were not. The two groups did not significantly differ in median age at diagnosis （t = 0.652, P = 0.513）, International Federation of Gynecology and Obstetrics （FIGO） stage （X2 = 0.565, P = 0.754）, differentiation （X2 = 1.728, P = 0.422）, resection status （X2 = 0.070, P = 0.791）, relapse （X2 = 0.109, P = 0.741）, chemotherapy course （t = -1.079, P - 0.282）, follow-up interval （t = 0.878, P = 0.382）, or PFS （t = 0.580, P = 0.562）. Median Kupperman score at the onset of HRT was 30.81 and 12.19 after the therapy （t： 3.302, P = 0.001）. According to the analysis, the strongest independent variables in predicting PFS were FIGO stage and disease that was not optimally debulked. Conclusions： Postoperative HRT is not a prognostic factor for PFS of patients with papillary SOC. However, multicenter studies are needed to verify and extend our findings.展开更多
基金This work was supported by grants from the Deutsche Krebshilfe(70114007)Wilhelm Sander Stiftung(Nr.2021.023.1),German Cancer Consortium(DKTK),Heidelberg.
文摘Background:The cellular tumor protein p53(TP53)is a tumor suppressor gene that is frequently mutated in human cancers.Among various cancer types,the very aggressive high-grade serous ovarian carcinoma(HGSOC)exhibits the high-est prevalence of TP53 mutations,present in>96%of cases.Despite intensive efforts to reactivate p53,no clinical drug has been approved to rescue p53 func-tion.In this study,our primary objective was to administer in vitro-transcribed(IVT)wild-type(WT)p53-mRNA to HGSOC cell lines,primary cells,and ortho-topic mouse models,with the aim of exploring its impact on inhibiting tumor growth and dissemination,both in vitro and in vivo.Methods:To restore the activity of p53,WT p53 was exogenously expressed in HGSOC cell lines using a mammalian vector system.Moreover,IVT WT p53 mRNA was delivered into different HGSOC model systems(primary cells and patient-derived organoids)using liposomes and studied for proliferation,cell cycle progression,apoptosis,colony formation,and chromosomal instabil-ity.Transcriptomic alterations induced by p53 mRNA were analyzed using RNA sequencing in OVCAR-8 and primary HGSOC cells,followed by ingenuity path-way analysis.In vivo effects on tumor growth and metastasis were studied using orthotopic xenografts and metastatic intraperitoneal mouse models.Results:Reactivation of the TP53 tumor suppressor gene was explored in differ-ent HGSOC model systems using newly designed IVT mRNA-based methods.The introduction of WT p53 mRNA triggered dose-dependent apoptosis,cell cycle arrest,and potent long-lasting inhibition of HGSOC cell proliferation.Transcriptome analysis of OVCAR-8 cells upon mRNA-based p53 reactivation revealed significant alterations in gene expression related to p53 signaling,such as apoptosis,cell cycle regulation,and DNA damage.Restoring p53 function concurrently reduces chromosomal instability within the HGSOC cells,under-scoring its crucial contribution in safeguarding genomic integrity by moderating the baseline occurrence of double-strand breaks arising from replication stress.Furthermore,in various mouse models,treatment with p53 mRNA reduced tumor growth and inhibited tumor cell dissemination in the peritoneal cavity in a dose-dependent manner.Conclusions:The IVT mRNA-based reactivation of p53 holds promise as a potential therapeutic strategy for HGSOC,providing valuable insights into the molecular mechanisms underlying p53 function and its relevance in ovarian cancer treatment.
基金supported by the grant from Beijing Natural Science Foundation(No.7222202)
文摘Background:High-grade serous ovarian cancer(HGSOC)is the biggest cause of gynecological cancer-related mortality because of its extremely metastatic nature.This study aimed to explore and evaluate the characteristics of candidate factors associated with the metastasis and progression of HGSOC.Methods:Transcriptomic data of HGSOC patients’samples collected from primary tumors and matched omental metastatic tumors were obtained from three independent studies in the National Center for Biotechnology Information(NCBI)Gene Expression Omnibus(GEO)database.Differentially expressed genes(DEGs)were selected to evaluate the effects on the prognosis and progression of ovarian cancer using data from The Cancer Genome Atlas(TCGA)database.Hub genes’immune landscapes were estimated by the Tumor Immune Estimation Resource(TIMER)database.Finally,using 25 HGSOC patients'cancer tissues and 10 normal fallopian tube tissues,immunohistochemistry(IHC)was performed to quantify the expression levels of hub genes associated with International Federation of Gynecology and Obstetrics(FIGO)stages.Results:Fourteen DEGs,ADIPOQ,ALPK2,BARX1,CD37,CNR2,COL5A3,FABP4,FAP,GPR68,ITGBL1,MOXD1,PODNL1,SFRP2,and TRAF3IP3,were upregulated in metastatic tumors in every database while CADPS,GATA4,STAR,and TSPAN8 were downregulated.ALPK2,FAP,SFRP2,GATA4,STAR,and TSPAN8 were selected as hub genes significantly associated with survival and recurrence.All hub genes were correlated with tumor microenvironment infiltration,especially cancer-associated fibroblasts and natural killer(NK)cells.Furthermore,the expression of FAP and SFRP2 was positively correlated with the International Federation of Gynecology and Obstetrics(FIGO)stage,and their increased protein expression levels in metastatic samples compared with primary tumor samples and normal tissues were confirmed by IHC(P=0.0002 and P=0.0001,respectively).Conclusions:This study describes screening for DEGs in HGSOC primary tumors and matched metastasis tumors using integrated bioinformatics analyses.We identified six hub genes that were correlated with the progression of HGSOC,particularly FAP and SFRP2,which might provide effective targets to predict prognosis and provide novel insights into individual therapeutic strategies for HGSOC.
文摘BACKGROUND Low grade serous carcinoma of the ovary(LGSOC)is a rare type of epithelial ovarian cancer with a low incidence rate.The origin of ovarian cancer has always been a hot topic in gynecological oncology research,and some scholars believe that the origin of ovarian malignant tumors is the fallopian tubes.Primary fallopian tube cancer is the lowest incidence of malignant tumors in the female reproductive system.There are only a few reports in the literature,but the mortality rate is very high.But in clinical practice,fallopian tube cancer is very common,but in most cases,it is classified as ovarian cancer.CASE SUMMARY We report a 54 years old postmenopausal woman who was hospitalized with a lower abdominal mass and underwent surgical treatment.The final pathological confirmation was low-grade serous carcinoma of the right ovary and low-grade serous carcinoma of the left fallopian tube.No special treatment was performed after the surgery,and the patient was instructed to undergo regular follow-up without any signs of disease progression.CONCLUSION The prognosis of LGSOC is relatively good,over 80%of patients still experience disease recurrence.
文摘Junctional adhesion molecule-A(JAM-A),also known as the F11 receptor(F11R),is one of the tight junction components.JAM-A is a transmembrane glycoprotein that regulates many cellular processes,i.e.,angiogenesis,leukocyte transendothelial migration,intercellular permeability,epithelial-to-mesenchymal transition,and platelet activation.Of note,it is involved in the pathogenesis of various cancer types,including gynecological cancers.Only a few studies are available about this cancer type.Observed aberrant JAM-A expression in gynecological cancers correlates with poor patient prognosis.To the best of our knowledge,conflicting JAM-A roles in various cancer types suggest that its involvement is complex and tumor-type specific.The underlying molecular mechanisms and pathways responsible for JAM-A functions were not fully elucidated and need to be identified.Finding appropriate novel molecular cancer biomarkers may reduce observed very high mortality rates and could contribute to personalized treatment development.The main aim of the present viewpoint article is to report the current knowledge about JAM-A participation in gynecological malignancies.
文摘Background Oncofetal protein high-mobility-group AT-hook protein 2 （HMGA2） is reactivated in serous ovarian cancer （SOC） and its overexpression correlates with poor prognosis.To explore the mechanism,we investigated whether HMGA2 could avoid microRNA regulation due to gene truncation or 3＇ UTR shortening by alternative polyadenylation.Methods Real-time reverse transcription polymerase chain reaction （RT-PCR） was used to evaluate the abundance of different regions of HMGA2 mRNA in 46 SOC samples.Rapid amplification of cDNA 3＇ ends （3＇ RACE） and Southern blotting were used to confirm the shortening of 3＇ untranslated region （UTR）.5＇ RACE and Southern blotting were used to prove the mRNA decay.Results No significant difference in the ratio of the stable coding region to the fragile region was observed between SOC and control normal fallopian tubes,indicating that the HMGA2 gene is not truncated in SOC.Varying degrees of 3＇ UTR shortening in SOC samples were observed by comparing the abundance of the proximal region and distal region of the HMGA2 3＇ UTR.The ratio of the proximal to the distal region of the 3＇ UTR correlated significantly with expression of the HMGA2 coding region in SOC （r=0.579,P ＜0.01）.Moreover,although the abundance of the HMGA2 coding region varied,all samples,including the very low expressed samples,exhibit relatively high levels of the proximal 3＇ UTR region,suggesting a dynamic decay of HMGA2 mRNA from the 5＇ end.The shortening of 3＇ UTR and the decay from the 5＇ end were confirmed by 3＇ RACE,5＇ RACE and subsequent Southern blotting.Conclusion Heterogeneous 3＇ UTR lengths render HMGA2 susceptible to different levels of negative regulation by microRNAs,which represents an important mechanism of HMGA2 reactivation in SOC.
文摘Background： Ovarian cancer is the most common cause of gynecological cancer-associated death. Iatrogenic menopause might adversely affect the quality of life and health outcomes in young female cancer survivors. We evaluated whether postoperative hormone replacement therapy （HRT） had a negative influence on the progression-free survival （PFS） of patients with papillary serous ovarian cancer （SOC）. Methods： We retrospectively reviewed the medical records of patients with papillary SOC, treated from January 1980 to December 2009, who suffered from menopause with or without HRT. Clinical characteristics of patients were compared between the two groups （HRT and non-HRT）. Blood samples were collected from all the participants to detect serum cancer antigen （CA） 125. Hazard ratios with 95% confidential intervals for each variable were calculated by univariable and multivariable conditional Logistic regression analyses. Results： Among 112 identified patients, 31 were HRT users and 81 were not. The two groups did not significantly differ in median age at diagnosis （t = 0.652, P = 0.513）, International Federation of Gynecology and Obstetrics （FIGO） stage （X2 = 0.565, P = 0.754）, differentiation （X2 = 1.728, P = 0.422）, resection status （X2 = 0.070, P = 0.791）, relapse （X2 = 0.109, P = 0.741）, chemotherapy course （t = -1.079, P - 0.282）, follow-up interval （t = 0.878, P = 0.382）, or PFS （t = 0.580, P = 0.562）. Median Kupperman score at the onset of HRT was 30.81 and 12.19 after the therapy （t： 3.302, P = 0.001）. According to the analysis, the strongest independent variables in predicting PFS were FIGO stage and disease that was not optimally debulked. Conclusions： Postoperative HRT is not a prognostic factor for PFS of patients with papillary SOC. However, multicenter studies are needed to verify and extend our findings.
