PRMT blockade induces defective DNA replication stress response and synergizes with PARP inhibition.

Multiple cancers exhibit aberrant protein arginine methylation by both type I arginine methyltransferases, predominately protein arginine methyltransferase 1 (PRMT1) and to a lesser extent PRMT4, and by type II PRMTs, predominately PRMT5. Here, we perform targeted proteomics following inhibition of PRMT1, PRMT4, and PRMT5 across 12 cancer cell lines. We find that inhibition of type I and II PRMTs suppresses phosphorylated and total ATR in cancer cells. Loss of ATR from PRMT inhibition results in defective DNA replication stress response activation, including from PARP inhibitors. Inhibition of type I and II PRMTs is synergistic with PARP inhibition regardless of homologous recombination function, but type I PRMT inhibition is more toxic to non-malignant cells. Finally, we demonstrate that the combination of PARP and PRMT5 inhibition improves survival in both BRCA-mutant and wild-type patient-derived xenografts without toxicity. Taken together, these results demonstrate that PRMT5 inhibition may be a well-tolerated approach to sensitize tumors to PARP inhibition.

Research on the Surface Deformation, Fault Rupture, and Coseismic Geohazard of the 2022 Luding Mw 6.8 Earthquake.

An Mw 6.8 earthquake occurred in Luding County, Ganzi Tibetan Autonomous Prefecture, Sichuan Province, on 5 September 2022. This seismic event triggered numerous coseismic geohazards in the seismic zone. In this study, the ascending- and descending-track synthetic aperture radar (SAR) images observed by the Sentinel-1A satellite are utilized to extract the coseismic surface deformation of the Luding earthquake. Subsequently, a faulting model is estimated based on the elastic dislocation theory, under the constraint of the InSAR observation. Additionally, the POT technique was employed to detect coseismic geohazards. High-spatial-resolution optical remote sensing images served to validate the reliability of the detection results. The coseismic interferometric synthetic aperture radar (InSAR) deformation field indicated a maximum deformation of ~190 mm and ~140 mm along the ascending and descending tracks, respectively. The estimated best-fitting faulting model suggests that the optimal seismogenic fault strike and dip angles are 169.3° and 70°, respectively. The fault slip predominantly exhibits left-lateral strike-slip characteristics and is concentrated at depths of 3-12 km. The estimated maximum fault slip was 2.67 m, occurring at a depth of 7 km. The pixel offset tracking (POT) result derived from the pre- and post-earthquake SAR images found a total of 245 medium- to large-scale coseismic geohazards, with a verification rate from optical images exceeding 64%. The distribution of these geohazards is notably dense within the significant fault rupture segment. Geohazards on the fault hanging wall are densely packed, whereas landslides along the Dadu River's fault footwall are also notably frequent.

Recurrent Neural Network Methods for Extracting Dynamic Balance Variables during Gait from a Single Inertial Measurement Unit.

Monitoring dynamic balance during gait is critical for fall prevention in the elderly. The current study aimed to develop recurrent neural network models for extracting balance variables from a single inertial measurement unit (IMU) placed on the sacrum during walking. Thirteen healthy young and thirteen healthy older adults wore the IMU during walking and the ground truth of the inclination angles (IA) of the center of pressure to the center of mass vector and their rates of changes (RCIA) were measured simultaneously. The IA, RCIA, and IMU data were used to train four models (uni-LSTM, bi-LSTM, uni-GRU, and bi-GRU), with 10% of the data reserved to evaluate the model errors in terms of the root-mean-squared errors (RMSEs) and percentage relative RMSEs (rRMSEs). Independent t-tests were used for between-group comparisons. The sensitivity, specificity, and Pearson's r for the effect sizes between the model-predicted data and experimental ground truth were also obtained. The bi-GRU with the weighted MSE model was found to have the highest prediction accuracy, computational efficiency, and the best ability in identifying statistical between-group differences when compared with the ground truth, which would be the best choice for the prolonged real-life monitoring of gait balance for fall risk management in the elderly.

Design and manufacture of one-size-fits-all healthcare face shields for the NHS during the COVID-19 pandemic.

During the COVID-19 pandemic, there was a shortage of personal protective equipment, PPE, which resulted in non-certified PPE being used by healthcare staffs. These would not provide the appropriate protection against the SARS-CoV-2 virus. Together with the local NHS Trust (University Hospitals of Derby and Burton (UHDB) NHS Foundation Trust) and a local small and medium enterprise (SME), Riverside Medical Packaging Ltd, the University of Derby (UoD) developed test protocols for PPE with a one-size-fits-all concept. Building on best practice in reviewing the literature and current design requirements, key design parameters were identified such as a minimum strap width and comfort level for healthcare related Face Shield. Two strap headbands made from fabric and elastomer with linear stiffness of 44.1 ± 0.3 N/m and 149.1 ± 3.1 N/m respectively were tested with respect to fit and comfort on small and large arc-shaped models. There was an exponential change in pressure from the side to the middle of the strap headbands. The high stiffness of the elastomer in a radial set-up influenced the pressure exerted on a wearer's head when the elastomer strap was used. Meanwhile the coefficient of friction between the fabric strap and arc-shaped model influenced the pressure exerted when a fabric strap was used. The ergonomics of the designed Face Shields supported the one-size-fits-all concept, whereby various gender and head circumferences were considered. The findings in this paper will promote new standards in the design of PPE with a one-size-fits-all target.

[Retrospective on ESP Courses in the Global English Era].

With the rise of the medical tourism industry in Taiwan and changes in the country's population structure, nurses are facing greater challenges than ever before. Both professional knowledge and English proficiency are indispensable. Various types of English for Specific Purposes (ESP) courses have emerged to assist healthcare professionals to build their English abilities and cope with the changing demands of their profession. However, related research indicates that the deficient state of English communication skills among nurses in Taiwan may hinder the country's ability to effectively promote medical internationalization and handle ongoing changes in its population structure. To effectively face this predicament, educators must re-examine the current design of ESP courses. Therefore, this article was developed to explore ESP courses from the three perspectives of language descriptions, needs analysis, and learning theories. Furthermore, the concepts and research related to these three perspectives, including the nurse-patient relationship, community of practice, situated learning, and English as a medium of instruction, were reviewed. Some insights into how these concepts may be applied to ESP courses are also proposed with the goals of better incorporating the needs of learners into course designs and placing learners at the center of language learning.

Risk control of host cell proteins in one therapeutic antibody produced by concentrated fed-batch (CFB) mode.

Multiple control strategies, including a downstream purification process with well-controlled parameters and a comprehensive release or characterization for intermediates or drug substances, were implemented to mitigate the potential risk of host cell proteins (HCPs) in one concentrated fed-batch (CFB) mode manufactured product. A host cell process specific enzyme-linked immunosorbent assay (ELISA) method was developed for the quantitation of HCPs. The method was fully validated and showed good performance including high antibody coverage. This was confirmed by 2D Gel-Western Blot analysis. Furthermore, a LC-MS/MS method with non-denaturing digestion and a long gradient chromatographic separation coupled with data dependent acquisition (DDA) on a Thermo/QE-HF-X mass spectrometer was developed as an orthogonal method to help identify the specific types of HCPs in this CFB product. Because of the high sensitivity, selectivity and adaptability of the new developed LC-MS/MS method, significantly more species of HCP contaminants were able to be identified. Even though high levels of HCPs were observed in the harvest bulk of this CFB product, the development of multiple processes and analytical control strategies may greatly mitigate potential risks and reduce HCPs contaminants to a very low level. No high-risk HCP was identified and the total amount of HCPs was very low in the CFB final product.

A Heuristic-Based Adaptive Iterated Greedy Algorithm for Lot-Streaming Hybrid Flow Shop Scheduling Problem with Consistent and Intermingled Sub-Lots.

Owing to the different quantities and processing times of sub-lots, intermingling sub-lots with each other, instead of fixing the production sequence of sub-lots of a lot as in the existing studies, is a more practical approach to lot-streaming flow shops. Hence, a lot-streaming hybrid flow shop scheduling problem with consistent and intermingled sub-lots (LHFSP-CIS) was studied. A mixed integer linear programming (MILP) model was established, and a heuristic-based adaptive iterated greedy algorithm (HAIG) with three modifications was designed to solve the problem. Specifically, a two-layer encoding method was proposed to decouple the sub-lot-based connection. Two heuristics were embedded in the decoding process to reduce the manufacturing cycle. Based on this, a heuristic-based initialization is proposed to improve the performance of the initial solution; an adaptive local search with four specific neighborhoods and an adaptive strategy has been structured to improve the exploration and exploitation ability. Besides, an acceptance criterion of inferior solutions has been improved to promote global optimization ability. The experiment and the non-parametric Kruskal-Wallis test (p = 0) showed the significant advantages of HAIG in effectiveness and robustness compared with five state-of-the-art algorithms. An industrial case study verifies that intermingling sub-lots is an effective technique to enhance the utilization ratio of machines and shorten the manufacturing cycle.

Effect of Powder Bed Fusion Laser Sintering on Dimensional Accuracy and Tensile Properties of Reused Polyamide 11.

Polyamide 11 (PA11) is a plant-based nylon made from castor beans. Powder bed fusion laser sintering (PBF-LS) is an additive manufacturing process used for PA11 which allows for the reuse of the unsintered powder. The unsintered powder is mixed with virgin powders at different refresh rates, a process which has been studied extensively for most semi-crystalline polyamides. However, there is lack of information on the effect of using 100% reused PA11 powder and the effect of the number of times it is reused on its own, during powder bed fusion laser sintering. This paper investigates the effect of reusing PA11 powder in PBF-LS and the effect of the number of times it is reused on the dimensional accuracy, density and thermal and tensile properties. From the 100% virgin powder to the third reuse of the powder, there is a decrease in powder wastage, crystallinity and tensile strength. These are associated with the polymerisation and cross-linking process of polymer chains, upon exposure to high temperatures. This results in a higher molecular weight and, hence, a higher density. From the fourth reuse to the tenth reuse, the opposite is observed, which is associated with an increase in high-viscosity unmolten particles, resulting in defects in the PBF-LS parts.

AKTIP loss is enriched in ERα-positive breast cancer for tumorigenesis and confers endocrine resistance.

Recurrent deletion of 16q12.2 is observed in luminal breast cancer, yet the causal genomic alterations in this region are largely unknown. In this study, we identify that loss of AKTIP, which is located on 16q12.2, drives tumorigenesis of estrogen receptor alpha (ERα)-positive, but not ERα-negative, breast cancer cells and is associated with poor prognosis of patients with ERα-positive breast cancer. Intriguingly, AKTIP-depleted tumors have increased ERα protein level and activity. Cullin-associated and neddylation-dissociated protein 1 (CAND1), which regulates the cullin-RING E3 ubiquitin ligases, protects ERα from cullin 2-dependent proteasomal degradation. Apart from ERα signaling, AKTIP loss triggers JAK2-STAT3 activation, which provides an alternative survival signal when ERα is inhibited. AKTIP-depleted MCF7 cells and ERα-positive patient-derived organoids are more resistant to ERα antagonists. Importantly, the resistance can be overcome by co-inhibition of JAK2/STAT3. Together, our results highlight the subtype-specific functional consequences of AKTIP loss and provide a mechanistic explanation for the enriched AKTIP copy-number loss in ERα-positive breast cancer.

Aquaporin-8 overexpression is involved in vascular structure and function changes in placentas of gestational diabetes mellitus patients.

To study the role and mechanism of aquaporin-8 (AQP8) in placental vascular development in gestational diabetes mellitus (GDM), hematoxylin-eosin staining and immunohistochemistry were utilized to analyze the histopathological changes in placentas in GDM patients. Transwell, CCK-8, and tube formation assays were performed to examine cell migration, proliferation, and tube formation. AQP8, vascular cell adhesion molecule 1 (VCAM-1), tumor necrosis factor alpha (TNF)-α, and vascular endothelial growth factor (VEGF)-A expression levels were investigated. Relative to the control group, the placentas in the GDM group showed morphological changes, the number of microvessels in the placental villi arterioles was significantly higher, and the area of microvessels in the arterioles of placental villi was significantly lower. The expression levels of VCAM-1, TNF-α, VEGF-A, and AQP8 in the GDM placentas and human umbilical vein endothelial cells (HUVECs) stimulated by high glucose were significantly higher than those in the control group, and AQP8 was located in placental endothelial cells. Overexpression of glucose and AQP8 inhibited tube formation, migration, and proliferation in HUVECs. High glucose levels can induce dysfunction in vascular endothelial cells and lead to pathological changes in the placental vascular structure in GDM. AQP8 overexpression in placental GDM can inhibit endothelial cell behavior, cause endothelial cell dysfunction, and further participate in the occurrence and development of GDM placental vascular lesions.

Tumor-intrinsic SIRPA promotes sensitivity to checkpoint inhibition immunotherapy in melanoma.

Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but many patients show resistance. Here we perform integrative transcriptomic and proteomic analyses on emerging immuno-oncology targets across multiple clinical cohorts of melanoma under anti-PD-1 treatment, on both bulk and single-cell levels. We reveal a surprising role of tumor-intrinsic SIRPA in enhancing antitumor immunity, in contrast to its well-established role as a major inhibitory immune modulator in macrophages. The loss of SIRPA expression is a marker of melanoma dedifferentiation, a key phenotype linked to immunotherapy efficacy. Inhibition of SIRPA in melanoma cells abrogates tumor killing by activated CD8+ T cells in a co-culture system. Mice bearing SIRPA-deficient melanoma tumors show no response to anti-PD-L1 treatment, whereas melanoma-specific SIRPA overexpression significantly enhances immunotherapy response. Mechanistically, SIRPA is regulated by its pseudogene, SIRPAP1. Our results suggest a complicated role of SIRPA in the tumor ecosystem, highlighting cell-type-dependent antagonistic effects of the same target on immunotherapy.

RPPA SPACE: an R package for normalization and quantitation of Reverse-Phase Protein Array data.

SUMMARY: Reverse-Phase Protein Array (RPPA) is a robust high-throughput, cost-effective platform for quantitatively measuring proteins in biological specimens. However, converting raw RPPA data into normalized, analysis-ready data remains a challenging task. Here, we present the RPPA SPACE (RPPA Superposition Analysis and Concentration Evaluation) R package, a substantially improved successor to SuperCurve, to meet that challenge. SuperCurve has been used to normalize over 170 000 samples to date. RPPA SPACE allows exclusion of poor-quality samples from the normalization process to improve the quality of the remaining samples. It also features a novel quality-control metric, 'noise', that estimates the level of random errors present in each RPPA slide. The noise metric can help to determine the quality and reliability of the data. In addition, RPPA SPACE has simpler input requirements and is more flexible than SuperCurve, it is much faster with greatly improved error reporting. AVAILABILITY AND IMPLEMENTATION: The standalone RPPA SPACE R package, tutorials and sample data are available via https://rppa.space/, CRAN (https://cran.r-project.org/web/packages/RPPASPACE/index.html) and GitHub (https://github.com/MD-Anderson-Bioinformatics/RPPASPACE). SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A multi-omic analysis of MCF10A cells provides a resource for integrative assessment of ligand-mediated molecular and phenotypic responses.

The phenotype of a cell and its underlying molecular state is strongly influenced by extracellular signals, including growth factors, hormones, and extracellular matrix proteins. While these signals are normally tightly controlled, their dysregulation leads to phenotypic and molecular states associated with diverse diseases. To develop a detailed understanding of the linkage between molecular and phenotypic changes, we generated a comprehensive dataset that catalogs the transcriptional, proteomic, epigenomic and phenotypic responses of MCF10A mammary epithelial cells after exposure to the ligands EGF, HGF, OSM, IFNG, TGFB and BMP2. Systematic assessment of the molecular and cellular phenotypes induced by these ligands comprise the LINCS Microenvironment (ME) perturbation dataset, which has been curated and made publicly available for community-wide analysis and development of novel computational methods ( synapse.org/LINCS_MCF10A ). In illustrative analyses, we demonstrate how this dataset can be used to discover functionally related molecular features linked to specific cellular phenotypes. Beyond these analyses, this dataset will serve as a resource for the broader scientific community to mine for biological insights, to compare signals carried across distinct molecular modalities, and to develop new computational methods for integrative data analysis.

Proteo-genomic characterization of virus-associated liver cancers reveals potential subtypes and therapeutic targets.

Primary liver cancer is a heterogeneous disease in terms of its etiology, histology, and therapeutic response. Concurrent proteomic and genomic characterization of a large set of clinical liver cancer samples can help elucidate the molecular basis of heterogeneity and thus serve as a valuable resource for personalized liver cancer treatment. In this study, we perform proteomic profiling of ~300 proteins on 259 primary liver cancer tissues with reverse-phase protein arrays, mutational analysis using whole genome sequencing and transcriptional analysis with RNA-Seq. Patients are of Japanese ethnic background and mainly HBV or HCV positive, providing insight into this important liver cancer subtype. Unsupervised classification of tumors based on protein expression profiles reveal three proteomic subclasses R1, R2, and R3. The R1 subclass is immunologically hot and demonstrated a good prognosis. R2 contains advanced proliferative tumor with TP53 mutations, high expression of VEGF receptor 2 and the worst prognosis. R3 is enriched with CTNNB1 mutations and elevated mTOR signaling pathway activity. Twenty-two proteins, including CDK1 and CDKN2A, are identified as potential prognostic markers. The proteomic classification presented in this study can help guide therapeutic decision making for liver cancer treatment.

Long noncoding RNA urothelial carcinoma associated 1 protects human placental vascular endothelial cells from hypoxia-induced damage by regulating the miR-197-3p/histone deacetylase-2 axis in patients with pregnancy-induced hypertension.

PURPOSE: Pregnancy-induced hypertension (PIH) is a major cause of mortality among pregnant women, fetuses, and newborns. This study assessed the role of long noncoding RNA (lncRNA) urothelial carcinoma associated 1 (UCA1) in PIH development. METHODS: Serum samples were collected from 30 pregnant women with PIH and 30 healthy pregnant women. Serum UCA1, miR-197-3p, and histone deacetylase-2 (HDAC2) mRNA level was evaluated using quantitative polymerase chain reaction. The expression of UCA1, miR-197-3p and HDAC2 in human placental vascular endothelial cells (HPVECs) was regulated by transfection. HPVECs were treated with hypoxia reoxygenation (H/R) to establish the PIH cell model. Methyl thiazolyl tetrazolium (MTT) assay, the terminal transferase uridyl nick end labelling (Tunel) assay and tubule formation assay were performed to assess the viability, apoptosis and angiogenesis of HPVECs. Dual-luciferase reporter gene assay, RNA pull-down assay, and RNA immunoprecipitation assay were performed to identify the binding between two genes. Western blot analysis was used for protein expression detection. RESULTS: In pregnant women with PIH, serum UCA1 and HDAC2 expression was downregulated and serum miR-197-3p expression was upregulated. H/R induction decreased the viability and angiogenesis of HPVECs, and increased the apoptosis of HPVECs. In H/R-induced HPVECs, UCA1 upregulation increased the viability and angiogenesis, and decreased the apoptosis. Downregulation of UCA1 had a contrasting result. UCA1 competitively binds to miR-197-3p to upregulate the expression of HDAC2. HDAC2 knockdown counteracted the effect of UCA1 upregulation on the viability, apoptosis and angiogenesis of HPVECs. CONCLUSIONS: LncRNA UCA1 protected HPVECs from hypoxia-induced damage by regulating the miR-197-3p/HDAC2 axis in PIH.

BET inhibition induces vulnerability to MCL1 targeting through upregulation of fatty acid synthesis pathway in breast cancer.

Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models. The mechanism of adaptive response to BET inhibition involves the upregulation of lipid synthesis enzymes including the rate-limiting stearoyl-coenzyme A (CoA) desaturase. Changes in lipid synthesis pathway are associated with increases in cell motility and membrane fluidity as well as re-localization and activation of HER2/EGFR. In turn, the HER2/EGFR signaling results in the accumulation of and vulnerability to the inhibition of MCL1. Drug response and genomics analyses reveal that MCL1 copy-number alterations are associated with effective BET and MCL1 co-targeting. The high frequency of MCL1 chromosomal amplifications (>30%) in basal-like breast cancers suggests that BET and MCL1 co-targeting may have therapeutic utility in this aggressive subtype of breast cancer.

Multi-modal molecular programs regulate melanoma cell state.

Melanoma cells display distinct intrinsic phenotypic states. Here, we seek to characterize the molecular regulation of these states using multi-omic analyses of whole exome, transcriptome, microRNA, long non-coding RNA and DNA methylation data together with reverse-phase protein array data on a panel of 68 highly annotated early passage melanoma cell lines. We demonstrate that clearly defined cancer cell intrinsic transcriptomic programs are maintained in melanoma cells ex vivo and remain highly conserved within melanoma tumors, are associated with distinct immune features within tumors, and differentially correlate with checkpoint inhibitor and adoptive T cell therapy efficacy. Through integrative analyses we demonstrate highly complex multi-omic regulation of melanoma cell intrinsic programs that provide key insights into the molecular maintenance of phenotypic states. These findings have implications for cancer biology and the identification of new therapeutic strategies. Further, these deeply characterized cell lines will serve as an invaluable resource for future research in the field.

Tumor Immune Microenvironment Changes by Multiplex Immunofluorescence Staining in a Pilot Study of Neoadjuvant Talazoparib for Early-Stage Breast Cancer Patients with a Hereditary BRCA Mutation.

PURPOSE: The immunological profile of early-stage breast cancer treated with neoadjuvant PARP inhibitors has not been described. The aim of this study was to delineate the changes in the tumor immune microenvironment (TiME) induced by talazoparib. PATIENTS AND METHODS: Patients with operable germline BRCA1/2 pathogenic variant (gBRCA1/2+) breast cancer were enrolled in a feasibility study of neoadjuvant talazoparib. Thirteen patients who received 8 weeks of neoadjuvant talazoparib were available for analysis, including 11 paired pre- and post-talazoparib core biopsies. Treatment-related changes in tumor-infiltrating lymphocytes were examined and immune cell phenotypes and their spatial distribution in the TiME were identified and quantified by multiplex immunofluorescence using a panel of 6 biomarkers (CD3, CD8, CD68, PD-1, PD-L1, and CK). RESULTS: Neoadjuvant talazoparib significantly increased infiltrating intratumoral and stromal T-cell and cytotoxic T-cell density. There was no difference in PD-1 or PD-L1 immune cell phenotypes in the pre- and post-talazoparib specimens and PD-L1 expression in tumor cells was rare in this cohort. Spatial analysis demonstrated that pre-talazoparib interactions between macrophages and T cells may correlate with pathologic complete response. CONCLUSIONS: This is the first study with phenotyping to characterize the immune response to neoadjuvant talazoparib in patients with gBRCA1/2+ breast cancer. These findings support an emerging role for PARP inhibitors in enhancing tumor immunogenicity. Further investigation of combinatorial strategies is warranted with agents that exploit the immunomodulatory effects of PARP inhibitors on the TiME.

Identification of potential gene markers in gestational diabetes mellitus.

This study aims to investigate underlying mechanisms of gestational diabetes mellitus (GDM). In this work, the GSE70493 dataset from GDM and control samples was acquired from Gene Expression Omnibus (GEO) database. Afterward, differentially expressed genes (DEGs) were screened between GDM and control samples. Subsequently, functional enrichment analysis and protein-protein interaction (PPI) network analysis of these DEGs were carried out. Furthermore, significant sub-modules were identified, and the functional analysis was also performed. Finally, we undertook a quantitative real-time polymerase chain reaction (qRT-PCR) with the purpose of confirming several key genes in GDM development. There were totally 528 up-regulated and 684 down-regulated DEGs between GDM and healthy samples. The functional analyses suggested that the above genes were dramatically enriched in type 1 diabetes mellitus (T1DM) process and immune-related pathways. Moreover, PPI analysis revealed that several members of human leukocyte antigen (HLA) superfamily, including down-regulated HLA-DQA1, HLA-DRB1, HLA-DPA1, and HLA-DQB1 served as hub genes. In addition, six significant sub-clusters were extracted and functional analysis suggested that these four genes in sub-module 1 were also associated with immune and T1DM-related pathways. Finally, they were also confirmed by qRT-PCR array. Besides, the four members of HLA superfamily might be implicated with molecular mechanisms of GDM, contributing to a deeper understanding of GDM development.

Hsa_circ_0063804 enhances ovarian cancer cells proliferation and resistance to cisplatin by targeting miR-1276/CLU axis.

PURPOSE: This article researched circ_0063804 effects on ovarian cancer (OC) development and resistance to cisplatin, aiming to provide a new target for OC therapy. METHODS: A total of 108 OC patients participated in this study. The circle structure of circ_0063804 was investigated using RNase R. Circ_0063804 expression in OC cells were up-regulated or down-regulated by transfection. Cell proliferation was assessed by cell counting kit-8 assay and colony formation assay. Flow cytometry was used to detect apoptosis. OC cells resistance to cisplatin was explored through MTT assay. Luciferase reporter assay was performed. qRT-PCR and Western blot was applied to research genes expression. Xenograft tumor experiment was conducted using nude mice. Ki67 expression in xenograft tumor was detected by immunohistochemistry. RESULTS: Circ_0063804 expression was up-regulated in OC patients and indicated poor prognosis (P < 0.05). Circ_0063804 had a stable circle structure. Circ_0063804 enhanced proliferation, resistance to cisplatin and reduced apoptosis of OC cells (P < 0.01). miR-1276 was down-regulated in OC patients and sponged by circ_0063804. CLU was directly inhibited by miR-1276 and up-regulated in OC patients. Circ_0063804 exacerbated malignant phenotype and resistance to cisplatin of OC cells in vitro by enhancing CLU expression via sponging miR-1276 (P < 0.01). Circ_0063804 silencing inhibited OC cells growth, resistance to cisplatin and Ki67 expression in vivo (P < 0.01). CONCLUSION: Circ_0063804 promoted OC cells proliferation and resistance to cisplatin by enhancing CLU expression via sponging miR-1276.