Therapeutic Target For Ovarian Cancer Research Articles

Insulin-like growth factor 2 mRNA-binding protein 2 is a therapeutic target in ovarian cancer.

Ovarian cancer (OC) is a fatal gynecologic disease. The most common treatment for OC patients is surgery combined with chemotherapy but most patients at advanced stages eventually develop relapse due to chemoresistance. This study examined the role and function of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) in OC. We observed that the expression of IGF2BP2 mRNA and protein was up-regulated in OC cells and tissues using quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. An increase in IGF2BP2 expression at mRNA and protein levels was verified by the analyses of The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC), respectively. Gene Expression Omnibus (GEO) and Cancer Cell Line Encyclopedia (CCLE) databases were applied to analyze the expression and clinical value of IGF2BP2. Gene set enrichment analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) analyses explored biological functions and the involvement of IGF2BP2 in cell growth. Indeed, the knockdown of IGF2BP2 resulted in the inhibition of OC cell proliferation evaluated by the Cell Counting Kit-8 assay. Genomic amplification of IGF2BP2 partly accounted for its overexpression. High expression of IGF2BP2 was associated with signal transducer and activator of transcription 1 (STAT1) and drug sensitivity and was correlated with an unfavorable survival outcome in OC patients. Furthermore, the responsiveness of chemotherapy and immunotherapy were analyzed using the "pRRophetic" R package and The Cancer Immune Atlas (TCIA) database, respectively. The low expression of IGF2BP2 was associated with chemoresistance but with high tumor microenvironment scores and tumor-infiltrating immune cells, suggesting that immunotherapy may apply in chemoresistant patients. The alteration of IGF2BP2 expression may respond to chemotherapy and immunotherapy. Thus, IGF2BP2 shows potential as a therapeutic target and diagnostic biomarker for OC.

Doublecortin-like kinase 1 (DCLK1) Promotes Platinum-Resistance and is a Novel Therapeutic Target for Ovarian Cancer

Doublecortin-like kinase 1 (DCLK1) Promotes Platinum-Resistance and is a Novel Therapeutic Target for Ovarian Cancer

Abstract B095: Sacituzumab govitecan-based drug combinations overcome platinum/PARP inhibitor resistance in ovarian cancer models

Abstract Background: Ovarian cancer causes more deaths than any other gynaecological cancer per year in the USA. Sacituzumab govitecan (SG) is a TROP2-targeted antibody-drug conjugate, approved for the treatment of triple-negative and hormone receptor-positive breast cancers. TROP2 is commonly overexpressed in ovarian cancer and represents an attractive, potential therapeutic target in ovarian cancer. This study investigated the in vitro activity of SG alone and in combination with targeted therapies/chemotherapies in ovarian cancer cell line models. Methods: This study utilized the PEO1 and PEO4 cell lines, which were derived from the same patient, with PEO4 acquiring a secondary restorative BRCA2 mutation to confer platinum resistance. Olaparib-resistant PEO1 (PEO1-Ola) cells were generated through continuous exposure to olaparib, to a maximum 13 μM, for four months. The anti-proliferative effects of SG, talazoparib, olaparib, carboplatin, and paclitaxel were tested in PEO1, PEO1-Ola, and PEO4 cell lines. Synergism was assessed using Combenefit software with the Loewe additivity model. Induction of caspase 3/7 activation, a marker of apoptosis, was tested with single agents and combinations using kinetic, fluorescent microscopy with the Incucyte S3 imaging system. Results: Olaparib and carboplatin resistance did not result in their cross-resistance. PEO1-Ola showed similar sensitivity to carboplatin as PEO1 parental cells, while carboplatin-resistant PEO4 cells displayed clinically achievable sensitivity to olaparib and talazoparib. SG was highly effective in all models tested. SG in combination with carboplatin or talazoparib was synergistic across all cell lines and resulted in induction of apoptosis. Conclusions: This pre-clinical study showed that TROP2-targeting ADC-based drug combinations warrant further investigation for the treatment of ovarian cancer. Citation Format: Neil T Conlon, Elena Möhrle, Luna Stockmann, John Crown. Sacituzumab govitecan-based drug combinations overcome platinum/PARP inhibitor resistance in ovarian cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B095.

Revealing the inhibitory effect of VASH1 on ovarian cancer from multiple perspectives

ABSTRACT The function of Vasohibin-1 (VASH1) in human cancer has not been thoroughly or comprehensively examined. Here, we identified the tumor suppressor part of VASH1 across cancers, including epithelial ovarian tumors. Our study carefully contrasted the expression of VASH1 in pancancer and nontumorous tissues in a public database to explore its regulatory role in clinical prognosis, diagnosis, tumor purity, and immune cell infiltration. Next, we explored the antitumor mechanism of VASH1 through drug sensitivity, functional enrichment, and phenotypic experiments in ovarian cancer. Research suggests that the expression of VASH1 in neoplastic tissues is lower than that in normal tissues. VASH1 affects the OS and RFS of several tumor types. In addition, VASH1 expression resulted in a high OS and RFS in the diagnosis of tumor and nontumor tissues and negatively regulated tumor purity. Moreover, VASH1 controls the tumor microenvironment by regulating immunocyte infiltration. In ovarian cancer, VASH1 can serve as a biomarker to estimate the efficacy of chemotherapy. Functional enrichment analysis suggests that VASH1 plays a tumor suppressor role by regulating the extracellular matrix receptor pathway. VASH1 inhibition of the malignant phenotype of ovarian cancer cells was further confirmed by in vivo experiments. These results indicate that VASH1 acts as a cancer-inhibiting factor and potential therapeutic target in ovarian cancer.

Extracellular vesicle-encapsulated microRNA-296-3p from cancer-associated fibroblasts promotes ovarian cancer development through regulation of the PTEN/AKT and SOCS6/STAT3 pathways.

Cancer-associated fibroblasts (CAFs), as important components of the tumor microenvironment, can regulate intercellular communication and tumor development by secreting extracellular vesicles (EVs). However, the role of CAF-derived EVs in ovarian cancer has not been fully elucidated. Here, using an EV-microRNA sequencing analysis, we reveal specific overexpression of microRNA (miR)-296-3p in activated CAF-derived EVs, which can be transferred to tumor cells to regulate the malignant phenotypes of ovarian cancer cells. Moreover, overexpression of miR-296-3p significantly promotes the proliferation, migration, invasion, and drug resistance of ovarian cancer cells invitro, as well as tumor growth invivo, while its inhibition has the opposite effects. Further mechanistic studies reveal that miR-296-3p promotes ovarian cancer progression by directly targeting PTEN and SOCS6 and activating AKT and STAT3 signaling pathways. Importantly, increased expression of miR-296-3p encapsulated in plasma EVs is closely correlated with tumorigenesis and chemoresistance in patients with ovarian cancer. Our results highlight the cancer-promoting role of CAF-derived EVs carrying miR-296-3p in ovarian cancer progression for the first time, and suggest that miR-296-3p encapsulated in CAF-derived EVs could be a diagnostic biomarker and therapeutic target for ovarian cancer.

Cancer stemness kinase inhibitor amcasertib: a promising therapeutic agent in ovarian cancer stem and cancer cell models with different genetic profiles.

Ovarian cancer, often referred to as the 'silent killer,' is a significant contributor to mortality rates. Emerging evidence implicates Nanog as a potential therapeutic target in ovarian cancer. Amcasertib (BBI-503) is an orally administered primary class stemness kinase inhibitor that effectively targets NANOG and various cancer stem cell pathways by specifically inhibiting serine-threonine stemness kinases. This study aimed to evaluate the antineoplastic effects of Nanog inhibition, a critical transcription factor associated with pluripotency and its role in ovarian cancer tumorigenesis, using the novel therapeutic agent Amcasertib in ovarian cancer cells characterized by distinct genetic profiles. The cytotoxicity of Amcasertib was assessed in both ovarian cancer and cancer stem cell models utilizing the Xelligence-RTCA system. The impact of the determined IC50 dose on apoptosis, invasion, migration, epithelial-mesenchymal transition (EMT), cell cycle progression, colony formation, and spheroid growth was evaluated using appropriate analytical techniques. Our findings revealed that Amcasertib exhibited significant antiproliferative effects and induced apoptosis in ovarian cancer and cancer stem cells. Moreover, Amcasertib caused G1 phase arrest and impeded colony formation in MDAH-2774 cells. Additionally, Amcasertib effectively inhibited spheroid growth in OVCAR-3 and OCSC cells. Notably, it demonstrated the ability to suppress invasion and migration in MDAH-2774 and OCSC cells. Furthermore, the suppression of Nanog-mediated stem cell-like features by Amcasertib was particularly pronounced in ER-negative ovarian cancer and cancer stem cells, highlighting its high anticancer efficacy in this subgroup. These results suggest that Amcasertib holds promise as a potential standalone or combination therapy agent for the treatment of ER-negative ovarian cancer.

MicroRNA-10a-5p-mediated downregulation of GATA6 inhibits tumor progression in ovarian cancer.

Ovarian cancer is the common cause of cancer-related death in women and is considered the most deadly gynecological cancer. It has been established that GATA-binding protein 6 (GATA6) is abnormally expressed in several types of malignant tumors and acts as an oncogenic protein or a tumor suppressor. However, the underlying mechanism of GATA6 in ovarian cancer progression has not been elucidated. Data in the present study revealed that GATA6 expression was negatively correlated to microRNA-10a-5p (miR-10a-5p) in ovarian cancer tissue and cells and that GATA6 is directly targeted by miR-10a-5p. Notably, upregulated miR-10a-5p dramatically inhibited ovarian cancer cell proliferation, tumorigenic ability, migration, and invasion by targeting GATA6. In vitro and in vivo experiments confirmed that miR-10a-5p-mediated downregulation of GATA6 suppressed Akt pathway activation. Overall, our findings suggest that miR-10a-5p could be a novel therapeutic target for ovarian cancer, and targeting the miR-10a-5p/GATA6/Akt axis could improve outcomes in this patient population.

Copine 1 predicts poor clinical outcomes by promoting M2 macrophage activation in ovarian cancer.

Copine 1 (CPNE1), a membrane-binding protein, influences the prognosis of various cancers. According to cBioPortal, CPNE1 amplification is a prevalent genetic mutation in ovarian cancer but with unknown oncogenic mechanism. This study analysed the CPNE1 expression in ovarian cancer using online datasets, as validated by immunohistochemistry (IHC), quantitative polymerase chain reaction (qPCR) and western blotting. Concurrently, the prognostic value of CPNE1 was accessed. Cell Counting Kit-8, colony formation, transwells and xenograft experiments were performed to evaluate the functions of CPNE1 during ovarian cancer carcinogenesis. CPNE1 and its related genes were analysed by g:Profiler and Tumour Immune Estimation Resource. Furthermore, human monocytic THP-1 cells were co-cultured with ES2 cells to investigate the effect of CPNE1 on macrophage polarization. The results of bioinformatic analysis, IHC, qPCR and western blotting indicated a higher CPNE1 in ovarian cancer. CPNE1 overexpression demonstrated an association with a poor prognosis of ovarian cancer. Functionally, CPNE1 overexpression increased ES2 and SKOV3 cell proliferation, invasion and migration in vitro and promoted ovarian tumour xenograft growth in vivo, while CPNE1 knockdown led to opposite effects. Additionally, CPNE1 expression demonstrated an association with immune cell infiltration in ovarian cancer, especially macrophage. CPNE1 promoted protumour M2 macrophage polarization by upregulating cluster of differentiation 163 (CD163), CD206 and interleukin-10. Our study revealed that CPNE1 mediated M2 macrophage polarization and provided a therapeutic target for ovarian cancer.

Endoplasmic Reticulum Stress-Related Ten-Biomarker Risk Classifier for Survival Evaluation in Epithelial Ovarian Cancer and TRPM2: A Potential Therapeutic Target of Ovarian Cancer.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignant tumor. Endoplasmic reticulum (ER) stress plays an important role in the malignant behaviors of several tumors. In this study, we established a risk classifier based on 10 differentially expressed genes related to ER stress to evaluate the prognosis of patients and help to develop novel medical decision-making for EOC cases. A total of 378 EOC cases with transcriptome data from the TCGA-OV public dataset were included. Cox regression analysis was used to establish a risk classifier based on 10 ER stress-related genes (ERGs). Then, through a variety of statistical methods, including survival analysis and receiver operating characteristic (ROC) methods, the prediction ability of the proposed classifier was tested and verified. Similar results were confirmed in the GEO cohort. In the immunoassay, the different subgroups showed different penetration levels of immune cells. Finally, we conducted loss-of-function experiments to silence TRPM2 in the human EOC cell line. We created a 10-ERG risk classifier that displays a powerful capability of survival evaluation for EOC cases, and TRPM2 could be a potential therapeutic target of ovarian cancer cells.

Advance in vasculogenic mimicry in ovarian cancer (Review).

Ovarian cancer (OC) is a common and highly prevalent malignant tumor in women, associated with a high mortality rate, easy recurrence and easy metastasis, which is predominantly at an advanced stage when detected in patients. This renders the cancer more difficult to treat, and consequently it is also associated with a low survival rate, being the malignancy with the highest mortality rate among the various gynecological tumors. As an important factor affecting the development and metastasis of OC, understanding the underlying mechanism(s) through which it is formed and developed is crucial in terms of its treatment. At present, the therapeutic methods of angiogenic mimicry for OC remain in the preliminary stages of exploration and have not been applied in actual clinical practice. In the present review, various signaling pathways and factors affecting angiogenic mimicry in OC were described, and the chemical synthetic drugs, natural compound extracts, small-molecule protein antibodies and their associated targets, and so on, that target angiogenic mimicry in the treatment of OC, were discussed. The purpose of this review was to provide new research ideas and potential theoretical support for the discovery of novel therapeutic targets for OC that may be applied in the clinic, with the aim of effectively reducing its metastasis and recurrence rates.

Quiescence as a therapeutic target in ovarian cancer (1245)

Quiescence as a therapeutic target in ovarian cancer (1245)

Extracellular vesicles targeting tumor microenvironment in ovarian cancer

Ovarian cancer (OC) is a prevalent neoplastic condition affecting women. Extracellular vesicles (EVs), nano-sized membrane vesicles, are secreted by various cells in both physiological and pathological states. The profound interplay between EVs and the tumor microenvironment (TME) in ovarian cancer is crucial. In this review, we explores the pivotal role of EVs in facilitating intercellular communication between cancer cells and the TME, emphasizing the potential of EVs as promising diagnostic markers and innovative therapeutic targets for ovarian cancer. The comprehensive analysis outlines the specific mechanisms by which EVs engage in communication with the constituents of the TME, including the modulation of tumor growth through EVs carrying matrix metalloproteinases (MMPs) and EV-mediated inhibition of angiogenesis, among other factors. Additionally, the we discuss the potential clinical applications of EVs that target the TME in ovarian cancer, encompassing the establishment of novel treatment strategies and the identification of novel biomarkers for early detection and prognosis. Finally, this review identifies novel strategies for therapeutic interventions, such as utilizing EVs as carriers for drug delivery and targeting specific EV-mediated signaling pathways. In summary, this manuscript offers valuable insights into the role of EVs in ovarian cancer and highlights the significance of comprehending intercellular communication in the realm of cancer biology.

Stromal DDR2 Promotes Ovarian Cancer Metastasis through Regulation of Metabolism and Secretion of Extracellular Matrix Proteins.

DDR2 is highly expressed by stromal cells in ovarian cancer that can mediate metastasis and is a potential therapeutic target in ovarian cancer.

LncRNAs and MiRNAs: New Targets for Resveratrol in Ovarian Cancer Research.

Ovarian cancer (OC) is the 3rd common gynecologic cancer. Numerous procedures are involved in the growth of OC, like migration, angiogenesis, proliferation, apoptosis, invasion, and metastasis. Therefore, a better knowledge of the molecular processes complicated in ovarian tumorigenesis can lead to better measures for the prevention and treatment of the disease and its diagnosis. Long non-coding RNAs (LncRNAs), a subclass of non-coding RNAs, are much more diverse than previously thought. It is suggested that these RNAs may play a role in controlling complex cellular signaling mechanisms via binding to proteins and influencing their function. Nevertheless, our acquaintance with the participation of LncRNAs in the pathogenesis of OC is still restricted. Especially, we do not yet recognize how to pharmacologically correct the epi-mutations. Resveratrol, a natural polyphenol mostly derived from grapes, has been evaluated in many studies to find its cancer therapeutic potential. In the current paper, we aimed to review the role of resveratrol as a potential natural product on lncRNAs as novel diagnostic and therapeutic targets in OC and represent new insights for further investigations.

ATAD2 is a driver and a therapeutic target in ovarian cancer that functions by upregulating CENPE

Ovarian cancer is a complex disease associated with multiple genetic and epigenetic alterations. The emergence of treatment resistance in most patients causes ovarian cancer to become incurable, and novel therapies remain necessary. We identified epigenetic regulator ATPase family AAA domain-containing 2 (ATAD2) is overexpressed in ovarian cancer and is associated with increased incidences of metastasis and recurrence. Genetic knockdown of ATAD2 or its pharmacological inhibition via ATAD2 inhibitor BAY-850 suppressed ovarian cancer growth and metastasis in both in vitro and in vivo models. Transcriptome-wide mRNA expression profiling of ovarian cancer cells treated with BAY-850 revealed that ATAD2 inhibition predominantly alters the expression of centromere regulatory genes, particularly centromere protein E (CENPE). In ovarian cancer cells, changes in CENPE expression following ATAD2 inhibition resulted in cell-cycle arrest and apoptosis induction, which led to the suppression of ovarian cancer growth. Pharmacological CENPE inhibition phenotypically recapitulated the cellular changes induced by ATAD2 inhibition, and combined pharmacological inhibition of both ATAD2 and CENPE inhibited ovarian cancer cell growth more potently than inhibition of either alone. Thus, our study identified ATAD2 as regulators of ovarian cancer growth and metastasis that can be targeted either alone or in combination with CENPE inhibitors for effective ovarian cancer therapy.

Ascites-derived CDCP1+ extracellular vesicles subcluster as a novel biomarker and therapeutic target for ovarian cancer.

Ovarian cancer (OVCA) is one of the most prevalent malignant tumors of the female reproductive system, and its diagnosis is typically accompanied by the production of ascites. Although liquid biopsy has been widely implemented recently, the diagnosis or prognosis of OVCA based on liquid biopsy remains the primary emphasis. In this study, using proximity barcoding assay, a technique for analyzing the surface proteins on single extracellular vesicles (EVs). For validation, serum and ascites samples from patients with epithelial ovarian cancer (EOC) were collected, and their levels of CDCP1 was determined by enzyme-linked immunosorbent assay. Tissue chips were prepared to analyze the relationship between different expression levels of CDCP1 and the prognosis of ovarian cancer patients. We discovered that the CUB domain-containing protein 1+ (CDCP1+) EVs subcluster was higher in the ascites of OVCA patients compared to benign ascites. At the same time, the level of CDCP1 was considerably elevated in the ascites of OVCA patients. The overall survival and disease-free survival of the group with high CDCP1 expression in EOC were significantly lower than those of the group with low expression. In addition, the receiver operating characteristic curve demonstrates that EVs-derived CDCP1 was a biomarker of early response in OVCA ascites. Our findings identified a CDCP1+ EVs subcluster in the ascites of OVCA patients as a possible biomarker for EOC prevention.

PSMD8 can serve as potential biomarker and therapeutic target of the PSMD family in ovarian cancer: based on bioinformatics analysis and in vitro validation

BackgroundThe ubiquity-proteasome system is an indispensable mechanism for regulating intracellular protein degradation, thereby affecting human antigen processing, signal transduction, and cell cycle regulation. We used bioinformatics database to predict the expression and related roles of all members of the PSMD family in ovarian cancer. Our findings may provide a theoretical basis for early diagnosis, prognostic assessment, and targeted therapy of ovarian cancer.MethodsGEPIA, cBioPortal, and Kaplan–Meier Plotter databases were used to analyze the mRNA expression levels, gene variation, and prognostic value of PSMD family members in ovarian cancer. PSMD8 was identified as the member with the best prognostic value. The TISIDB database was used to analyze the correlation between PSMD8 and immunity, and the role of PSMD8 in ovarian cancer tissue was verified by immunohistochemical experiments. The relationship of PSMD8 expression with clinicopathological parameters and survival outcomes of ovarian cancer patients was analyzed. The effects of PSMD8 on malignant biological behaviors of invasion, migration, and proliferation of ovarian cancer cells were studied by in vitro experiments.ResultsThe expression levels of PSMD8/14 mRNA in ovarian cancer tissues were significantly higher than those in normal ovarian tissues, and the expression levels of PSMD2/3/4/5/8/11/12/14 mRNA were associated with prognosis. Up-regulation of PSMD4/8/14 mRNA expression was associated with poor OS, and the up-regulation of PSMD2/3/5/8 mRNA expression was associated with poor PFS in patients with ovarian serous carcinomas. Gene function and enrichment analysis showed that PSMD8 is mainly involved in biological processes such as energy metabolism, DNA replication, and protein synthesis. Immunohistochemical experiments showed that PSMD8 was mainly expressed in the cytoplasm and the expression level was correlated with FIGO stage. Patients with high PSMD8 expression had poor prognosis. Overexpression of PSMD8 significantly enhanced the proliferation, migration, and invasion abilities in ovarian cancer cells.ConclusionWe observed different degrees of abnormal expression of members of PSMD family in ovarian cancer. Among these, PSMD8 was significantly overexpressed in ovarian malignant tissue, and was associated with poor prognosis. PSMDs, especially PSMD8, can serve as potential diagnostic and prognostic biomarkers and therapeutic targets in ovarian cancer.

LGALS1 regulates cell adhesion to promote the progression of ovarian cancer.

The present study aimed to explore the significance and molecular mechanisms of galectin-1 (LGALS1) in ovarian cancer (OC). Using the Gene Expression Omnibus database and The Cancer Genome Atlas database, the results of the present study demonstrated that LGALS1 mRNA expression was markedly increased in OC and associated with advanced tumor, lymphatic metastasis and residual lesions. In Kaplan-Meier analysis, patients who expressed LGALS1 highly had a poor prognosis. Furthermore, using The Cancer Genome Atlas database, differentially expressed genes that are potentially regulated by LGALS1 in OC were determined. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis were used to build a biological network of upregulated differentially expressed genes. The results of the enrichment analysis revealed that the upregulated differentially expressed genes were primarily associated with 'ECM-receptor interaction', 'cell-matrix adhesion' and 'focal adhesion', which are closely associated with the metastasis of cancer cells. Subsequently, cell adhesion was selected for further analysis. The results demonstrated that LGALS1 was co-expressed with the candidate genes. Subsequently, the elevated expression levels of candidate genes were verified in OC tissues, and survival analysis indicated that high expression of candidate genes was associated with shortened overall survival of patients with OC. In the present study, OC samples were also collected to verify the high protein expression levels of LGALS1 and fibronectin 1. The results of the present study highlighted that LGALS1 may regulate cell adhesion and participate in the development of OC. Therefore, LGALS1 exhibits potential as a therapeutic target in OC.

Carnitine palmitoyltransferase 1A promotes mitochondrial fission by enhancing MFF succinylation in ovarian cancer

Mitochondria are dynamic organelles that are important for cell growth and proliferation. Dysregulated mitochondrial dynamics are highly associated with the initiation and progression of various cancers, including ovarian cancer. However, the regulatory mechanism underlying mitochondrial dynamics is still not fully understood. Previously, our study showed that carnitine palmitoyltransferase 1A (CPT1A) is highly expressed in ovarian cancer cells and promotes the development of ovarian cancer. Here, we find that CPT1A regulates mitochondrial dynamics and promotes mitochondrial fission in ovarian cancer cells. Our study futher shows that CPT1A regulates mitochondrial fission and function through mitochondrial fission factor (MFF) to promote the growth and proliferation of ovarian cancer cells. Mechanistically, we show that CPT1A promotes succinylation of MFF at lysine 302 (K302), which protects against Parkin-mediated ubiquitin-proteasomal degradation of MFF. Finally, the study shows that MFF is highly expressed in ovarian cancer cells and that high MFF expression is associated with poor prognosis in patients with ovarian cancer. MFF inhibition significantly inhibits the progression of ovarian cancer in vivo. Overall, CPT1A regulates mitochondrial dynamics through MFF succinylation to promote the development of ovarian cancer. Moreover, our findings suggest that MFF is a potential therapeutic target for ovarian cancer.

TMTC1 promotes invasiveness of ovarian cancer cells through integrins β1 and β4

Ovarian cancer is the most lethal gynecological malignancy and is characterized by peritoneal disseminated metastasis. Although O-mannosyltransferase TMTC1 is highly expressed by ovarian cancer, its pathophysiological role in ovarian cancer remains unclear. Here, immunohistochemistry showed that TMTC1 was overexpressed in ovarian cancer tissues compared with adjacent normal ovarian tissues, and high TMTC1 expression was associated with poor prognosis in patients with ovarian cancer. Silencing TMTC1 reduced ovarian cancer cell viability, migration, and invasion in vitro, as well as suppressed peritoneal tumor growth and metastasis in vivo. Moreover, TMTC1 knockdown reduced cell-laminin adhesion, which was associated with the decreased phosphorylation of FAK at pY397. Conversely, TMTC1 overexpression promoted these malignant properties in ovarian cancer cells. Glycoproteomic analysis and Concanavalin A (ConA) pull-down assays showed that integrins β1 and β4 were novel O-mannosylated protein substrates of TMTC1. Furthermore, TMTC1-mediated cell migration and invasion were significantly reversed by siRNA-mediated knockdown of integrin β1 or β4. Collectively, these results suggest that TMTC1-mediated invasive behaviors are primarily through integrins β1 and β4 and that TMTC1 is a potential therapeutic target for ovarian cancer.