Bei Lin

MRPL13 enhances mitochondrial function and promotes tumor progression in ovarian cancer by inhibiting mPTP opening via SLC25A6

Abstract Tumor cells typically exhibit dysregulation of mitochondrial energy metabolism and cell death. The role of mitochondrial function in ovarian cancer (OC) progression has garnered substantial attention, yet its precise molecular mechanisms remain elusive. Mitochondrial ribosomal protein L13 (MRPL13), involved in the translation of oxidative phosphorylation (OXPHOS) complex subunits, plays a critical role in regulating mitochondrial function. Our study demonstrated that MRPL13 is highly expressed in OC tissues and correlated with poor prognosis. Both in vitro and in vivo experiments confirmed that MRPL13 overexpression significantly promotes the malignant biological behavior of OC, while MRPL13 knockdown induces the opposite phenotype. Moreover, MRPL13 knockdown impairs mitochondrial function in OC cells, leading to decreased OXPHOS and ATP levels, increased reactive oxygen species (ROS) generation, mitochondrial depolarization, aberrant opening of the mitochondrial permeability transition pore (mPTP), and mitochondrial structural damage. Mechanistically, MRPL13 specifically interacts with SLC25A6 and facilitates its degradation via lysine (K)48-linked ubiquitination. MRPL13 inhibits mPTP opening by accelerating the degradation of SLC25A6, thereby preventing cytochrome c release into the cytoplasm, inhibiting cell death, and enhancing mitochondrial function. In conclusion, our study elucidates the mechanism by which the MRPL13-SLC25A6 axis enhances mitochondrial function and promotes tumor progression in OC by inhibiting mPTP opening, suggesting that MRPL13 holds significant potential for prognostic evaluation and targeted therapy in OC.

First case of endometrial cancer after yolk sac tumor in a patient with Li-Fraumeni syndrome

Abstract Background Li-Fraumeni syndrome (LFS) is a rare autosomal dominant disease with high penetrance caused by a germline variant of TP53 gene. We report the first case of endometrial cancer after yolk sac tumor with LFS. Case presentation The presented female patient underwent right adnexectomy at age 23 because of a yolk sac tumor of the ovary. At the age of 27, the patient was diagnosed with endometrial adenocarcinoma, received cytoreductive surgery and chemotherapy. Given that her personal cancer history along with a strong family history of cancer, her father passing away from lung cancer at age 48 and her grandmother dying of ovarian cancer at age 50, the patient was referred for genetic counseling and testing. Genetic screening revealed a heterozygous pathogenic TP53 c.844C > T, p.( R282 W) with NM_000546.5 variant, a class 5 (C5) variant. This is the first reported case of a yolk sac tumor accompanied by subsequent endometrial cancer that is associated with LFS. Conclusions We reported a first case of an endometrial cancer after yolk sac tumor patient with a tumor family history of harboring the germline TP53 pathogenic variation which expanded types of tumor that can be presented in patients with LFS. This case highlights the importance of genetic testing for patients with malignant tumors, as well as patients with a family history of malignant tumors. And our case highlights the necessity of screening for gynecologic tumor in LFS patients.

Oxidative Stress Response Biomarkers of Ovarian Cancer Based on Single-Cell and Bulk RNA Sequencing

Background. The occurrence and development of ovarian cancer (OV) are significantly influenced by increased levels of oxidative stress (OS) byproducts and the lack of an antioxidant stress repair system. Hence, it is necessary to explore the markers related to OS in OV, which can aid in predicting the prognosis and immunotherapeutic response in patients with OV. Methods. The single-cell RNA-sequencing (scRNA-seq) dataset GSE146026 was retrieved from the Gene Expression Omnibus (GEO) database, and Bulk RNA-seq data were obtained from TCGA and GTEx databases. The Seurat R package and SingleR package were used to analyze scRNA-seq and to identify OS response-related clusters based on ROS markers. The “limma” R package was used to identify the differentially expressed genes (DEGs) between normal and ovarian samples. The risk model was constructed using the least absolute shrinkage and selection operator (LASSO) regression analysis. The immune cell infiltration, genomic mutation, and drug sensitivity of the model were analyzed using the CIBERSORT algorithm, the “maftools,” and the “pRRophetic” R packages, respectively. Results. Based on scRNA-seq data, we identified 12 clusters; OS response-related genes had the strongest specificity for cluster 12. A total of 151 genes were identified from 2928 DEGs to be significantly correlated with OS response. Finally, nine prognostic genes were used to construct the risk score (RS) model. The risk score model was an independent prognostic factor for OV. The gene mutation frequency and tumor immune microenvironment in the high- and low-risk score groups were significantly different. The value of the risk score model in predicting immunotherapeutic outcomes was confirmed. Conclusions. OS response-related RS model could predict the prognosis and immune responses in patients with OV and provide new strategies for cancer treatment.

ZNF703 promotes tumor progression in ovarian cancer by interacting with HE4 and epigenetically regulating PEA15

AbstractBackgroundIt is known that the transcription factor zinc finger protein 703 (ZNF703) plays an important role in physiological functions and the occurrence and development of various tumors. However, the role and mechanism of ZNF703 in ovarian cancer are unclear.Materials and methodsImmunohistochemistry was used to analyze the expression of ZNF703 in ovarian cancer patients and to assess the effect of ZNF703 expression on the survival and prognosis of ovarian cancer patients. ZNF703 overexpression and suppression expression experiments were used to evaluate the effect of ZNF703 on malignant biological behavior of ovarian cancer cells in vitro. Detecting the interaction between HE4 and ZNF703 by immunofluorescence colocalization and coprecipitation, and nuclear translocation. Chromatin immunoprecipitation-sequencing (ChIP-Seq), dual luciferase reporter assay, ChIP-PCR, in vivo model were applied to study the molecular mechanism of ZNF703 affecting the development of ovarian cancer.ResultsZNF703 was highly expressed in ovarian cancer tissues, and its expression level is related to the prognosis of ovarian cancer patients. In vivo and in vitro experiments confirmed that ZNF703 overexpression/inhibition expression will promoted/inhibited the malignant biological behavior of ovarian cancer. Mechanically, ZNF703 interacted with HE4, and HE4 promoted nuclear translocation of ZNF703. ChIP-Seq identified multiple regulatory targets of ZNF703, of which ZNF703 directly binds to the enhancer region of PEA15 to promote the transcription of PEA15 and thereby promoted the proliferation of cancer cells.ConclusionThe results showed that ZNF703 as an oncogene played an important role in the epigenetic modification of ovarian cancer proliferation, and suggested that ZNF703 as a transcription factor may become a prognostic factor and a potential therapeutic target for ovarian cancer.

Overexpression of BMPER in Ovarian Cancer and the Mechanism by which It Promotes Malignant Biological Behavior in Tumor Cells

Background. BMPER has been reported to be associated with the biological behavior of a few malignant tumors, but the mechanism is still unclear. We aimed to detect BMPER expression in ovarian epithelial tumor tissues and its effects on their biological behaviors, as well as to elucidate the possible mechanism. Methods. BMPER expression in ovarian epithelial tumor tissues was detected by immunohistochemistry. BMPER expression in ovarian cancer cell lines was inhibited via RNA interference. Changes in the malignant behaviors of ovarian cancer cells were detected by MTT, wound healing, Transwell, and flow cytometry assays. Changes in proteins in the MAPK and autophagy‐related signaling pathways were detected by Western blot analysis. Results. The expression of BMPER was significantly upregulated in ovarian epithelial malignant tumors and was related to increased lymph node metastasis and lower survival rate. High BMPER expression is an independent risk factor for poor prognosis in patients. Inhibition of BMPER inhibited the proliferation, invasion, and migration of ovarian cancer cells and promoted apoptosis. In addition, BMPER downregulation decreased the expression of PCNA, Bcl‐2, MMP2, and MMP9 and increased the expression of Bax. Moreover, the levels of p‐ERK, p‐MEK, and the autophagy‐related protein p‐mTOR were decreased, and Beclin 1 levels and the LC3II/I ratio were increased. Conclusions. Our findings indicated that BMPER is closely related to poor prognosis in ovarian cancer. BMPER plays a role in promoting the malignant biological behavior of tumor cells through the MAPK and autophagy‐related signaling pathways.

Identification of immune‐enhanced molecular subtype associated with BRCA1 mutations, immune checkpoints and clinical outcome in ovarian carcinoma

Abstract Ovarian carcinoma has the highest mortality among the malignant tumours in gynaecology, and new treatment strategies are urgently needed to improve the clinical status of ovarian carcinoma patients. The Cancer Genome Atlas (TCGA) cohort were performed to explore the immune function of the internal environment of tumours and its clinical correlation with ovarian carcinoma. Finally, four molecular subtypes were obtained based on the global immune‐related genes. The correlation analysis and clinical characteristics showed that four subtypes were all significantly related to clinical stage; the immune scoring results indicated that most immune signatures were upregulated in C3 subtype, and the majority of tumour‐infiltrating immune cells were upregulated in both C3 and C4 subtypes. Compared with other subtypes, C3 subtype had a higher BRCA1 mutation, higher expression of immune checkpoints, and optimal survival prognosis. These findings of the immunological microenvironment in tumours may provide new ideas for developing immunotherapeutic strategies for ovarian carcinoma.

Exosomal ANXA2 derived from ovarian cancer cells regulates epithelial‐mesenchymal plasticity of human peritoneal mesothelial cells

AbstractOvarian cancer, one of the malignant gynaecological tumours with the highest mortality rate among female reproductive system, is prone to metastasis, recurrence and chemotherapy resistance, causing a poor prognosis. Exosomes can regulate the epithelial‐mesenchymal plasticity of tumour cells, remodel surrounding tumour microenvironment, and affect tumour cell proliferation, invasion and metastasis. However, the function and mechanism of exosomes in the intraperitoneal implantation of ovarian cancer remain unclear. In this study, exosomal annexin A2 (ANXA2) derived from ovarian cancer cells was co‐cultured with human peritoneal mesothelial (HMrSV5) cells; functional experiments were conducted to explore the effects of exosomal ANXA2 on the biological behaviour of HMrSV5 and the related mechanisms. This study showed that ANXA2 in ovarian cancer cells can be transferred to HMrSV5 cells through exosomes, exosomal ANXA2 can not only promote the migration, invasion and apoptosis of HMrSV5 cells, but also regulates morphological changes and fibrosis of HMrSV5 cells. Furthermore, ANXA2 promotes the mesothelial‐mesenchymal transition (MMT) and degradation of the extracellular matrix of HMrSV5 cells through PI3K/AKT/mTOR pathway, finally affects pre‐metastasis microenvironment of ovarian cancer, which provides a new theoretical basis for the mechanism of intraperitoneal implantation and metastasis of ovarian cancer.

PHGDH Inhibitor CBR‐5884 Inhibits Epithelial Ovarian Cancer Progression via ROS/Wnt/β‐Catenin Pathway and Plays a Synergistic Role with PARP Inhibitor Olaparib

PHGDH attaches importance to serine biosynthesis in cancer cells and maintaining mitochondrial redox homeostasis. However, the role of PHGDH inhibitor CBR‐5884 in cell ROS level and its downstream pathways has not been explored in epithelial ovarian cancer. Thus, we investigated the function and possible mechanism of PHGDH inhibitor CBR‐5884 on epithelial ovarian cancer in vitro and in vivo. A2780, OVCAR3, and ES‐2 were treated with CBR‐5884 at different concentrations or different time points. Results showed that CBR‐5884 inhibited epithelial ovarian cancer cell proliferation, migration, and invasion and increases cell ROS level. Meanwhile, CBR‐5884 exerts antitumor effect through activating ROS/Wnt/β‐catenin pathway. Besides, CBR‐5884 exerts antitumor effect in vivo. What’s more, we explored the effect of CBR‐5884 with or without PARP inhibitor Olaparib, which showed that the two together had a larger effect. In conclusion, PHGDH inhibitor CBR‐5884 inhibits epithelial ovarian cancer proliferation, migration, and invasion through activating ROS/Wnt/β‐catenin pathway and plays a synergistic role with PARP inhibitor olaparib, which provided a theoretical basis for PHGDH inhibitor CBR‐5884 in clinical treatment.

Interaction between TMEFF1 and AHNAK proteins in ovarian cancer cells: Implications for clinical prognosis

TMEFF1 is a newly discovered protein involved in the physiological functions of the central nervous system, embryonic development, and other biological processes. Our previous study revealed that TMEFF1 acts as a tumor-promoting gene in ovarian cancer. AHNAK, as a giant scaffolding protein, plays a role in the formation of the blood-brain barrier, cell architecture and the regulation of cardiac calcium channels. However, its role in ovarian cancer remains poorly researched. In this study, we detected the expression of AHNAK and TMEFF1 in 148 different ovarian cancer tissues, determined their relationship with pathological parameters and prognosis, clarified the interaction between the two proteins, and explored the related cancer-promoting mechanisms through immunohistochemistry, immunoprecipitation, immunofluorescence double staining, western blotting, and bioinformatics. The high expression of ANHAK and TMEFF1 in ovarian cancer indicated a higher degree of tumor malignancy and a worse prognosis. Furthermore, the expression of TMEFF1 and AHNAK was significantly positively correlated. The results also showed that AHNAK and TMEFF1 co-localized and interacted with each other in ovarian cancer tissues and cells. And knockdown of AHNAK promoted proliferation, migration and invasion of ovarian cancer cells in vitro. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that AHNAK and related genes were enriched during mitosis regulation, cytoskeleton formation, gene epigenetics, etc., whereas TMEFF1 and related genes are enriched during immune regulation and other processes. We also clarified the network of kinases, microRNA, and transcription factor targets, and the impact of genetic mutations on prognosis. Notably, AHNAK was regulated by the expression of TMEFF1 and can activate the MAPK pathways. Overall, high expression of AHNAK and TMEFF1 in ovarian cancer cells indicated a higher degree of tumor malignancy and a worse prognosis. Therefore, the interaction between AHNAK and TMEFF1 may become a potential anti-tumor target for ovarian cancer treatment.