Mutations in the human myeloproliferative leukemia (MPL) protein gene are known to cause congenital amegakaryocytic thrombocytopenia (CAMT). The prognosis of this heritable disorder is poor and bone marrow transplantation is the only effective treatment. Here, by using the TALEN (transcription activator-like effector nuclease) technology, we created a zebrafish mpl mutant to model human CAMT. Disruption of zebrafish mpl lead to a severe reduction in thrombocytes and a high bleeding tendency, as well as deficiencies in adult hematopoietic stem/progenitor cells. We further demonstrated that thrombocytopenia in mpl mutant zebrafish was caused by impaired Tpo/Mpl/Jak2 signaling, resulting in reduced proliferation of thrombocyte precursors. These results indicate that mpl mutant zebrafish develop thrombocytopenia resembling the human CAMT. To utilize fully zebrafish to study thrombocyte biology and thrombocytopenia disorders, we generated a transgenic reporter line Tg(mpl:eGFP)smu4, in which green fluorescent protein (GFP) expression was driven by the mpl promoter. Detailed characterization of Tg(mpl:eGFP)smu4 fish confirmed that the thrombocyte lineage was specifically marked by GFP expression. In conclusion, we generated the first transmissible congenital thrombocytopenia zebrafish model mimicking human CAMT and a thrombocyte-specific transgenic line. Together with Tg(mpl:eGFP)smu4, mpl mutant zebrafish provide a useful tool for drug screening and study of thrombocytopoiesis.
RNF183, a member of the E3 ubiquitin ligase, has been shown to involve in carcinogenesis and proposed as one of the biomarkers in Uterine Corpus Endometrial Carcinoma (UCEC). However, no research focused on the role of RNF183 in UCEC. We analyzed the expression and immune infiltration of RNF183 in UCEC. TIMER, UALCAN, and GEPIA were used to analyze the gene expression of RNF183. We emplored Kaplan-Meier Plotter to examine the overall survival and progression-free survival of RNF183, and applied GeneMANIA to identify RNF183-related functional networks. LinkedOmics was helpful to identify the differential gene expression of RNF183, and to further analyze gene ontology and the genome pathways in the Kyoto Protocol. Finally, we used TIMER to investigate the immune infiltration of RNF183 in UCEC. Otherwise, we partly verified the results of bioinformatics analysis that RNF183 controlled ERα expression in ERα-positive Ishikawa cells dependent on its RING finger domain. We also found that ERα increased the stability of RNF183 through the post-translational mechanism. Together, patients with a high level of RNF183 harbor favorable overall and progression-free survival. High expression of RNF183 was associated with a low stage, endometrioid, and TP53 Non-Mutant status in endometrial cancer. The RNF183 expression was greater at higher expression and the tumor stage was greater at the lower level. On the side of immunization, high level of RNF183 in UCEC is negatively related to tumor purity, infiltrating levels of CD4 + T cells, neutrophils, and dendritic cells. Besides, the expression of RNF183 in UCEC is significantly correlated with the expression of several immune cell markers, including B cell, M1 macrophage marker, M2 Macrophage, Dendritic cell, Th1 markers, Th2 markers, Treg markers, and T cell exhaustion markers, indicating its role in regulating tumor immunity. These results suggested that RNF183 may be considered as a novel prognostic factor in endometrial cancer and an early diagnostic indicator for patients with UCEC.
Objective As a gate-keeper enzyme link, pyruvate dehydrogenase E1 subunit alpha (PDHA1) functions as a key regulator during glycolysis and the mitochondrial citric acid cycle, which has been reported in several tumors. Nevertheless, the effects of PDHA1 on biological behaviors and metabolism remain unclear in cervical cancer (CC) cells. The study aims to explore the PDHA1 effects on glucose metabolism in CC cells and its possible mechanism. Methods We first determined the expression levels of PDHA1 and activating protein 2 alpha (AP2α) as a PDHA1 potential transcription factor. The effects of PDHA1 in vivo were evaluated through a subcutaneous xenograft mouse model. Cell Counting Kit-8 assay, 5-ethynyl-2′-deoxyuridine (EdU) labeling assay, Transwell invasion assay, wound healing assay, Terminal deoxynucleotidyl transferase dUTP nick end labeling assay and flow cytometry were performed in CC cells. Oxygen consumption rate (OCR) levels were determined to reflect aerobic glycolysis level in gastric cancer cells. Reactive oxygen species (ROS) level was measured with 2′, 7′-dichlorofluorescein diacetate kit. The relationship between PDHA1 and AP2α was examined by conducting chromatin immunoprecipitation assay and electrophoretic mobility shift assay. Results In CC tissues and cell lines, PDHA1 was downregulated, while AP2α was upregulated. Overexpression of PDHA1 remarkedly inhibited the proliferation, invasion and migration of CC cells, and tumor growth in vivo, as well as promoted OCR, apoptosis and ROS production. Moreover, AP2α directly bound to PDHA1 within suppressor of cytokine signaling 3 promoter region to negatively regulate PDHA1 expression level. What is more, PDHA1 knockdown could effectively reversed the AP2α silencing-mediated suppressive effects on cell proliferation, invasion, migration, and the promotive effects of AP2α knockdown on OCR, apoptosis and ROS production. Conclusions Our findings demonstrate that AP2α negatively regulated PDHA1 via binding to PDHA1 gene promoter to promote malignant CC cell behaviors, which may provide a potential approach for CC therapeutics.
BackgroundThe oncogenic potential of special AT-rich binding protein 1 (SATB1) has been reported in various types of cancer, but its function in cervical cancer remains not fully investigated. This study aimed to investigate the effect of SATB1 mRNA expression on tumor progression and outcomes in the cervical cancer patients.MethodsA total of 33 cervical cancer patients treated in our hospital from September 2012 to December 2015 were included. The mRNA expression level of STAB1 in cervical cancer tissue was determined by real-time PCR, and the patients were divided into dichotomous groups based on their SATB1 expression level. Clinical characteristics, recurrence, and survival outcomes were compared between groups.ResultsCompared with the SATB1-low group, the SATB1-high group had significantly advanced International Federation of Gynecology and Obstetrics (FIGO) stages (P=0.037) and histologic grade (P=0.036). Kaplan–Meier analysis showed that SATB1-high group had a worse overall survival (P=0.078, marginal significant). In the subgroup analysis of pathological types, adenocarcinomas group (n=8) had a significantly higher SATB1 expression level as compared with the squamous cell carcinomas (n=18) and adenosquamous carcinomas (n=7) groups (both P<0.05). Cervical squamous cell carcinomas patients with a high-expression SATB1 (n=8) had more advanced FIGO stages (P=0.015) and histologic grades (P=0.060, marginal significant) as well as a higher (P=0.069, marginal significant) incidence of lymphatic metastasis than those with a low expression of SATB1 (n=10).ConclusionThese results showed that expression of SATB1 may have an effect on the disease progression and survival outcome of cervical cancer.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.