0.17–2% of mature cystic teratoma of the ovary (MCTO) undergo malignant transformation, of which 80% are squamous cell carcinoma (SCC) transformation in MCTO. We aim to investigate the clinical characteristics and treatment of SCC transformation in MCTO We systematically searched PubMed database and individual patient data about SCC transformation in MCTO were extracted. The published cases were combined with 6 cases of SCC transformation in MCTO from Qilu Hospital, Shandong University. The incidence of SCC transformation in MCTO was 0.3%. A total of 435 cases of SCC transformation in MCTO were enrolled in the analysis. The mean age of diagnosis was 53.5 (range 19–87) years old. The most common clinical manifestations were abdominal pain (47.3%) and abdominal mass (26.0%). StageI,II, III and IV accounted for 50.0, 18.8, 26.8 and 4.4% of all cases, respectively. Patients with stage I had significantly better prognosis than stage II, III and IV patients (P < 0.01). Hysterectomy can improve overall survival (P < 0.01). For patients younger than 45 years old with stageIA orIC, there was no difference in mortality between fertility-sparing and radical surgery (P = 1.00). Adjuvant chemotherapy can improve survival in patients with advanced stage (P = 0.02), and chemotherapy with platinum was related to better prognosis (P = 0.02). SCC transformation in MCTO is a rare malignancy mainly occurs in older age. FIGO stage is an independent prognostic factor. Hysterectomy and platinum-based chemotherapy are associated with better survival. Fertility-sparing surgery is feasible for young patients with early stage.
Abstract Progesterone resistance can significantly restrict the efficacy of conservative treatment for patients with endometrial cancer who wish to preserve their fertility or those who suffer from advanced and recurrent cancer. SREBP1 is known to be involved in the occurrence and progression of endometrial cancer, although the precise mechanism involved remains unclear. In the present study, we carried out microarray analysis in progesterone-sensitive and progesterone-resistant cell lines and demonstrated that SREBP1 is related to progesterone resistance. Furthermore, we verified that SREBP1 is over-expressed in both drug-resistant tissues and cells. Functional studies further demonstrated that the inhibition of SREBP1 restored the sensitivity of endometrial cancer to progesterone both in vitro and in vivo, and that the over-expression of SREBP1 promoted resistance to progesterone. With regards to the mechanism involved, we found that SREBP1 promoted the proliferation of endometrial cancer cells and inhibited their apoptosis by activating the NF-κB pathway. To solve the problem of clinical application, we found that Fatostatin, an inhibitor of SREBP1, could increase the sensitivity of endometrial cancer to progesterone and reverse progesterone resistance by inhibiting SREBP1 both in vitro and in vivo. Our results highlight the important role of SREBP1 in progesterone resistance and suggest that the use of Fatostatin to target SREBP1 may represent a new method to solve progesterone resistance in patients with endometrial cancer.
Ovarian cancer is the most lethal gynecological malignancy.Recurrence and chemoresistance are tough challenges leading to poor prognosis.HJURP is a molecular chaperone of CENP-A, which is associated with aggressive progression in multiple tumors.However, the function of HJURP in ovarian cancer has not been elucidated.In our study, we found HJURP was over-expressed in ovarian cancer and high expression of HJURP was correlated to unfavorable prognosis.HJURP knockdown could inhibit proliferation, metastasis and induce G0/G1 stagnation of ovarian cancer cells.Besides, next-generation sequencing (NGS) unveiled that WEE1 was down-regulated by silencing HJURP.Further mechanistic research revealed that HJURP regulated WEE1 through MYC, and luciferase assay indicated that MYC was a transcription factor of WEE1.Additionally, we investigated that silencing HJURP increased sensitivity of ovarian cancer cells to cisplatin via MYC/WEE1 axis, and HJURP participated in DNA repair of cisplatin-induced damage.More interestingly, silencing HJURP could enhance sensitivity of ovarian cancer cells to AZD1775 and improve the synergistic effect of cisplatin plus AZD1775 combined therapy.Collectively, our data displays that HJURP promotes tumor progression and chemoresistance of ovarian cancer, and HJURP has potential to be a novel therapeutic target in the combined treatment with cisplatin and AZD1775 in ovarian cancer.
Ovarian cancer is a type of gynecological cancer with the highest mortality rate worldwide. Due to a lack of effective screening methods, most cases are diagnosed at later stages where the survival rates are poor. Thus, it is termed a 'silent killer' and is the most lethal of all the malignancies in women. IQ motif containing GTPase Activating Protein 3 (IQGAP3) is a member of the Rho family of GTPases, and plays a crucial role in the development and progression of several types of cancer. The aim of the present study was to investigate the oncogenic functions and mechanisms of IQGAP3 on the proliferation and metastasis of high-grade serous ovarian cancer (HGSOC). Therefore, the expression levels of IQGAP3 in HGSOC and normal tissue samples were compared, and IQGAP3 knockdown was performed to examine its functional role using various in vitro and in vivo experiments. It was demonstrated that the expression of IQGAP3 was upregulated in HGSOC tissues compared with the healthy tissues; this differential expression was also observed in the ovarian cancer cell lines. Functional experimental results suggested that IQGAP3 silencing significantly reduced proliferation, migration and invasion in ovarian cancer cell lines. Moreover, in vivo experimental findings validated the in vitro results, where the tumorigenic and metastatic capacities of IQGAP3-silenced cells were significantly lower in the nude mice compared with the mice implanted with the control cells. Furthermore, knockdown of IQGAP3 resulted in increased apoptosis, and the effects of IQGAP3 expression on various epithelial-mesenchymal transition markers were identified, suggesting a possible mechanism associated with the role of IQGAP3 in metastasis. The effect of IQGAP3 silencing on chemosensitivity towards olaparib was also assessed. Collectively, the present results indicated that IQGAP3 is a potential diagnostic and prognostic marker, and a putative therapeutic target of HGSOC.
Abnormal lipid metabolism plays a dual role in tumorigenesis, specifically in the occurrence and development of cancers. Monoacylglycerol lipase (MAGL), a hydrolase that is important for lipid metabolism, plays a vital role in different aspects of tumorigenesis. Many studies have shown that MAGL is highly elevated in a variety of cancers and plays an active role. However, its potential role in supporting endometrial cancer (EC) growth and progression has not yet been explored in depth.Immunohistochemistry and quantitative real-time reverse transcription polymerase chain reaction were performed to estimate the protein and messenger RNA (mRNA) levels of MAGL in tumor tissues. Then, JZL184 and small interfering RNA (siRNA) were used to decrease the expression of MAGL in EC cells. The gene and protein expression levels of MAGL were measured using quantitative real-time PCR and western blotting, respectively. Additionally, the effect of MAGL on tumor growth in EC was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide , cell cycle and western blotting assay in vitro.We found that MAGL was overexpressed in EC and was significantly correlated with surgical-pathological stage, myometrial invasion, number of pregnancies and body mass index. The growth and cell cycle progression of tumor cells were significantly impaired in vitro by the pharmacological and siRNA-mediated MAGL inhibition. In addition, MAGL inhibition seemed to repress two target genes, Cyclin D1 and Bcl-2.In summary, we have demonstrated that MAGL is involved in EC growth and progression. Our results suggest that targeting MAGL may be a novel and valid treatment for EC.
Ovarian cancer is a fatal tumor in the female, majorly associated with chemotherapy resistance. Lactylation, a novel post-translational modification, is proven to be involved in multiple biological processes. This study aims to unravel the role of histone lactylation in the development of chemoresistance in ovarian cancer.
Methods
We utilized GSEA to investigate alterations in glycolysis in cisplatin sensitive/resistant patients. Differential expression of H3K9la was demonstrated using WB and IHC. Cell viability or apoptosis were measured using CCK8 or apoptosis kit, respectively. Then ChiP-seq and ChiP-qPCR were performed to identify downstream targets of H3K9la. GCN5, the potential regulator of H3K9la, was validated using protein-protein interactions and cell experiments. And IP-mass spectrometry was used to identify lactylation sites for non-histone. Lastly, we established ovarian cancer PDX models to validate the therapeutic effects of GCN5.
Results
Cisplatin-resistant ovarian cancer is characterized by increased glycolysis and H3K9la expression. Inhibiting glycolysis decreased H3K9la levels and made ovarian cancer cells more sensitive to cisplatin. RAD50 were targets of H3K9la, which facilitated HR repair and conferred cisplatin resistance. Our study also found that lactylation of RAD50 enhanced HR repair. Additionally, GCN5 was identified as an upregulator of H3K9la. When combined with cisplatin, CPTH2 was effective in repressing tumor growth and burden of PDX models.
Conclusion/Implications
Our study demonstrates the crucial importance of histone lactylation in regulating cisplatin response of ovarian cancer. Additionally, we identified novel potential therapy targets to overcome chemotherapy resistance, improving prognosis for patients.
Ovarian carcinoma remains the most lethal gynecological carcinoma. Abnormal expression of splicing factors is closely related to the occurrence and development of tumors. The DEAD-box RNA helicases are important members of the splicing factor family. However, their role in the occurrence and progression of ovarian cancer is still unclear. In this study, we identified DEAD-box helicase 23 (DDX23) as a key DEAD-box RNA helicase in ovarian cancer using bioinformatics methods. We determined that DDX23 was upregulated in ovarian cancer and its high expression predicted poor prognosis. Functional assays indicated that DDX23 silencing significantly impeded cell proliferation/invasion in vitro and tumor growth in vivo . Mechanistically, transcriptomic analysis showed that DDX23 was involved in mRNA processing in ovarian cancer cells. Specifically, DDX23 regulated the mRNA processing of FOXM1. DDX23 silencing reduced the production of FOXM1C, the major oncogenic transcript of FOXM1 in ovarian cancer, thereby decreasing the FOXM1 protein expression and attenuating the malignant progression of ovarian cancer. Rescue assays indicated that FOXM1 was a key executor in DDX23-induced malignant phenotype of ovarian cancer. Furthermore, we confirmed that DDX23 was transcriptionally activated by the transcription factor (TF) E2F1 in ovarian cancer using luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays. In conclusion, our study demonstrates that high DDX23 expression is involved in malignant behavior of ovarian cancer and DDX23 may become a potential target for precision therapy of ovarian cancer.
Abstract Endometrial cancer is a common gynecological malignancy. With the onset of EC patients younger, conservative treatment with progesterone has become an important option for patients trying to preserve reproductive function. However, progesterone resistance is a key factor affecting the efficacy of therapy and it is urgent to clarify the mechanism so as to propose a potential target and inhibit the development of endometrial adenocarcinoma and progesterone resistance. MGLL, an important factor involved in lipid mobilization, is overexpressed in many tumors, however the biological function of MGLL in the development of endometrial adenocarcinoma and the process of progesterone resistance still remains unclear. In this study, we first found MGLL was highly expressed in progesterone resistant samples of endometrial adenocarcinoma, and then we verified its expression was increased in endometrial adenocarcinoma. Through in vitro and in vivo experiments, we demonstrated that overexpression of MGLL promoted tumor proliferation, metastasis and the occurrence of progestogen resistance, knockdown MGLL inhibited tumor proliferation, metastasis and reversed progestogen resistance. In addition, knockdown of MGLL can sensitize endometrial adenocarcinoma cells to progesterone, possibly by affecting ROS generation and reducing the expression of AKR1C1. Finally, it was verified that ABX-1431, MGLL inhibitor, reversed progesterone resistance and enhanced the sensitivity of endometrial adenocarcinoma to progesterone both in vitro and in vivo. In conclusion, the high expression of MGLL is involved in the occurrence and development of endometrial adenocarcinoma and progesterone resistance. Targeted inhibition of MGLL by inhibitors may be an effective method for the treatment of progesterone resistance in endometrial adenocarcinoma.
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