HPV16-miRNAs exert oncogenic effects through enhancers in human cervical cancer.

BACKGROUND: Cervical cancer is a human papillomavirus (HPV)-related disease. HPV type 16 (HPV16), which is the predominant cause of cervical cancer, can encode miRNAs (HPV16-miRNAs). However, the role of HPV16-miRNAs in the pathogenesis of cervical cancer remains unclear. METHODS: Human cervical cancer cell lines SiHa (HPV16-positive) and C33A (HPV-negative), and cervical cancer tissues were collected to investigate the expression levels of two HPV16-miRNAs (HPV16-miR-H1 and HPV16-miR-H6). The overexpression and knockdown of HPV16-miR-H1 and HPV16-miR-H6 were performed using the lentiviral vector system and miRNA inhibitors, respectively. RNA-sequencing (RNA-seq) analysis and H3K27ac chromatin immunoprecipitation and sequencing (CHIP-seq) experiments were utilized to explore the roles of HPV16-miR-H1 and HPV16-miR-H6 facilitated by enhancers. CCK8, EdU, transwell, and wound healing assays were performed to verify the effects of HPV16-miR-H1 and HPV16-miR-H6 on cell proliferation and migration. RESULTS: HPV16-miR-H1 and HPV16-miR-H6 were highly expressed in both SiHa cells and tissue samples from HPV16-positive cervical cancer patients. RNA-seq analysis showed that HPV16-miR-H1 and HPV16-miR-H6 induced the upregulation of numerous tumor progression-associated genes. H3K27ac CHIP-seq experiments further revealed that HPV16-miR-H1 and HPV16-miR-H6 modulated the expression of critical genes by regulating their enhancer activity. The functional study demonstrated that HPV16-miR-H1 and HPV16-miR-H6 increased the migratory capacity of SiHa cells. CONCLUSIONS: Our data shed light on the role of HPV16-encoded miRNAs in cervical cancer, particularly emphasizing their involvement in the miRNA-enhancer-target gene system. This novel regulatory mechanism of HPV16-miRNAs provides new insights and approaches for the development of therapeutic strategies by targeting HPV16-positive cervical cancer.

Comparison of Down Sizing Strategy (HANGZHOU Solution) and Standard Annulus Sizing Strategy in type 0 bicuspid aortic stenosis patients undergoing transcatheter aortic valve replacement: Rationale and design of a randomized clinical trial.

BACKGROUND: There has not been a consensus on the prothesis sizing strategy in type 0 bicuspid aortic stenosis (AS) patients undergoing transcatheter aortic valve replacement (TAVR). Modifications to standard annular sizing strategies might be required due to the distinct anatomical characteristics. We have devised a Down Sizing Strategy for TAVR using a self-expanding valve specifically for patients with type 0 bicuspid AS. The primary aim of this study is to compare the safety and efficacy of Down Sizing Strategy with the Standard Annulus Sizing Strategy in TAVR for patients with type 0 bicuspid AS. TRIAL DESIGN: It is a prospective, multi-center, superiority, single-blinded, randomized controlled trial comparing the Down Sizing and Standard Annulus Sizing Strategy in patients with type 0 bicuspid aortic stenosis undergoing transcatheter aortic valve replacement. Eligible participants will include patients with severe type 0 bicuspid AS, as defined by criteria such as mean gradient across aortic valve ≥40 mmHg, peak aortic jet velocity ≥4.0 m/s, aortic valve area (AVA) ≤1.0 cm², or AVA index ≤0.6 cm2/m2. These patients will be randomly assigned, in a 1:1 ratio, to either the Down Sizing Strategy group or the Standard Sizing Strategy group. In the Down Sizing Strategy group, a valve one size smaller will be implanted if the "waist sign" manifests along with less than mild regurgitation during balloon pre-dilatation. The primary end point of the study is a composite of VARC-3 defined device success, absence of both permanent pacemaker implantation due to high-degree atrioventricular block and new-onset complete left bundle branch block. CONCLUSION: This study will compare the safety and efficacy of Down Sizing Strategy with the Standard Annulus Sizing Strategy and provide valuable insights into the optimal approach for sizing in TAVR patients with type 0 bicuspid AS. We hypothesize that the Down Sizing Strategy will demonstrate superiority when compared to the Standard Annulus Sizing Strategy. (Down Sizing Strategy (HANGZHOU Solution) vs Standard Sizing Strategy TAVR in Bicuspid Aortic Stenosis (Type 0) (TAILOR-TAVR), NCT05511792).

Weakly Supervised Exaggeration Transfer for Caricature Generation With Cross-Modal Knowledge Distillation.

Caricature generation aims to translate portrait photos into caricatures with exaggerated and hand-drawn artistic styles. Previous methods faced challenges in creating diverse and meaningful exaggeration effects, yielding unsatisfactory and uncontrollable results. To overcome this, we proposed ETCari, a novel weakly supervised exaggeration transfer network. ETCari enables the learning of diverse exaggeration caricature styles from various artists, better meeting individual customization requirements and achieving diversified exaggeration while retaining identity features. Specifically, we use the thin-plate spline control point deformation field as the ground truth, serving as the loss for weakly supervised learning to address the challenge of no labels. We convert input to an intermediate modality for domain adaptation, training a teacher model. Subsequently, we perform cross-modal knowledge distillation to train the student model, simplifying preprocessing during inference and avoiding the impact of face parser errors. Experiments on the WebCaricature dataset demonstrate that ETCari effectively performs exaggeration transfer, generating appealing caricatures.

Primary Human Breast Cancer-Associated Endothelial Cells Favor Interactions with Nanomedicines.

Cancer nanomedicines predominately rely on transport processes controlled by tumor-associated endothelial cells to deliver therapeutic and diagnostic payloads into solid tumors. While the dominant role of this class of endothelial cells for nanoparticle transport and tumor delivery is established in animal models, the translational potential in human cells needs exploration. Using primary human breast cancer as a model, the differential interactions of normal and tumor-associated endothelial cells with clinically relevant nanomedicine formulations are explored and quantified. Primary human breast cancer-associated endothelial cells exhibit up to ≈2 times higher nanoparticle uptake than normal human mammary microvascular endothelial cells. Super-resolution imaging studies reveal a significantly higher intracellular vesicle number for tumor-associated endothelial cells, indicating a substantial increase in cellular transport activities. RNA sequencing and gene expression analysis indicate the upregulation of transport-related genes, especially motor protein genes, in tumor-associated endothelial cells. Collectively, the results demonstrate that primary human breast cancer-associated endothelial cells exhibit enhanced interactions with nanomedicines, suggesting a potentially significant role for these cells in nanoparticle tumor delivery in human patients. Engineering nanoparticles that leverage the translational potential of tumor-associated endothelial cell-mediated transport into human solid tumors may lead to the development of safer and more effective clinical cancer nanomedicines.

Environmental pollutants and male infertility: Effects on CatSper.

Infertility is a growing health concern among many couples worldwide. Men account for half of infertility cases. CatSper, a sperm-specific Ca2+ channel, is expressed on the cell membrane of mammalian sperm. CatSper plays an important role in male fertility because it facilitates the entry of Ca2+ necessary for the rapid change in sperm motility, thereby allowing it to navigate the hurdles of the female reproductive tract and successfully locate the egg. Many pollutants present in the environment have been shown to affect the functions of CatSper and sperm, which is a matter of capital importance to understanding and solving male infertility issues. Environmental pollutants can act as partial agonists or inhibitors of CatSper or exhibit a synergistic effect. In this article, we briefly describe the structure, functions, and regulatory mechanisms of CatSper, and discuss the body of literature covering the effects of environmental pollutants on CatSper.

PGC1α-Inducing Senomorphic Nanotherapeutics Functionalized with NKG2D-Overexpressing Cell Membranes for Intervertebral Disc Degeneration.

Cellular senescence is a significant contributor to intervertebral disc aging and degeneration. However, the application of senotherapies, such as senomorphics targeting senescence markers and the senescence-associated secretory phenotype (SASP), remains limited due to challenges in precise delivery. Given that the natural killer group 2D (NKG2D) ligands are increased on the surface of senescent nucleus pulposus (NP) cells, the NKG2D-overexpressing NP cell membranes (NNPm) are constructed, which is expected to achieve a dual targeting effect toward senescent NP cells based on homologous membrane fusion and the NKG2D-mediated immunosurveillance mechanism. Then, mesoporous silica nanoparticles carrying a peroxisome proliferator-activated receptor-É£ coactivator 1α (PGC1α)inducer (SP) are coated with NNPm (SP@NNPm) and it is found that SP@NNPm selectively targets senescent NP cells, and the SP cores exhibit pH-responsive drug release. Moreover, SP@NNPm effectively induces PGC1α-mediated mitochondrial biogenesis and mitigates senescence-associated markers induced by oxidative stress and the SASP, thereby alleviating puncture-induced senescence and disc degeneration. This dual-targeting nanotherapeutic system represents a novel approach to delivery senomorphics for disc degeneration treatment.

High-efficiency flexible organic solar cells with a polymer-incorporated pseudo-planar heterojunction.

Organic solar cells (OSCs) are considered as a crucial energy source for flexible and wearable electronics. Pseudo-planar heterojunction (PPHJ) OSCs simplify the solution preparation and morphology control. However, non-halogenated solvent-printed PPHJ often have an undesirable vertical component distribution and insufficient donor/acceptor interfaces. Additionally, the inherent brittleness of non-fullerene small molecule acceptors (NFSMAs) in PPHJ leads to poor flexibility, and the NFSMAs solution shows inadequate viscosity during the printing of acceptor layer. Herein, we propose a novel approach termed polymer-incorporated pseudo-planar heterojunction (PiPPHJ), wherein a small amount of polymer donor is introduced into the NFSMAs layer. Our findings demonstrate that the incorporation of polymer increases the viscosity of acceptor solution, thereby improving the blade-coating processability and overall film quality. Simultaneously, this strategy effectively modulates the vertical component distribution, resulting in more donor/acceptor interfaces and an improved power conversion efficiency of 17.26%. Furthermore, PiPPHJ-based films exhibit superior tensile properties, with a crack onset strain of 12.0%, surpassing PPHJ-based films (9.6%). Consequently, large-area (1 cm2) flexible devices achieve a considerable efficiency of 13.30% and maintain excellent mechanical flexibility with 82% of the initial efficiency after 1000 bending cycles. These findings underscore the significant potential of PiPPHJ-based OSCs in flexible and wearable electronics.

Roles of organokines in intervertebral disc homeostasis and degeneration.

The intervertebral disc is not isolated from other tissues. Recently, abundant research has linked intervertebral disc homeostasis and degeneration to various systemic diseases, including obesity, metabolic syndrome, and diabetes. Organokines are a group of diverse factors named for the tissue of origin, including adipokines, osteokines, myokines, cardiokines, gastrointestinal hormones, and hepatokines. Through endocrine, paracrine, and autocrine mechanisms, organokines modulate energy homeostasis, oxidative stress, and metabolic balance in various tissues to mediate cross-organ communication. These molecules are involved in the regulation of cellular behavior, inflammation, and matrix metabolism under physiological and pathological conditions. In this review, we aimed to summarize the impact of organokines on disc homeostasis and degeneration and the underlying signaling mechanism. We focused on the regulatory mechanisms of organokines to provide a basis for the development of early diagnostic and therapeutic strategies for disc degeneration.

Macropinocytic cups function as signal platforms for the mTORC2-AKT pathway to modulate LPS-induced cytokine expression in macrophages.

Macropinocytosis is a large-scale endocytosis process that is primarily observed in phagocytes as part of their cellular function to ingest antigens. Once phagocytes encounter gram-negative bacteria, the receptor proteins identify lipopolysaccharides (LPSs), which trigger radical membrane ruffles that gradually change to cup-like structures. The open area of the cups closes to generate vesicles called macropinosomes. The target bacteria are isolated by the cups and engulfed by the cells as the cups close. In addition to its ingestion function, macropinocytosis also regulates the AKT pathway in macrophages. In the current study, we report that macropinocytic cups are critical for LPS-induced AKT phosphorylation (pAKT) and cytokine expression in macrophages. High-resolution scanning electron microscope (SEM) observations detailed the macropinocytic cup structures induced by LPS stimulation. Confocal microscopy revealed that AKT and the kinase molecule mTORC2 were localized in the cups. The biochemical analysis showed that macropinocytosis inhibition blocked LPS-induced pAKT. RNA-Seq, qPCR, and ELISA analyses revealed that the inhibition of macropinocytosis or the AKT pathway causes a decrease in the expression of pro-inflammatory cytokines IL-6 and IL-1α. Moreover, activation of the transcription factor NF-κB, which regulates the cytokine expression downstream of the AKT/IκB pathway, was hindered when macropinocytosis or AKT were inhibited. These results indicate that LPS-induced macropinocytic cups function as signal platforms for the AKT pathway to regulate the cytokine expression by modulating NF-κB activity in LPS-stimulated macrophages. Based on these findings, we propose that macropinocytosis may be a good therapeutic target for controlling cytokine expression.

Electroacupuncture alleviates intestinal inflammation via a distinct neuro-immune signal pathway in the treatment of postoperative ileus.

BACKGROUND: The induction of intestinal inflammation as a result of abdominal surgery is an essential factor in postoperative ileus (POI) development. Electroacupuncture (EA) at ST36 has been demonstrated to relieve intestinal inflammation and restore gastrointestinal dysmotility in POI. This study aims to elucidate the neuroimmune pathway involved in the anti-inflammatory properties of EA in POI. METHODS: After intestinal manipulation (IM) was performed to induce POI, intestinal inflammation and motility were assessed 24 h post-IM, by evaluating gastrointestinal transit (GIT), cytokines expression, and leukocyte infiltration. Experimental surgery, pharmacological intervention, and genetic knockout mice were used to elucidate the neuroimmune mechanisms of EA. RESULTS: EA at ST36 significantly improved GIT and reduced the expression of pro-inflammatory cytokines and leukocyte infiltration in the intestinal muscularis following IM in mice. The anti-inflammatory effectiveness of EA treatment was abolished by sub-diaphragmatic vagotomy, whereas splenectomy did not hinder the anti-inflammatory benefits of EA treatment. The hexamethonium chloride (HEX) administration contributes to a notable reduction in the EA capacity to suppress inflammation and enhance motility dysfunction, and EA is ineffective in α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice. CONCLUSIONS: EA at ST36 prevents intestinal inflammation and dysmotility through a neural circuit that requires vagal innervation but is independent of the spleen. Further findings revealed that the process involves enteric neurons mediating the vagal signal and requires the presence of α7nAChR. These findings suggest that utilizing EA at ST36 may represent a possible therapeutic approach for POI and other immune-related gastrointestinal diseases.

Effect of Pore Confinement of Ionic Liquids on Solute Diffusion within Mesoporous Silica Microparticles.

The transport properties of the ionic liquid (IL) 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF6]) confined within silica microparticles with well-ordered, accessible mesopores (5.4 or 9 nm diameter) were investigated. [BMIM][PF6] confinement was confirmed by using differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy. The transport properties of the confined IL were studied using the neutral and cationic fluorescent probes 4-(dicyanomethylene)-2-methyl-6-(4-dimethylaminostyryl)-4H-pyran (DCM) and rhodamine 6G, respectively, through fluorescence recovery after photobleaching (FRAP) in confocal microscopy. The diffusivity of DCM in 9 nm pores is 0.026 ± 0.0091 µm2/s, which is 2 orders of magnitude less than in the bulk ionic liquid. The pore size did not affect the diffusivity of DCM in unmodified silica nanopores. The diffusivity of the cationic probe is reduced by 63% relative to that of the neutral probe. Diffusivity is increased with water content, where equilibrium hydration of the system leads to a 37% increase in DCM diffusivity. The most dramatic impact on diffusivity was caused by tethering an IL-like methylimidazolium chloride group to the pores, which increased the pore hydrophobicity and resulted in 3-fold higher diffusivity of DCM compared to bare silica pores. Subsequent exchange of the chloride anion from the tethering group with PF6- decreased the diffusivity to half that of bare silica. The diffusion of probe molecules is affected most strongly by the pore wall effects on probe interactions rather than by the pore size itself, which suggests that understanding pore wall diffusion is critical to the design of nanoconfined ILs for separations, catalysis, and energy storage.

Recent development of VEGFR small molecule inhibitors as anticancer agents: A patent review (2021-2023).

VEGFR, a receptor tyrosine kinase inhibitor (TKI), is an important regulatory factor that promotes angiogenesis and vascular permeability. It plays a significant role in processes such as tumor angiogenesis, tumor cell invasion, and metastasis. VEGFR is mainly composed of three subtypes: VEGFR-1, VEGFR-2, and VEGFR-3. Among them, VEGFR-2 is the crucial signaling receptor for VEGF, which is involved in various pathological and physiological functions. At present, VEGFR-2 is closely related to a variety of cancers, such as non-small cell lung cancer (NSCLC), Hepatocellular carcinoma, Renal cell carcinoma, breast cancer, gastric cancer, glioma, etc. Consequently, VEGFR-2 serves as a crucial target for various cancer treatments. An increasing number of VEGFR inhibitors have been discovered to treat cancer, and they have achieved tremendous success in the clinic. Nevertheless, VEGFR inhibitors often exhibit severe cytotoxicity, resistance, and limitations in indications, which weaken the clinical therapeutic effect. In recent years, many small molecule inhibitors targeting VEGFR have been identified with anti-drug resistance, lower cytotoxicity, and better affinity. Here, we provide an overview of the structure and physiological functions of VEGFR, as well as some VEGFR inhibitors currently in clinical use. Also, we summarize the in vivo and in vitro activities, selectivity, structure-activity relationship, and therapeutic or preventive use of VEGFR small molecule inhibitors reported in patents in the past three years (2021-2023), thereby presenting the prospects and insights for the future development of targeted VEGFR inhibitors.

NR4A1 depletion inhibits colorectal cancer progression by promoting necroptosis via the RIG-I-like receptor pathway.

Necroptosis is a regulated necrotic cell death mechanism and plays a crucial role in the progression of cancers. However, the potential role and mechanism of necroptosis in colorectal cancer (CRC) has not been fully elucidated. In this study, we found that nuclear receptor subfamily 4 group A member 1 (NR4A1) was highly expressed in CRC cells treated with TNF-α, Smac mimetic, and z-VAD-FMK (TSZ). The depletion of NR4A1 significantly enhanced the sensitivity of CRC cells to TSZ-induced necroptosis, while NR4A1 overexpression suppressed these effects, as evidenced by the LDH assay, flow cytometry analysis of cell death, PI staining, and expression analysis of necrosome complexes (RIPK1, RIPK3, and MLKL). Moreover, NR4A1 deficiency made HT29 xenograft tumors sensitive to necroptotic cell death in vivo. Mechanistically, NR4A1 depletion promoted necroptosis activation in CRC through the RIG-I-like receptor pathway by interacting with DDX3. Importantly, the RIG-I pathway agonist poly(I:C) or inhibitor cFP abolished the effects of NR4A1 overexpression or suppression on necroptosis in CRC cells. Moreover, we observed that NR4A1 was highly expressed in CRC tissues and was associated with a poor prognosis. In conclusion, our results suggest that NR4A1 plays a critical role in modulating necroptosis in CRC cells and provide a new therapeutic target for CRC.

Role function and job satisfaction of community nurses in China: A cross-sectional study.

AIM: To evaluate role function and job satisfaction, determine their relationship, and explore the factors influencing job satisfaction among community nurses in China. DESIGN: Cross-sectional study. METHODS: This study was conducted between March and June 2020 on a cluster random sampling of 302 community nurses from 24 community health centres and stations in Xi'an, China. Self-reported data were collected using the Demographics Questionnaire, Role Function of Community Nurses Questionnaire, and Job Satisfaction of Community Nurses Scale. Descriptive statistics, Pearson's correlation analysis, and multiple linear regression analyses were performed to analyse data. RESULTS: Community nurses' main role function was organiser and manager (M = 2.56, SD = 0.987) and coordinator (M = 2.43, SD = 0.971). The lowest job satisfaction was for salary and benefits (M = 3.12, SD = 0.891) and personal development (M = 3.65, SD = 0.738). A positive correlation was found between the roles of caregiver, educator, navigator, and salary and benefits (p < 0.05) among community nurses. Multiple linear regression analyses indicated that monthly income and working experience in nursing explained 61.1% of the variance in job satisfaction.

Spatial patterns of Holocene temperature changes over mid-latitude Eurasia.

The Holocene temperature conundrum, the discrepancy between proxy-based Holocene global cooling and simulated global annual warming trends, remains controversial. Meanwhile, reconstructions and simulations show inconsistent spatial patterns of terrestrial temperature changes. Here we report Holocene alkenone records to address spatial patterns over mid-latitude Eurasia. In contrast with long-term cooling trends in warm season temperatures in northeastern China, records from southwestern Siberia are characterized by colder conditions before ~6,000 years ago, thus long-term warming trends. Together with existing records from surrounding regions, we infer that colder airmass might have prevailed in the interior of mid-latitude Eurasian continent during the early to mid-Holocene, perhaps associated with atmospheric response to remnant ice sheets. Our results challenge the proposed seasonality bias in proxies and modeled spatial patterns in study region, highlighting that spatial patterns of Holocene temperature changes should be re-considered in record integrations and model simulations, with important implications for terrestrial hydroclimate changes.

Sliding and Fretting Wear Behavior of Biomedical Ultrafine-Grained TiNbZrTaFe/Si Alloys in Simulated Physiological Solution.

This work investigated the wear behavior of ultrafine-grained Ti65Nb23.33Zr5Ta1.67Fe5 (at.%, TNZTF) and Ti65Nb23.33Zr5Ta1.67Si5 (at.%, TNZTS) alloys fabricated by high-energy ball milling and spark plasma sintering. Wear tests were conducted in a simulated physiological solution under both reciprocating sliding and fretting wear conditions with different loads, frequencies, and stroke lengths. The microstructures, mechanical properties, and anti-wear properties of the investigated alloys were characterized. The results showed that the TNZTF and TNZTS alloys had much less wear volume than the commonly used Ti-6Al-4V (TC4) alloy and commercially pure titanium (CP-Ti). The TNZTF and TNZTS alloys exhibited much more smooth wear surfaces and shallower wear scars compared with TC4 and CP-Ti. The investigated alloys exhibited different wear mechanisms under the reciprocating sliding wear conditions, while they were similar under the fretting wear conditions. Compared with TC4 and CP-Ti, the fabricated TNZTF and TNZTS alloys showed a substantially higher wear resistance, owing to their ultrafine-grained microstructure and superior hardness. Additionally, the addition of Nb and Zr further enhanced the wear resistance by forming a protective Nb2O5 and ZrO2 oxide film. This work provides guidance for designing new biomedical titanium alloys with excellent wear resistance.

Correction: He et al. Biology, Ecology and Management of Tephritid Fruit Flies in China: A Review. Insects 2023, 14, 196.

In the original publication [...].

CMBEE: A constraint-based multi-task learning framework for biomedical event extraction.

OBJECTIVE: Event extraction plays a crucial role in natural language processing. However, in the biomedical domain, the presence of nested events adds complexity to event extraction compared to single events, and these events usually have strong semantic relationships and constraints. Previous approaches ignored the binding connections between these complex nested events. This study aims to develop a unified framework based on event constraint information that jointly extract biomedical event triggers and arguments and enhance the performance of nested biomedical event extraction. MATERIAL AND METHODS: We propose a multi-task learning framework based on constraint information called CMBEE for the task of biomedical event extraction. The N-tuple form of event patterns is used to represent the constrained information, which is integrated into role detection and event type classification tasks. The framework use attention mechanism and gating mechanism to explore the fusion of multiple tuple information, as well as local and global constrained information fusion methods to dig further into the connections between events. RESULTS: Experimental results demonstrate that our proposed method achieves the highest F1 score on a multilevel event extraction biomedical (MLEE) corpus and performs favorably on the biomedical natural language processing shared task 2013 Genia event corpus (GE 13). CONCLUSIONS: The experimental results indicate that modeling event patterns and constraints for multi-event extraction tasks is effective for complex biomedical event extraction. The fusion strategy proposed in this study, which incorporates different constraint information, helps to better express semantic information.

GTPase-activating protein ARAP1 regulates circular dorsal ruffles as a nutrient uptake mechanism in the Hep3B hepatocellular carcinoma cell line.

Circular dorsal ruffles (CDRs), large-scale rounded membrane ruffles, function as precursors of macropinocytosis. We recently reported that CDRs are exposed in the Hep3B hepatocellular carcinoma cell line, while not in other hepatocellular carcinoma cell lines, indicating that the CDRs in Hep3B are associated with malignant potential. In this study, we investigated the cellular function of CDRs in Hep3B cells by focusing on the molecular mechanisms of the GTPase-activating protein ARAP1. ARAP1 was localized to the CDRs, the sizes of which were reduced by deletion of this protein. High-resolution scanning electron micrographs revealed that CDRs comprise small vertical lamellipodia, the expression pattern of which was disrupted in ARAP1 KO cells. Extracellular solute uptake, rate of cell growth, and malignant potential were attenuated in the KO cells. ARAP1 is also localized in Hep3B cell mitochondria, although not in those of the Huh7 hepatocellular carcinoma cell line. On the basis of these findings, we propose that the aberrant expression of ARAP1 in Hep3B cells modulates CDRs, thereby resulting in an excess uptake of nutrients as an initial event in cancer development. SUMMARY STATEMENT: ARAP1 regulates circular dorsal ruffles (CDRs) in the Hep3B HCC cell line and deletion of this protein attenuates malignant potential, thereby indicating the involvement of CDRs in cancer development.

HOOK3 suppresses proliferation and metastasis in gastric cancer via the SP1/VEGFA axis.

HOOK3, a member of the human hook microtubule-tethering protein family, has been implicated in the progression of cancer. However, the role of HOOK3 in the pathogenesis of gastric cancer (GC) remains incompletely understood. In this study, we investigated the expression of HOOK3 protein in GC tissues using immunohistochemistry (IHC). The findings of our study indicate that the expression levels of HOOK3 in GC tissues were relatively low. Furthermore, a significant negative association was seen between HOOK3 expression and the prognosis of patients with GC. The suppression of HOOK3 resulted in a notable increase in the proliferation, migration, invasion, and survival of GC cells. Conversely, the overexpression of HOOK3 had the opposite impact, reducing these cellular processes. Moreover, in vivo tests have shown evidence that the overexpression of HOOK3 significantly inhibited the formation of tumors and the spread of GC cells to the lungs. In a mechanistic manner, the analysis of RNA-seq data demonstrated that the knockdown of HOOK3 resulted in a notable increase in the expression of vascular endothelial growth factor A (VEGFA) in GC cells. Furthermore, the upregulation of VEGFA counteracted the impacts of HOOK3 upregulation on the proliferation, migration, invasion, and survival of GC cells. Furthermore, it was revealed that specificity protein 1 (SP1) exhibited the ability to bind to the promoter region of VEGFA. Moreover, the overexpression of SP1 successfully counteracted the inhibitory impact of HOOK3 overexpression on the expression of VEGFA in GC cells. In summary, the results of our study indicate that HOOK3 has a role in inhibiting the growth, migration, invasion, and survival of GC cells by modulating the SP1/VEGFA pathway. These findings contribute significant knowledge to our understanding of the underlying mechanisms involved in the development of GC.