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Sesquilignans PD is a natural phenylpropanoid compound that was isolated from Zanthoxylum nitidum var. tomentosum. In this study, we assessed the antitumor effect of PD on SK-Hep-1 and HepG2 cells and the underlying molecular mechanisms. The results revealed that PD markedly inhibited the proliferation and migration of both liver cancer cells. Moreover, PD induced apoptosis, autophagy, and reactive oxygen species (ROS) production in liver cancer cells. Notably, PD increased the protein levels of p-p38 MAPK and p-ERK1/2 in liver cancer cells. This is the first report on the anticancer effect of PD, which is mediated via increased ROS production and MAPK signaling activation. [ABSTRACT FROM AUTHOR]

Summary: Chloroplast Unusual Positioning 1 (CHUP1) plays an important role in the chloroplast avoidance and accumulation responses in mesophyll cells. In epidermal cells, prior research showed silencing CHUP1‐induced chloroplast stromules and amplified effector‐triggered immunity (ETI); however, the underlying mechanisms remain largely unknown.CHUP1 has a dual function in anchoring chloroplasts and recruiting chloroplast‐associated actin (cp‐actin) filaments for blue light‐induced movement. To determine which function is critical for ETI, we developed an approach to quantify chloroplast anchoring and movement in epidermal cells. Our data show that silencing NbCHUP1 in Nicotiana benthamiana plants increased epidermal chloroplast de‐anchoring and basal movement but did not fully disrupt blue light‐induced chloroplast movement.Silencing NbCHUP1 auto‐activated epidermal chloroplast defense (ECD) responses including stromule formation, perinuclear chloroplast clustering, the epidermal chloroplast response (ECR), and the chloroplast reactive oxygen species (ROS), hydrogen peroxide (H2O2). These findings show chloroplast anchoring restricts a multifaceted ECD response.Our results also show that the accumulated chloroplastic H2O2 in NbCHUP1‐silenced plants was not required for the increased basal epidermal chloroplast movement but was essential for increased stromules and enhanced ETI. This finding indicates that chloroplast de‐anchoring and H2O2 play separate but essential roles during ETI. [ABSTRACT FROM AUTHOR]

(-)-Epigallocatechin-3-O-gallate (EGCG), one of the green tea catechins, exhibits significant antioxidant properties that play an essential role in various diseases. However, the functional role and underlying mechanism of EGCG in stimulating of hepatic stellate cells (HSCs) remain unexplored in transcriptomics sequencing studies. The present study suggests that oral administration of EGCG at a dosage of 200 mg/kg/day for a duration of four weeks exhibits significant therapeutic potential in a murine model of liver fibrosis induced by CCl4. The activation of HSCs in vitro was dose-dependently inhibited by EGCG. The sequencing analysis data reveled that EGCG exerted a regulatory effect on the calcium signal in mouse HSCs, resulting in a decrease in calcium ion concentration. Further analysis revealed that EGCG inhibited the expression of phospholipase C epsilon-1 (PLCE1) and inositol 1, 4, 5-trisphosphate (IP3) in activated mouse HSCs. Additionally, EGCG contributes to the reduction the concentration of calcium ions by regulating PLCE1. After the knockdown of PLCE1, free calcium ion concentrations decreased, resulting in the inhibition of both cell proliferation and migration. Interestingly, the expression of PLCE1 and cytosolic calcium levels were regulated by reactive oxygen species(ROS). Furthermore, our findings suggest that ROS might inhibit the expression of PLCE1 by inhibiting TFEB, a transcription activator involved in the nuclear translocation process. Our study provided novel evidence regarding the regulatory effects of EGCG on activated HSCs (aHSCs) in mice by the calcium signaling pathway, emphasizing the crucial role of PLCE1 within the calcium signaling network of HSCs. The proposition was also made that PLCE1 holds promise as a novel therapeutic target for murine liver fibrosis. [ABSTRACT FROM AUTHOR]

Collective cell invasion underlies several biological processes such as wound healing, embryonic development, and cancerous invasion. Here, we investigate the impact of cell motility on invasion in epithelial monolayers and its coupling to cellular mechanical properties, such as cell-cell adhesion and cortex contractility. We develop a two-dimensional computational model for cells with active motility based on the cellular Potts model, which predicts that the cellular invasion speed is mainly determined by active cell motility and is independent of the biological and mechanical properties of the cells. We also find that, in general, motile cells out-compete and invade non-motile cells, however, this can be reversed by differential cell proliferation. Stable coexistence of motile and static cell types is also possible for certain parameter regimes. [ABSTRACT FROM AUTHOR]

Functional magnetic resonance spectroscopy (fMRS) measures dynamic changes in metabolite concentration in response to neural stimulation. The biophysical basis of these changes remains unclear. One hypothesis suggests that an increase or decrease in the glutamate signal detected by fMRS could be due to neurotransmitter movements between cellular compartments with different T2 relaxation times. Previous studies reporting glutamate (Glu) T2 values have generally sampled at echo times (TEs) within the range of 30–450 ms, which is not adequate to observe a component with short T2 (<20 ms). Here, we acquire MRS measurements for Glu, (t) total creatine (tCr) and total N‐acetylaspartate (tNAA) from the visual cortex in 14 healthy participants at a range of TE values between 9.3–280 ms during short blocks (64 s) of flickering checkerboards and rest to examine both the short‐ and long‐T2 components of the curve. We fit monoexponential and biexponential Glu, tCr and tNAA T2 relaxation curves for rest and stimulation and use Akaike information criterion to assess best model fit. We also include power calculations for detection of a 2% shift of Glu between compartments for each TE. Using pooled data over all participants at rest, we observed a short Glu T2‐component with T2 = 10 ms and volume fraction of 0.35, a short tCr T2‐component with T2 = 26 ms and volume fraction of 0.25 and a short tNAA T2‐component around 15 ms with volume fraction of 0.34. No statistically significant change in Glu, tCr and tNAA signal during stimulation was detected at any TE. The volume fractions of short‐T2 component between rest and active conditions were not statistically different. This study provides evidence for a short T2‐component for Glu, tCr and tNAA but no evidence to support the hypothesis of task‐related changes in glutamate distribution between short and long T2 compartments. [ABSTRACT FROM AUTHOR]

The influence of extracellular matrix (ECM) stiffness on cell behavior is a well‐established phenomenon. Tumor development is associated with the stiffening of the ECM. However, the understanding of the role of biomechanical behavior and mechanotransduction pathways in the oncogenesis of tumor cells remains limited. In this study, we constructed in vitro models using Polydimethylsiloxane substrates to create soft and stiff substrates. We then evaluated the migration of lung cancer cells A549 using video‐microscopy and transwell assays. The mechanical properties were assessed through the utilization of atomic force microscopy, Optical Magnetic Twisting Cytometry, and traction force analysis. Additionally, the expression of Calponin 3 (CNN3) was evaluated using reverse transcription‑quantitative PCR and immunofluorescence techniques. Our observations indicate that the presence of a stiff substrate enhances A549 motility, as evidenced by increased stiffness and traction force in A549 cells on the stiff substrate. Furthermore, we observed a decrease in CNN3 expression in A549 cells on the stiff substrate. Notably, when CNN3 was overexpressed, it effectively inhibited the migration and invasion of A549 cells on the stiff substrate. The results of our study provide novel perspectives on the mechanisms underlying cancer cell migration in response to substrate mechanical properties. [ABSTRACT FROM AUTHOR]

Background: Diabetic cardiomyopathy (DCM), characterized by myocardial fibrosis, is a major cause of mortality and morbidity in diabetic patients; the inhibition of cardiac fibrosis is a fundamental strategy for treating DCM. Gastrodin (GAS), a compound extracted from Gastrodia elata protects against DCM, but the molecular mechanism underlying its antifibrotic effect has not been elucidated. Methods: In vivo, the effects of GAS were investigated using C57BL/6 mice with DCM, which was induced by administering a high-sugar, high-fat (HSF) diet and streptozotocin (STZ). We assessed the cardiac function in these mice and detected histopathological changes in their hearts and the degree of cardiac fibrosis. In vitro, neonatal rat cardiac fibroblasts (CFs) were transformed into myofibroblasts by exposing them to high glucose combined with high palmitic acid (HG-PA), and CFs were induced by pEX-1 (pGCMV/MCS/EGFP/Neo) plasmid-mediated overexpression of KLK8, which contains the rat KLK8 gene. The KLK8 siRNA was knocked down to study the effects of GAS on CF differentiation, collagen synthesis, and cell migration by specific mechanisms of action of GAS. Results: GAS attenuated pathological changes in the hearts of DCM mice, rescued impaired cardiac function, and attenuated cardiac fibrosis. Additionally, the results of molecular docking analysis showed that GAS binds to kinin-releasing enzyme-related peptidase 8 (KLK8) to inhibit the increase in protease-activated receptor-1 (PAR-1), thus attenuating myocardial fibrosis. Specifically, GAS attenuated the transformation of neonatal rat CFs to myofibroblasts exposed to HG-PA. Overexpressing KLK8 promoted CF differentiation, collagen synthesis, and cell migration, and KLK8 siRNA attenuated HG-PA-induced CF differentiation, collagen synthesis, and cell migration. Further studies revealed that a PAR-1 antagonist, but not a PAR-2 antagonist, could attenuate CF differentiation, collagen synthesis, and cell migration. Additionally, GAS inhibited KLK8 upregulation and PAR1 activation, thus blocking the differentiation, collagen synthesis, and cell migration of HG-PA-exposed CFs and triggering TGF-β1/Smad3 signaling. Conclusion: GAS alleviated pathological changes in the hearts of DCM model mice induced by an HSF diet combined with STZ. KLK8 mediated HG-PA-induced differentiation, collagen synthesis, and the migration of CFs. GAS attenuated the differentiation, collagen synthesis, and migration of CFs by inhibiting the KLK8-PAR1 signaling axis, a process in which TGF-β1 and Smad3 are involved. [ABSTRACT FROM AUTHOR]

Key points The peristaltic reflex has been a central concept in gastrointestinal motility; however, evidence was published recently suggesting that post‐stimulus responses that follow inhibitory neural responses provide the main propulsive force in colonic motility. This new concept was based on experiments on proximal colon where enteric inhibitory neural inputs are mainly nitrergic. However, the nature of inhibitory neural inputs changes from proximal to distal colon where purinergic inhibitory regulation dominates. In spite of the transition from nitrergic to purinergic regulation, post‐stimulus responses and propulsive contractions were both blocked by antagonists of a conductance (ANO1) exclusive to interstitial cells of Cajal (ICC). How purinergic neurotransmission, transduced by PDGFRα+ cells, can influence ANO1 in ICC is unknown. We compared neural responses in proximal and distal colon. Post‐stimulus responses were blocked by inhibition of nitrergic neurotransmission in proximal colon, but P2Y1 receptor antagonists were more effective in distal colon. Ca2+ entry through voltage‐dependent channels (CaV3) enhances Ca2+ release in ICC. Thus, we reasoned that hyperpolarization caused by purinergic responses in PDGFRα+ cells, which are electrically coupled to ICC, might decrease inactivation of CaV3 channels and activate Ca2+ entry into ICC via anode‐break upon cessation of inhibitory responses. Post‐stimulus responses in distal colon were blocked by MRS2500 (P2Y1 receptor antagonist), apamin (SK channel antagonist) and NNC55‐0396 (CaV3 antagonist). These compounds also blocked propagating contractions in mid and distal colon. These data provide the first clear demonstration that integration of functions in the smooth muscle–ICC–PDGFRα+ cell (SIP) syncytium generates a major motility behaviour. Propagating propulsive contractions initiated by the enteric nervous system are a major motility behaviour in the colon. A major component of contractions, necessary for propulsive contractions, occurs at cessation of enteric inhibitory neurotransmission (post‐stimulus response) and is generated by interstitial cells of Cajal (ICC), which are electrically coupled to smooth muscle cells. The nature of enteric inhibitory neurotransmission shifts from proximal colon, where it is predominantly due to nitric oxide, to distal colon, where it is predominantly due to purine neurotransmitters. Different cells transduce nitric oxide and purines in the colon. ICC transduce nitric oxide, but another type of interstitial cell, PDGFRα+ cells, transduces input from purinergic neurons. However, the post‐stimulus responses in proximal and distal colon are still generated in ICC. This paper explores how integrated behaviours of ICC, PDGFRα+ cells and smooth muscle cells accomplish propulsive motility in the colon. [ABSTRACT FROM AUTHOR]

Background: Melanoma is an aggressive tumor with a high mortality rate. Metformin, a commonly prescribed diabetes medication, has shown promise in cancer prevention and treatment. Long noncoding RNAs (lncRNAs) are non-protein-coding RNA molecules that play a key role in tumor development by interacting with cellular chromatins. Despite the benefits of metformin, the anticancer mechanism underlying its effect on the regulation of lncRNAs in melanoma remains unclear. Methods: We investigated the lncRNA profiles of human melanoma cells with and without metformin treatment using a next-generation sequencing approach (NGS). Utilizing public databases, we analyzed the expression levels and clinical impacts of LINC00094 and miR-1270 in melanoma. The expression levels of LINC00094 and miR-1270 were verified in human cell lines and clinical samples by real-time PCR and in situ hybridization. The biological roles of LINC00094 and miR-1270 in cell growth, proliferation, cell cycle, apoptosis, and motility were studied using in vitro assays. Results: We identify a novel long noncoding RNA, namely LINC00094, whose expression considerably decreased in melanoma cells after metformin treatment. In situ hybridization analysis revealed substantially higher expression of LINC00094 in cutaneous melanoma tissue compared with adjacent normal epidermis and normal control tissues (P < 0.001). In nondiabetic patients with melanoma, the overall survival of high LINC00094 expression group was shorter than the low LINC00094 expression group with borderline statistical significance (log-rank test, P = 0.057). Coexpression analysis of LINC00094 indicated its involvement in the mitochondrial respiratory pathway, with its knockdown suppressing genes associated with mitochondrial oxidative phosphorylation, glycolysis, antioxidant production, and metabolite levels. Functional analysis revealed that silencing-LINC00094 inhibited the proliferation, colony formation, invasion, and migration of melanoma cells. Cell cycle analysis following LINC00094 knockdown revealed G1 phase arrest with reduced cell cycle protein expression. Combined TargetScan and reporter assays revealed a direct link between miR-1270 and LINC00094. Ectopic miR-1270 expression inhibited melanoma cell growth and motility while inducing apoptosis. Finally, through in silico analysis, we identified two miR-1270 target genes, CD276 and centromere protein M (CENPM), which may be involved in the biological functions of LINC00094. Conclusions: Overall, LINC00094 expression may regulate melanoma cell growth and motility by modulating the expression of miR-1270, and targeting genes of CD276 and CENPM indicating its therapeutic potential in melanoma treatment. [ABSTRACT FROM AUTHOR]

Objective: This study aims to explore the regulatory mechanisms of Wnt signaling in the invasion and recurrence of ameloblastoma (AM) to provide a new theoretical basis for its treatment. Methods: Bulk RNA sequencing was employed to analyze samples from AM patients, and identify differentially expressed genes. Subsequently, bioinformatics methods such as Weighted Gene Co-Expression Network Analysis (WGCNA), DESeq2, and KEGG enrichment analysis were utilized to construct gene co-expression networks and identify pathways associated with invasion and recurrence. Furthermore, in vitro experiments, including Cell Counting Kit-8 (CCK-8), Wound healing assays, Western blotting, and qPCR were conducted to validate the effects of Wnt signaling on AM biological functions and the expression of related genes and proteins. Results: Bioinformatics analysis revealed significant activation of the Wnt signaling pathway during AM invasion and recurrence, and differential gene analysis identified specific gene expression patterns associated with the Wnt signaling pathway. In vitro experiments further demonstrated that the standard Wnt/β-catenin pathway activator, Laduviglusib significantly activated Wnt signaling, leading to a marked increase in the mRNA and protein expression levels of TCF7, β-catenin, WNT2B, and LEF1, thereby enhancing the proliferation and migration capabilities of AM cells. Conclusion: This study reveals the critical role of aberrant Wnt signaling activation in AM proliferation and migration, identifying it as a key driver of AM invasion and recurrence. The findings provide new insights into the mechanisms underlying AM invasion and recurrence, laying the foundation for developing novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Spontaneous locomotion is a common feature of most metazoan cells, generally attributed to the properties of actomyosin networks. This force-producing machinery has been studied down to the most minute molecular details, especially in lamellipodium-driven migration. Nevertheless, how actomyosin networks work inside contraction-driven amoeboid cells still lacks unifying principles. Here, using stable motile blebs from HeLa cells as a model amoeboid motile system, we imaged the dynamics of the actin cortex at the single filament level and revealed the co-existence of three distinct rheological phases. We introduce "advected percolation," a process where rigidity percolation and active advection synergize, spatially organizing the actin network's mechanical properties into a minimal and generic locomotion mechanism. Expanding from our observations on simplified systems, we speculate that this model could explain, down to the single actin filament level, how amoeboid cells, such as cancer or immune cells, can propel efficiently through complex 3D environments. [Display omitted] • Actin filament density at the cell front controls bleb protrusion • A solid-like actomyosin cortex in the cell middle sterically enables cell propulsion • The material properties of amoeboid cells organize spatially by advected percolation • Stable blebs in adhesive environments can fragment into cytoplasts García-Arcos et al. propose a universal framework for amoeboid migration: actin filaments and myosin motors spatially self-organize and give rise to different material properties in different parts of the cell. A solid-like state in the actin network found in the middle of the cell enables efficient cell propulsion. [ABSTRACT FROM AUTHOR]

Background: In China, Tongguanteng injection (TGT) is widely used in the treatment or adjuvant treatment of various types of cancer. However, the effect and mechanism of TGT in osteosarcoma is not clear. Methods: The 143B and MG-63 cells were treated with different concentrations of TGT. Cell proliferation, migration, invasion and apoptosis were detected using CCK8 assay, transwell assay and flow cytometry. Differentially expressed genes (DEGs) were screened using RNA sequencing (RNA-seq). The identified mRNA and protein expression associated with the IRE1/CHOP pathway was validated by RT-PCR and western blot assay. To explore the underlying mechanisms, 4-phenylbutyric acid (4-PBA) was selected as a specific endoplasmic reticulum (ER) stress inhibitor. Small interfering RNA (siRNA) or pEX‐3-ERN1 plasmid was transfected into 143B cells to silence or overexpress IRE1, respectively. The potential downstream proteins, including CHOP, and apoptosis associated proteins, caspase-3 and PARP1 were determined. Furthermore, the effect of TGT was demonstrated in 143B cell tumor-bearing mice in vivo. H&E staining, TUNEL staining and immunohistochemistry were conducted in tumor tissues obtained from the xenograft mouse model. Results: TGT was shown to dramatically suppress the proliferation, migration and invasion, and induce apoptosis of osteosarcoma 143B and MG-63 cells in vitro. The identified DEGs included HSPA5 (encoding BiP) and ERN1 (encoding the IRE1 protein), as well as apoptosis-associated gene DDIT3 (encoding the CHOP protein). The term "IRE1-mediated unfolded protein response" was screened to be the most enriched biological process GO term. The expression of ER stress-associated proteins including ATF6, BiP, p-IRE1, XBP1s and CHOP, as well as apoptosis-associated cleaved caspase-3 and cleaved PARP1 proteins, was significantly upregulated by TGT treatment in osteosarcoma 143B cells, suggesting that TGT might promote the apoptosis of osteosarcoma 143B cells through the IRE1/CHOP pathway. Furthermore, knocking down IRE1 with si-IRE1 or inhibiting of ER stress with 4-PBA suppressed the expression of ATF6, BiP, XBP1s and CHOP induced by TGT, as well as the expression of cleaved caspase-3 and cleaved PARP1. On the contrary, overexpressing IRE1 promoted CHOP expression and induced osteosarcoma cell apoptosis. Consistent with in vitro results, TGT dramatically inhibited the tumor growth and promoted the expression of p-IRE1 and CHOP in tumor-bearing mice. Conclusion: The findings suggest that TGT exerts an anti-osteosarcoma effect in vitro and in vivo. The underlying mechanism might be associated with the activation of IRE1/CHOP pathway in ER stress. Our findings suggest that targeting IRE1/CHOP pathway might be a potential novel approach for osteosarcoma treatment. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer diagnosed in women worldwide. However, the effective treatment for breast cancer progression is still being sought. The activation of cannabinoid receptor (CB) has been shown to negatively affect breast cancer cell survival. Our previous study also reported that breast cancer cells responded to various combinations of CB1 and CB2 agonists differently. Nonetheless, the mechanism underlying this effect and whether this phenomenon can be seen in other cancer characteristics remain unknown. Therefore, this study aims to further elucidate the effects of highly selective CB agonists and their combination on triple-negative breast cancer proliferation, cell cycle progression, invasion, lamellipodia formation as well as proteomic profile of MDA-MB-231 breast cancer cells. The presence of CB agonists, specifically a 2:1 (ACEA: GW405833) combination, prominently inhibited colony formation and induced the S-phase cell cycle arrest in MDA-MB-231 cells. Furthermore, cell invasion ability and lamellipodia formation of MDA-MB-231 were also attenuated by the exposure of CB agonists and their 2:1 combination ratio. Our proteomic analysis revealed proteomic profile alteration in MDA-MB-231 upon CB exposure that potentially led to breast cancer suppression, such as ZPR1/SHC1/MAPK-mediated cell proliferation and AXL/VAV2/RAC1-mediated cell motility pathways. Our findings showed that selective CB agonists and their combination suppressed breast cancer characteristics in MDA-MB-231 cells. The exposure of CB agonists also altered the proteomic profile of MDA-MB-231, which could lead to cell proliferation and motility suppression. [ABSTRACT FROM AUTHOR]

Fluid viscosity and osmolarity are among some of the underappreciated mechanical stimuli that cells can detect. Abnormal changes of multiple fluidic factors such as viscosity and osmolarity have been linked with diseases such as cystic fibrosis, cancer, and coronary heart disease. Changes in viscosity have been recently suggested as a regulator of cell locomotion. These novel studies focus on cell migration and spreading on glass substrates and through microchannels, and it remains a question whether viscosity impacts the cellular remodeling of extracellular matrices (ECMs). Here, we demonstrate that elevated viscosity induces cellular remodeling of collagen substrates and enhances cell spreading on ECM‐mimetic substrates. Our results expand on recent work showing that viscosity induces increased cellular forces and demonstrates that viscosity can drive local ECM densification. Our data further show that microtubules, Ras‐related C3 botulinum toxin substrate 1 (Rac1), actin‐related protein 2/3 (Arp2/3) complex, Rho‐associated protein kinase 1 (ROCK), and myosin are important regulators of viscosity‐induced ECM remodeling. In the context of viscosity‐induced cell spreading, cells cultured on glass and collagen substrates exhibit markedly different responses to pharmacological treatments, indicating that microtubules, Rac1, and Arp2/3 play distinct roles in regulating cellular spreading depending on the substrate. In addition, our results demonstrate that high osmotic pressures override viscosity‐induced cell spreading by suppressing membrane ruffling. Our results demonstrate viscosity as a regulator of ECM remodeling and cell spreading in a fibrillar microenvironment. We also reveal a complex interplay between viscosity and osmolarity. We anticipate that our research can pave the way for future investigations into the crucial roles played by viscosity in both physiological and pathological conditions. [ABSTRACT FROM AUTHOR]

Vaccinia virus (VACV)–induced cell migration is thought to be closely related to the rapid transmission of viral infection in the body. The limited studies are mainly based on scratch assay using traditional cell culture techniques, which inevitably ignores the influences of extracellular microenvironment. Physical confinement, inherently presenting in vivo, has proven to be a critical extern cue in modulating migration behaviors of multiple cells, while its impacts on VACV-induced cell motility remain unclear. Herein, we developed a migration assay microchip featuring confined microchannel array to investigate the effect of physical confinement on infected cell morphology and motility during VACV infection. Results showed that different from the random cell migration observed in traditional scratch assay on planar substrate, VACV-infected cells exhibited accelerated directionally persistent migration under confinement microenvironment. Moreover, single-directed elongated dominant lamella appeared to contrast distinctly with multiple protrusions stretched in random directions under unconfined condition. Additionally, the Golgi complex tended to relocate behind the nucleus confined within the microchannel axis compared to the classical reorientation pattern. These differences in characteristic subcellular architecture and organelle reorientation of migrating cells revealed cell biological mechanisms underlying altered migration behavior. Collectively, our study demonstrates that physical confinement acting as a guidance cue has profound impacts on VACV-induced migration behaviors, which provides new insight into cell migration behavior and viral rapid spread during VACV infection. [ABSTRACT FROM AUTHOR]

Endometriosis (EMT) has a significant impact on women's physical and mental health. In this study, high-throughput sequencing technology was employed to detect differences in gut microbiota between EMT patients and healthy individuals (CTL). Additionally, Spearman correlation analysis was utilized to analyze the correlation between different bacterial genera and EMT biomarkers (CA125 and CA199). The results demonstrated that at the phylum level, the relative abundances of Proteobacteria and Desulfobacterota_G_459546 in the EMT group were significantly higher than those in the CTL group, while the relative abundances of Bacteroidota and Firmicutes_A in the EMT group were significantly lower than those in the CTL group. At the genus level, the relative abundances of Burkholderiales and Sphingomonadales in the EMT group were significantly higher than those in the CTL group, while the relative abundances of Bacteroidales and Roseburia in the EMT group were significantly lower than those in the CTL group. The correlation analysis results show that CA125 and CA199 are significantly positively correlated with Burkholderiales and Sphingomonadales , and significantly negatively correlated with Bacteroidales , Oscillospirales , and Roseburia. The PICRUSt2 results show that the relative abundance in the cell motility and xenobiotics biodegradation and metabolism pathways in the EMT group was higher than that in the CTL group, while the relative abundance in the translation, replication and repair, folding, sorting and degradation, metabolism of terpenoids and polyketides and metabolism of cofactors and vitamins pathways in the EMT group was lower than that in the CTL group. In brief, there is a close correlation between the imbalance of gut microbiota and the onset of EMT. The intestinal microbiota has great significance broad prospects for the prevention, diagnosis and treatment of EMT. [ABSTRACT FROM AUTHOR]

The progression and outcome of bladder cancer (BLCA) are critically affected by the propensity of tumor metastasis. Our previous study revealed that activation of the mevalonate (MVA) pathway promoted migration of BLCA cells; however, the exact mechanism is unclear. Here we show that elevated expression of MVA pathway enzymes in BLCA cells, correlating with poorer patient prognosis by analyzing single-cell and bulk-transcriptomic datasets. Inhibition of the MVA pathway, either through knockdown of farnesyl diphosphate synthase (FDPS) or using inhibitors such as zoledronic acid or simvastatin, led to a marked reduction in BLCA cell migration. Notably, this effect was reversed by administering geranylgeranyl pyrophosphate (GGPP), not farnesyl pyrophosphate (FPP) or cholesterol, indicating the specificity of geranylgeranylation for cell motility. Moreover, we found that RhoB, a Rho GTPase family member, was identified as a key effector of the impact of the MVA pathway on BLCA metastasis. The post-translational modification of RhoB by GGPP-mediated geranylgeranylation influenced its protein stability through the ubiquitin-proteasome pathway. Additionally, overexpression of RhoB was found to block the membrane translocation of integrin β1 in BLCA cells. In summary, our findings underscore the role of the MVA pathway in BLCA metastasis, providing insights into potential therapeutic targets of this malignancy. RhoB plays an important role in the effect of MVA pathway inhibition on the migratory capacity of bladder cancer cells and its protein stability is closely related to GGPP-mediated geranylgeranyl modification. [ABSTRACT FROM AUTHOR]

Background: Assay of Transposase Accessible Chromatin Sequencing (ATAC-seq) is a high-throughput sequencing technique that detects open chromatin regions across the genome. These regions are critical in facilitating transcription factor binding and subsequent gene expression. Herein, we utilized ATAC-seq to identify key molecular targets regulating the development and progression of hepatocellular carcinoma (HCC) and elucidate the underlying mechanisms. Methods: We first compared chromatin accessibility profiles between HCC and normal tissues. Subsequently, RNA-seq data was employed to identify differentially expressed genes (DEGs). Integrating ATAC-seq and RNA-seq data allowed the identification of transcription factors and their putative target genes associated with differentially accessible regions (DARs). Finally, functional experiments were conducted to investigate the effects of the identified regulatory factors and corresponding targets on HCC cell proliferation and migration. Results: Enrichment analysis of DARs between HCC and adjacent normal tissues revealed distinct signaling pathways and regulatory factors. Upregulated DARs in HCC were enriched in genes related to the MAPK and FoxO signaling pathways and associated with transcription factor families like ETS and AP-1. Conversely, downregulated DARs were associated with the TGF-β, cAMP, and p53 signaling pathways and the CTCF family. Integration of the datasets revealed a positive correlation between specific DARs and DEGs. Notably, PRPF3 emerged as a gene associated with DARs in HCC, and functional assays demonstrated its ability to promote HCC cell proliferation and migration. To the best of our knowledge, this is the first report highlighting the oncogenic role of PRPF3 in HCC. Furthermore, ZNF93 expression positively correlated with PRPF3, and ChIP-seq data indicated its potential role as a transcription factor regulating PRPF3 by binding to its promoter region. Conclusion: This study provides a comprehensive analysis of the epigenetic landscape in HCC, encompassing both chromatin accessibility and the transcriptome. Our findings reveal that ZNF93 promotes the proliferation and motility of HCC cells through transcriptional regulation of a novel oncogene, PRPF3. [ABSTRACT FROM AUTHOR]

Background: Osteocalcin is a small protein abundant in the bone extracellular-matrix, that serves as a marker for mature osteoblasts. To become activated, osteocalcin undergoes a specific post-translational carboxylation. Osteocalcin is expressed at advanced stages of embryogenesis and after birth, when bone formation takes place. Neural crest cells (NCCs) are a unique cell population that evolves during early stages of development. While initially NCCs populate the dorsal neural-tube, later they undergo epithelial-to-mesenchymal-transition and migrate throughout the embryo in highly-regulated manner. NCCs give rise to multiple cell types including neurons and glia of the peripheral nervous system, chromaffin cells and skin melanocytes. Remarkably, in the head region, NCCs give rise to cartilage and bone. Finding: Here we report that osteocalcin is detected in cranial NCCs. Analysis of chick embryos at stages of cranial NCC migration revealed that osteocalcin mRNA and protein is expressed in pre-migratory and migratory NCCs in-vivo and ex-vivo. Addition of warfarin, an inhibitor of osteocalcin carboxylation, onto neural-tube explants, reduced the amount of NCC migration. These results provide the first evidence of osteocalcin presence in cranial NCCs, much before they give rise to craniofacial skeleton, and propose its possible involvement in the regulation of NCC migration. [ABSTRACT FROM AUTHOR]

Mechanical control is fundamental for cellular localization within a tissue, including for tumor-associated macrophages (TAMs). While the innate immune sensing pathways cGAS-STING and RLR-MAVS impact the pathogenesis and therapeutics of malignant diseases, their effects on cell residency and motility remain incompletely understood. Here, we uncovered that TBK1 kinase, activated by cGAS-STING or RLR-MAVS signaling in macrophages, directly phosphorylates and mobilizes Zyxin, a key regulator of actin dynamics. Under pathological conditions and in STING or MAVS signalosomes, TBK1-mediated Zyxin phosphorylation at S143 facilitates rapid recruitment of phospho-Zyxin to focal adhesions, leading to subsequent F-actin reorganization and reduced macrophage migration. Intratumoral STING-TBK1-Zyxin signaling was evident in TAMs and critical in antitumor immunity. Furthermore, myeloid-specific or global disruption of this signaling decreased the population of CD11b+ F4/80+ TAMs and promoted PD-1-mediated antitumor immunotherapy. Thus, our findings identify a new biological function of innate immune sensing pathways by regulating macrophage tissue localization, thus providing insights into context-dependent mitigation of antitumor immunity. Synopsis: Although the role of innate immune sensing pathways is well-studied in the pathogenesis of malignancies, whether they influence immune cell migration is not known. This study shows that innate immune signaling via cGAS-STING or RLR-MAVS regulates tumor-associated macrophage tissue residency through activation of the TBK1-Zyxin axis. STING signalosomes recruit and directly phosphorylate Zyxin, thus promoting its localization to focal adhesions. TBK1-Zyxin-mediated chemo-mechanical signaling enhances macrophage adhesion in response to cGAS-STING or RLR-MAVS signaling. STING-TBK1-Zyxin signaling activation in mouse intratumoral tumor-associated macrophages detains TAMs in the tumor and reduces antitumor immunity responses. Myeloid-specific or global inhibition of cGAS-STING-TBK1-Zyxin signaling facilitates antitumor immunotherapy. Innate immune sensing pathways activate the TBK1 kinase for phosphorylation of the actin dynamics regulator Zyxin to trap macrophages in the tumor. [ABSTRACT FROM AUTHOR]

In this paper, we introduce an innovative hybrid discrete‐continuum model that provides a comprehensive framework for understanding the intricate interactions between tumor cells, immune cells, and the effects of immunotherapy. This study distinguishes itself by addressing the limitations of traditional diffusion models, which often fail to capture the irregular and nonlocal movements of cells within the complex tumor microenvironment. To overcome these challenges, we employ fractional time derivatives and the fractional Laplacian operator, offering a more accurate representation of anomalous diffusion processes that are critical in cancer dynamics. Our research begins with a rigorous mathematical analysis, where we establish the global existence of a unique mild solution, laying a solid theoretical foundation for the model. A key innovation of our study is the introduction of the “invasion threshold,” a critical parameter inspired by the next‐generation operator used in epidemiological modeling. This threshold provides a powerful tool for determining the existence and stability of equilibrium points, offering deep insights into the conditions that either promote or inhibit tumor growth under immunotherapeutic interventions. By integrating a hybrid discrete‐continuum approach, we capture the individual behavior of each cell, allowing for a more detailed exploration of the dynamic interplay within the tumor microenvironment. This model not only advances our understanding of tumor‐immune interactions but also holds potential for informing more effective therapeutic strategies, making a significant contribution to the field of mathematical oncology. [ABSTRACT FROM AUTHOR]

Eukaryotic cells depend on dynamic changes in shape to fulfill a wide range of cellular functions, maintain essential biological processes, and regulate cellular behavior. The single-celled, predatory ciliate Lacrymaria exhibits extraordinary dynamic shape-shifting using a flexible "neck" that can stretch 7–8 times the length of its body to capture prey. The molecular mechanism behind this morphological change remains a mystery. We have observed that when in an active state, Lacrymaria repeatedly extends and contracts its neck to enable 360-degree space search and prey capture. This remarkable morphological change involves a unique actin-myosin system rather than the Ca2+-dependent system found in other contractile ciliates. Two cytoskeletons are identified in the cortex of the Lacrymaria cell, namely the myoneme cytoskeleton and the microtubule cytoskeleton. The myoneme cytoskeleton is composed of centrin-myosin proteins, exhibiting distinct patterns between the neck and body, with their boundary seemingly associated with the position of the macronucleus. A novel giant protein forming a ladder-like structure was discovered as a component of the microtubule cytoskeleton. Thick centrin-myosin fibers are situated very close to the right side of the ladders in the neck but are far away from such structures in the body. This arrangement enables the decoupling of the neck and body. Plasmodium -like unconventional actin has been discovered in Lacrymaria , and this may form highly dynamic short filaments that could attach to the giant protein and myosin, facilitating coordination between the two cytoskeletons in the neck. In summary, this fascinating organism employs unconventional cytoskeletal components to accomplish its extraordinary dynamic shape-shifting. [Display omitted] • Lacrymaria uses a unique actin-myosin system for neck morphology changes • Two cytoskeletal structures with unconventional components work together • The centrin-myosin-based myoneme shows distinct patterns in neck and body • A giant protein forms a ladder structure in the microtubule cytoskeleton Qin et al. discover the mechanism behind the remarkable shape-shifting of the unicellular predator, Lacrymaria. They identify two key cytoskeletal structures: a centrin-myosin-based myoneme and a giant protein-containing microtubule cytoskeleton. These structures work together to decouple the neck and body, enabling its dynamic neck morphology. [ABSTRACT FROM AUTHOR]

Shear stress plays a crucial role in modulating cell adhesion and signaling. We present a microfluidic shear stress generator used to investigate the adhesion dynamics of Dictyostelium discoideum, an amoeba cell model organism with well-characterized adhesion properties. We applied shear stress and tracked cell adhesion, motility, and detachment using time-lapse videomicroscopy. In the precise shear conditions generated on-chip, our results show cell migration patterns are influenced by shear stress, with cells displaying an adaptive response to shear forces as they alter their adhesion and motility behavior. Additionally, we observed that DH1-10 wild-type D. discoideum cells exhibit stronger adhesion and resistance to shear-induced detachment compared to phg2 adhesion-defective mutant cells. We also highlight the influence of cell density on detachment kinetics. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the leading cause of cancer death in women, with risk factors including environmental radiation exposure and hormones. This study examined the expression of genes associated with cell motility necessary for cancer progression in cells of varying malignancy exposed to radiation and estrogen. The expression of these genes was also compared with patient data provided by other researchers. The results indicated that these genes showed increased expression in response to radiation alone or in combination with estrogen. Additionally, in patients, the expression of most of these genes was found to be higher in normal tissues adjacent to the tumor ones. The estrogen receptor alpha (ESR1) and the estrogen receptor beta (ESR2) genes, which are significant for patient characterization and treatment, were used to carry out correlations. The analysis of the patient data revealed a low correlation between the genes related to motility and ESR1 expression, whereas a positive correlation was observed between the genes in this study and ESR2 expression. Furthermore, patients with high expression levels of the microtubule-associated protein 1B gene or tubulin alpha-1A gene exhibited a decreased survival rate. These findings suggest that there may be potential for exploring new therapeutic strategies based on the association between patients' expression of hormone receptors and genes associated with cell motility. Breast cancer is a major global health concern as it is the primary cause of cancer death for women. Environmental radiation exposure and endogenous factors such as hormones increase breast cancer risk, and its development and spread depend on cell motility and migration. The expression of genes associated with cell motility, such as ADAM12, CYR61, FLRT2, SLIT2, VNN1, MYLK, MAP1B, and TUBA1A, was analyzed in an experimental breast cancer model induced by radiation and estrogen. The results showed that TUBA1A, SLIT2, MAP1B, MYLK, and ADAM12 gene expression increased in the irradiated Alpha3 cell line but not in the control or the malignant Tumor2 cell line. Bioinformatic analysis indicated that FLERT2, SLIT2, VNN1, MAP1B, MYLK, and TUBA1A gene expressions were found to be higher in normal tissue than in tumor tissue of breast cancer patients. However, ADAM12 and CYR61 expressions were found to be higher in tumors than in normal tissues, and they had a negative correlation with ESR1 gene expression. Concerning ESR2 gene expression, there was a negative correlation with CYR61, but there was a positive correlation with FLRT2, MYLK, MAP1B, and VNN1. Finally, a decreased survival rate was observed in patients exhibiting high expression levels of TUBA1A and MAP1B. These genes also showed a negative ER status, an important parameter for endocrine therapy. The genes related to motility were affected by ionizing radiation, confirming its role in the initiation process of breast carcinogenesis. In conclusion, the relationship between the patient's expression of hormone receptors and genes associated with cell motility presents a novel prospect for exploring therapeutic strategies. [ABSTRACT FROM AUTHOR]

Objective: Hepatocellular carcinoma (HCC) is a highly lethal cancer with significant mortality, primarily attributed to metastasis. Although Protocadherin Gamma Subfamily A, 9 (PCDHGA9) has been identified as a tumor suppressor gene in cancer metastasis, its role in HCC remains ambiguous. This study clarifies the role of PCDHGA9 in HCC by examining its expression, clinical significance, and molecular activities. Methods: Tissue microarray immunofluorescence analysis evaluated the expression of PCDHGA9 and its clinical relevance. In vitro experiments involved manipulating PCDHGA9 levels in SK-HEP-1 cells to assess migration through wound-healing and transwell assays. In vivo, shPCDHGA9 cell injections were utilized to observe effects on tumor growth and metastasis. Protein analysis and Western Blot validated epithelial-mesenchymal transition (EMT)-related proteins. Subsequent to TGF-β treatment, cell proliferation and apoptosis were quantified using cell counting kit-8 and flow cytometry, respectively, followed by investigation of TGF-β effects on PCDHGA9 N6-methyladenosine (m6A) modification via Methylated RNA immunoprecipitation, RT-qPCR, and Western blot analysis. Results: Downregulation of PCDHGA9 expression in HCC tissues is correlated with poor prognosis. In vitro experiments demonstrated that modulating PCDHGA9 expression influenced HCC cell migration. In vivo, PCDHGA9 knockdown is correlated with increased metastasis. Furthermore, TGF-β stimulation promoted cell proliferation and inhibited apoptosis. Mechanistically, TGF-β-mediated m6A modification led to PCDHGA9 decay, promoting EMT in HCC cells. Conclusion: PCDHGA9 serves as a potential tumor suppressor in HCC by inhibiting EMT. During this process, TGF-β is observed to exert regulatory control over m6A modifications of PCDHGA9. [ABSTRACT FROM AUTHOR]

Several soluble factors secreted by the stromal cells and cancer cells within the tumor microenvironment facilitate the progression and invasiveness of ovarian cancer. In ovarian cancer cells, lysophosphatidic acid (LPA) modulates the transcriptome profile and promotes cell invasiveness by the downregulation of autophagy. Here, we further elucidate this mechanism by focusing on the molecular and cellular events regulating autophagy. Transcriptomic and Western blotting analyses revealed NKX3-2, a transcriptional factor, to be among the genes hyperexpressed in LPA-stimulated ovarian cancer cells. Bioinformatic analyses revealed that in ovarian cancer patients, the expression of NKX3-2 positively correlates with genes involved in cell motility and migration, while it negatively correlates with macromolecular catabolic pathways. In various ovarian cancer cell lines, NKX3-2 silencing abrogated LPA-induced cell migration. Mechanistically, this effect is linked to the restoration of the HDAC6-mediated relocation of the lysosomes in the para-golgian area, and this results in an increase in autolysosome formation and the overall upregulation of autophagy. Silencing the expression of ATG7 or BECN1, two autophagy genes, rescued the migratory phenotype of the NKX3-2-silenced ovarian cancer cells. Taken together, these data reveal the mechanism by which the LPA-NKX3-2 axis promotes the invasiveness of ovarian cancer cells and supports the possibility of targeting NKX3-2 to reduce the migratory capacity of cancer cells in response to a permissive microenvironment. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the critical yet understudied role of miRNAs in areca nut-induced carcinogenesis in head and neck cancer (HNC). Through comprehensive profiling, we identified 84 miRNAs, comprising 39 oncogenic miRNAs (OncomiRs) and 45 tumor-suppressive miRNAs (TsmiRs) associated with areca nut-induced HNC. Further analysis of the oncogenic mechanisms revealed that 740 genes are cross-regulated by a cluster of eight hub TsmiRs. These areca nut-modulated miRNAs significantly impact key cancer-related pathways, including p53, PI3K-AKT, MAPK, and Ras signaling, and regulate critical oncogenic processes related to cell motility and survival. Moreover, miR-499a-5p was validated as a vital regulator, which mitigated areca nut-induced cancer progression, including cell migration, invasion, and chemoresistance. Our findings highlight the potential of this miRNA panel for clinical applications in risk assessment, diagnosis, and prognosis of areca nut-associated malignancies, opening new avenues for future research and clinical practice. Background: While miRNAs are increasingly recognized for their role in tumorigenesis, their involvement in head and neck cancer (HNC) remains insufficiently explored. Additionally, the carcinogenic mechanisms of areca nut, a major habitual carcinogen in Southeast Asia, are not well understood. Methods and results: This study adopts a systematic approach to identify miRNA profiles associated with areca nut-induced HNC. Using miRNA microarray analysis, we identified 292 miRNAs dysregulated in areca nut-treated HNC cells, with 136 upregulated and 156 downregulated. Bioinformatic analysis of the TCGA-HNSC dataset uncovered a set of 692 miRNAs relevant to HNC development, comprising 449 overexpressed and 243 underexpressed in tumor tissues. Integrating these datasets, we defined a signature of 84 miRNAs, including 39 oncogenic miRNAs (OncomiRs) and 45 tumor-suppressive miRNAs (TsmiRs), highlighting their pivotal role in areca nut-induced carcinogenesis. MultiMiR analysis identified 740 genes cross-regulated by eight hub TsmiRs, significantly impacting key cancer-related pathways (p53, PI3K-AKT, MAPK, and Ras) and critical oncogenic processes. Moreover, we validated miR-499a-5p as a vital regulator, demonstrating its ability to mitigate areca nut-induced cancer progression by reducing cell migration, invasion, and chemoresistance. Conclusions: Thus, this miRNA signature addresses a crucial gap in understanding the molecular underpinnings of areca nut-induced carcinogenesis and offers a promising platform for clinical applications in risk assessment, diagnosis, and prognosis of areca nut-associated malignancies. [ABSTRACT FROM AUTHOR]

Simple Summary: Glioblastoma (GBM) is the deadliest form of primary brain cancer, and the survival of patients is only about 15 months after diagnosis, even with aggressive treatment. Many cellular factors that are used by GBM cells to divide abnormally and invade brain tissue to result in patient death are unknown. Here, we investigated the potential role of the cellular enzyme QSOX1, which creates specific bonds within proteins, in GBM cell proliferation, migration in a dish, and invasion into brain tissue in our chick embryo brain tumor model system. By experimentally reducing QSOX1 protein production in GBM cells, we found that this reduction resulted in less proliferation, slower migration, and less invasion into brain tissue. These results show the importance of the QSOX1 enzyme in GBM cells in order for them to exhibit their abnormal aggressive behavior that drives this incurable cancer. Background: Quiescin Sulfhydryl Oxidase 1 (QSOX1) is an enzyme that catalyzes the oxidation of free thiols to generate disulfide bonds in a variety of proteins, including the cell surface and extracellular matrix. QSOX1 has been reported to be upregulated in a number of cancers, and the overexpression of QSOX1 has been correlated with aggressive cancers and poor patient prognosis. Glioblastoma (GBM) brain cancer has been practically impossible to treat effectively, with cells that rapidly invade normal brain tissue and escape surgery and other treatment. Thus, there is a crucial need to understand the multiple mechanisms that facilitate GBM cell invasion and to determine if QSOX1 is involved. Methods and Results: Here, we investigated the function of QSOX1 in human glioblastoma cells using two cell lines derived from T98G cells, whose proliferation, motility, and invasiveness has been shown by us to be dependent on disulfide bond-containing adhesion and receptor proteins, such as L1CAM and the FGFR. We lentivirally introduced shRNA to attenuate the QSOX1 protein expression in one cell line, and a Western blot analysis confirmed the decreased QSOX1 expression. A DNA content/cell cycle analysis using flow cytometry revealed 27% fewer knockdown cells in the S-phase of the cell cycle, indicating a reduced proliferation. A cell motility analysis utilizing our highly quantitative SuperScratch time-lapse microscopy assay revealed that knockdown cells migrated more slowly, with a 45% decrease in migration velocity. Motility was partly rescued by the co-culture of knockdown cells with control cells, indicating a paracrine effect. Surprisingly, knockdown cells exhibited increased motility when assayed using a Transwell migration assay. Our novel chick embryo orthotopic xenograft model was used to assess the in vivo invasiveness of knockdown vs. control cells, and tumors developed from both cell types. However, fewer invasive knockdown cells were observed after about a week. Conclusions: Our results indicate that an experimental reduction in QSOX1 expression in GBM cells leads to decreased cell proliferation, altered in vitro migration, and decreased in vivo invasion. [ABSTRACT FROM AUTHOR]

Cell migration is a fundamental and functional cellular process, influenced by a complex microenvironment consisting of different cells and extracellular matrix. Recent research has highlighted that, besides biochemical cues from the microenvironment, physical cues can also greatly alter cellular behavior. However, due to the complexity of the microenvironment, little is known about how the physical interactions between migrating cells and surrounding microenvironment instructs cell movement. Here, we explore various examples of three-dimensional microenvironment reconstruction models in vitro and describe how the physical interplay between migrating cells and the neighboring microenvironment controls cell behavior. Understanding this mechanical cooperation will provide key insights into organ development, regeneration, and tumor metastasis. [ABSTRACT FROM AUTHOR]

Background: Long noncoding RNAs (lncRNAs) are reported that play an important role in regulating tumorigenesis. This study aims to develop a ferroptosis‐related lncRNA gene signature for predicting biochemical recurrence of prostate cancer (PCa) and prove a functional lncRNA BCRP3 as a promotor toward PCa progression. Methods: The ferroptosis‐related lncRNA were identified by interoperating the databases of The Cancer Genome Atlas (TCGA) and FerrDb. A predictive model for biochemical recurrence of PCa was established based on the LASSO Cox regression. Kaplan–Meier cures were applied in the measurement of the impact on patients' survival caused by key lncRNAs. Meanwhile, the molecular assays of CCK8, EdU, wound healing, and Transwell were conducted to evaluate the tumor‐suppressive effect of BCRP3 in vitro. Results: This study presented that 17 differentially expressed ferroptosis‐related lncRNAs were confirmed and further screened out 9 key lncRNAs for the establishment of risk model. The nomogram involved the risk model was also proved with an excellent predictive performance toward 1‐, 3‐, and 5‐year survival with the area of curves (AUC) as 0.77, 0.79, and 0.65 separately. Notably, the lncRNA BCRP3 was significantly correlated with the survival of PCa patients based on multivariate Cox regression. Additionally, downregulation of BCRP3 effectively inhibited the proliferation, migration, and invasion of PC3 cells which further proved its anti‐tumor function. Conclusion: We developed a ferroptosis‐related lncRNA risk model for predicting biochemical recurrence, which assisting in the clinical therapy of patients with PCa. [ABSTRACT FROM AUTHOR]

Background: Fidgetin-like 1 (FIGNL1) is extensively overexpressed in a variety of cancers. It facilitates non-small cell lung cancer tumor cell proliferation and hepatocellular carcinoma formation due to abnormal DNA repair. Clinically relevant data indicates that its high expression is linked with the poor prognosis of patients with renal clear-cell carcinoma, low-grade gliomas, and hepatocellular carcinoma. Nevertheless, the scope of FIGNL1's involvement in cancer, particularly colorectal cancer (CRC), remains unclear. Aims: To investigate the function of FIGNL1 in CRC. Study Design: Cell culture study Methods: The TCGA database and immunohistochemistry analysis were employed to investigate FIGNL1 expression in CRC tissue. A cell viability assay was performed using the Cell Counting Kit-8. The cell migration and invasion were evaluated using the transwell assay. Small interfering RNA (siRNA) transfection was conducted to knockdown FIGNL1 expression. Infection with FIGNL1 overexpression lentivirus was performed to promote FIGNL1 overexpression. The STRING database was employed for predicting protein interaction. Results: FIGNL1 was substantially upregulated in human CRC tissues and was associated with TNM stages and lymph node metastasis in patients. The inhibition of CRC cell proliferation, migration, and invasion in Caco-2 cells was achieved by silencing FIGNL1 using siRNA. Additional investigations suggested that FIGNL1 overexpression could promote CRC cell proliferation, migration, and invasion via P38 signaling pathway activation in Colo-205 cells. Subsequent experiments demonstrated that FIGNL1-mediated P38 phosphorylation was contingent upon SPIDR interaction. Conclusion: These results implied that FIGNL1 was a potential anticancer drug target, which also offered a novel strategy for future CRC treatment. [ABSTRACT FROM AUTHOR]

Background: Endometriosis (EM) is an inflammatory condition in which the endometrium is observed to develop outside the uterine cavity. Endometrium has conventionally been recognized as a rich source of endometrial mesenchymal stem cells (E-MSCs). The influence of dienogest, a medication frequently prescribed for EM, on E-MSCs has not been extensively investigated. Aims: To explore effects of dienogest on the E-MSCs derived from healthy (E-MSCs-control) and diseased (E-MSCs-endometriosis) endometrial tissue samples in vitro. Study Design: In vitro study. Methods: We collected samples from healthy and diseased endometrial tissues. E-MSCs were derived from both healthy and EM tissues. The effect of dienogest (VISANNE) on E-MSCs was assessed by examining cell proliferation, telomerase activity, cell migration, and estrogen secretion levels after the isolation and characterization of E-MSCs. Results: We discovered that cellular proliferation rate was higher in the E-MSCs derived from EM tissues compared to those derived from healthy tissue. The proliferation rate and telomerase activity were both suppressed by dienogest treatment, particularly in E-MSCs-endometriosis. The drug treatment also resulted in a decrease in the migration capacity of E-MSCs-endometriosis, from 60.4% to 59.2%. The expression of CXCL12, Ki67, and beta-catenin was analyzed in both E-MSCs-endometriosis and E-MSCs-control. The CXCL12 and Ki67 expressions were quite elevated in the E-MSCs-endometriosis without drug treatment compared to the E-MSCs-control. Following the treatment, these levels declined drastically to the levels close to E-MSCs-control. Similarly, this decrease in gene expression was accompanied by a decrease in estrogen secretion into the medium. Conclusion: This research demonstrates that dienogest exerts a substantial impact on both stromal and stem cells, as it effectively controls the disease by reversing EM markers, despite the absence of progesterone receptors on endometrial stem cells. [ABSTRACT FROM AUTHOR]

Objective: Pigmented villonodular synovitis (PVNS) is a rare benign proliferative disease affecting the soft‐tissue lining the synovial joints and tendons. Its etiology is poorly understood, largely limiting the availability of current therapeutic options. Here, we mapped the synovial gene and protein profiles of patients with PVNS, revealed a link between synovial inflammation and invasion, and elucidated the potential molecular mechanism involved. Methods: The expression of synovial genes from 6 control individuals, 7 patients with osteoarthritis (OA), and 19 patients with PVNS was analyzed via RNA sequencing. Protein profiles from 5 control individuals, 10 patients with OA, and 32 patients with PVNS were analyzed using label‐free proteomics. Microarray and reverse transcription–polymerase chain reaction analyses and immunohistochemical staining were used to evaluate inflammatory cytokine and target gene expression levels in synovial tissue, epithelial cells, and synovial fibroblasts (FLSs) derived from tissue of patients with PVNS. Various signaling pathway inhibitors, small interfering RNAs, and Western blots were used for molecular mechanism studies. Transwell migration and invasion assays were subsequently performed. Results: In total, 522 differentially expressed proteins were identified in the tissues of patients with PVNS. By integrating RNA sequencing and microarray analyses, significant changes in the expression of epithelial–mesenchymal transition (EMT)‐related genes, including transforming growth factor TGF‐b induced, neural cadherin, epithelial cadherin, SNAIL, and TWIST, were confirmed in the tissue of patients with PVNS compared to the control tissue. In vitro, TGFβ induced EMT and increased epithelial cell migration and invasion. Moreover, TGFβ not only promoted interactions between epithelial cells and FLSs but also directly increased the migration and invasion abilities of FLSs by activating the classical Smad2/3 and nonclassical JNK/AKT signaling pathways. Conclusion: This study provides overall protein and gene profiles of PVNS and identifies the crucial role of TGFβ in synovial invasion pathology. Exploring the related molecular mechanism may also reveal a new strategy or target for PVNS therapy. [ABSTRACT FROM AUTHOR]

Purpose: To uncover the possible effects of zerumbone on the viability, motility, and angiogenesis of human retinal microvascular endothelial cells and to clarify the mechanism. Methods: 5-Ethynyl-2′-deoxyuridine assays were conducted to confirm the effects of zerumbone on the viability of human retinal microvascular endothelial cells. Wound healing, tube formation, and immunoblot assays were conducted to confirm the role of zerumbone in human retinal microvascular endothelial cell motility and angiogenesis, and regulation on vascular endothelial growth factor expression. ELISA was performed to confirm its effects on vascular endothelial growth factor secretion. Colivelin was used to activate the STAT3. Results: We revealed that zerumbone suppressed the viability of human retinal microvascular endothelial cells. Zerumbone restrained the motility and angiogenesis of human retinal microvascular endothelial cells via targeting STAT3 and regulating the expression and secretion of vascular endothelial growth factor in vitro. Zerumbone treatment suppressed the angiogenesis, whereas Colivelin treatment reversed the suppression of angiogenesis caused by zerumbone. Conclusion: Zerumbone restrained the viability, motility and angiogenesis of human retinal microvascular endothelial cells by inhibiting vascular endothelial growth factor expression. [ABSTRACT FROM AUTHOR]

Objective: To observe the therapeutic effects and underlying mechanism of baicalin against colon cancer. Methods: The effects of baicalin on the proliferation and growth of colon cancer cells MC38 and CT26. WT were observed and predicted potential molecular targets of baicalin for colon cancer therapy were studied by network pharmacology. Furthermore, molecular docking and drug affinity responsive target stability (DARTS) analysis were performed to confirm the interaction between potential targets and baicalin. Finally, the mechanisms predicted by in silico analyses were experimentally verified in-vitro and in-vivo. Results: Baicalin significantly inhibited proliferation, invasion, migration, and induced apoptosis in MC38 and CT26 cells (all P<0.01). Additionally, baicalin caused cell cycle arrest at the S phase, while the G0/G1 phase was detected in the tiny portion of the cells. Subsequent network pharmacology analysis identified 6 therapeutic targets associated with baicalin, which potentially affect various pathways including 39 biological processes and 99 signaling pathways. In addition, molecular docking and DARTS predicted the potential binding of baicalin with cyclin dependent kinase inhibitor 2A (CDKN2A), protein kinase B (AKT), caspase 3, and mitogen-activated protein kinase (MAPK). In vitro, the expressions of CDKN2A, MAPK, and p-AKT were suppressed by baicalin in MC38 and CT26 cells. In vivo, baicalin significantly reduced the tumor size and weight (all P<0.01) in the colon cancer mouse model via inactivating p-AKT, CDKN2A, cyclin dependent kinase 4, cyclin dependent kinase 2, interleukin-1, tumor necrosis factor α, and activating caspase 3 and mouse double minute 2 homolog signaling (all P<0.05). Conclusion: Baicalin suppressed the CDKN2A protein level to prevent colon cancer and could be used as a therapeutic target for colon cancer. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) have been confirmed to be an important modulator and therapeutic target of cervical cancer (CC). The aim of this study is to explore the role and mechanism of circ_0081723 in CC progression. Circ_0081723, microRNA-545-3p (miR-545-3p), and CREB3 regulatory factor (CREBRF) levels were detected using quantitative real-time PCR (qRT-PCR) assay. CREBRF, ki-67, Bcl-2 related X protein (Bax), and E-cadherin expression levels were determined using western blot (WB) and immunohistochemistry (IHC) assays. Cell proliferation was assessed using Cell Counting Kit-8 (CCK-8), cell colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) assays. Flow cytometry was used to measure cell apoptosis. Cell migration and invasion were examined using Transwell assay. Interaction between miR-545-3p and circ_0081723 or CREBRF was verified using dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assays. The biological role of circ_0081723 on CC growth was examined using the xenograft tumor model in vivo. Circ_0081723 and CREBRF were increased, and miR-545-3p was decreased in CC tissues and cells. Circ_0081723 silencing suppressed CC cell growth and motility whereas boosted CC cell apoptosis. Besides, circ_0081723 acted as a molecular sponge for miR-545-3p, and circ_0081723 knockdown-induced effects were largely reversed by miR-545-3p downregulation in CC cells. Moreover, miR-545-3p repressed CC progression by targeting CREBRF. Circ_0081723 absence blocked xenograft tumor growth in vivo. Circ_0081723 stimulated CC cell malignant behaviors by regulating the miR-545-3p/CREBRF pathway, providing a possible circRNA-targeted therapy for CC. [ABSTRACT FROM AUTHOR]

While the structural organization and molecular biology of neurons are well characterized, the physical process of axonal elongation remains elusive. The classic view posited elongation occurs through the deposition of cytoskeletal elements in the growth cone at the tip of a stationary array of microtubules. Yet, recent studies reveal axonal microtubules and docked organelles flow forward in bulk in the elongating axons of Aplysia, chick sensory, rat hippocampal, and Drosophila neurons. Noting that the morphology, molecular components, and subcellular flow patterns of growth cones strongly resemble the leading edge of migrating cells and the polar regions of dividing cells, our working hypothesis is that axonal elongation utilizes the same physical mechanisms that drive cell crawling and cell division. As a test of that hypothesis, here we take experimental data sets of sub-cellular flow patterns in cells undergoing cytokinesis, mesenchymal migration, amoeboid migration, neuronal migration, and axonal elongation. We then apply active fluid theory to develop a biophysical model that describes the different sub-cellular flow profiles across these forms of motility and how this generates cell motility under low Reynolds numbers. The modeling suggests that mechanisms for generating motion are shared across these processes, and differences arise through modifications of sub-cellular adhesion patterns and the profiles of internal force generation. Collectively, this work suggests that ameboid and mesenchymal cell crawling may have arisen from processes that first developed to support cell division, that growth cone motility and cell crawling are closely related, and that neuronal migration and axonal elongation are fundamentally similar, differing primarily in the motion and strength of adhesion under the cell body. [ABSTRACT FROM AUTHOR]

Background: Triple‐negative breast cancer, a subtype of breast cancer, is characterized by a poor prognosis. Recent studies have shown that miRNA30b acts as an oncogene and is vital for the proliferation of malignancies across various systems. This study aimed to elucidate the impact of miRNA30b on the proliferation, migration, and invasion capabilities of breast cancer cells in vitro. Methods: Triple‐negative breast cancer cell lines MDA‐MB‐231 were transiently transfected with miRNA30b inhibitor, mimic, or the negative control by Lipofectamine 2000. Successful transfection was confirmed by quantitative real‐time polymerase chain reaction (qRT‐PCR). Functional assays, including CCK8, clone formation, scratch, and transwell assays, were conducted to evaluate the proliferation, invasion, and migration ability of MDA‐MB‐231 cells in each group. The target protein of miRNA30b was determined using an online prediction data website, and the dual‐luciferase assay confirmed whether there was a binding site between miRNA30b and ADAM12. The effect was further verified by Western blot analysis. Results: MDA‐MB‐231 cells were transfected with miRNA30b inhibitor, mimic, and negative control. miRNA30b expression was downregulated in the cells. Relative to the negative control group, miRNA30b expression significantly increased in the mimic group and decreased in the miRNA30b inhibitor group, with the differences being statistically significant. The miRNA30b mimic group exhibited a significant increase in miRNA30b expression and a corresponding promotion of cell proliferation, colony formation, and migration. Conversely, the miRNA30b inhibitor group displayed significantly reduced miRNA30b expression and suppressed cell proliferation, colony formation, and migration abilities compared to the negative control cells. Bioinformatics software predicted ADAM12 as a potential target of miRNA30b. Dual‐luciferase assays confirmed the presence of a binding site between miRNA30b and ADAM12. Western blot analysis revealed that overexpression of miRNA30b downregulated ADAM12 expression in MDA‐MB‐231 cells. Conclusions: miRNA30b could promote proliferation, migration, and invasion of TNBC cell lines MDA‐MB‐231. The effect of miRNA30b on triple‐negative breast cancer would be achieved partly at least through inhibiting the expression of ADAM12. [ABSTRACT FROM AUTHOR]

Objectives: Circadian rhythm disruption (CRD) is implicated with numerous gastrointestinal motility diseases, with the enteric nervous system (ENS) taking main responsibility for the coordination of gastrointestinal motility. The purpose of this study is to explore the role of circadian rhythms in ENS remodeling and to further elucidate the underlying mechanisms. Methods: First, we established a jet-lagged mice model by advancing the light/dark phase shift by six hours every three days for eight weeks. Subsequent changes in gastrointestinal motility and the ENS were then assessed. Additionally, a triple-transgenic mouse strain (Nestin-creERT2 × Ngfr-DreERT2: DTRGFP) was utilized to track the effects of CRD on the differentiation of enteric neural precursor cells (ENPCs). RNA sequencing was also performed to elucidate the underlying mechanism. Results: Compared to the control group, CRD significantly accelerated gastrointestinal motility, evidenced by faster intestinal peristalsis (P < 0.01), increased fecal output (P < 0.01), and elevated fecal water content (P < 0.05), as well as enhanced electrical field stimulation induced contractions (P < 0.05). These effects were associated with an increase in the number of glial cells and nitrergic neurons in the colonic myenteric plexus. Additionally, ENPCs in the colon showed a heightened differentiation into glial cells and nitrergic neurons. Notably, the NR1D1/nuclear factor-kappaB (NF-κB) axis played a crucial role in the CRD-mediated changes in ENPCs differentiation. Supplementation with NR1D1 agonist or NF-κB antagonist was able to restore gastrointestinal motility and normalize the ENS in jet-lagged mice. Conclusions: CRD regulates the differentiation of ENPCs through the NR1D1/NF-κB axis, resulting in dysfunction of the ENS and impaired gastrointestinal motility in mice. [ABSTRACT FROM AUTHOR]

In certain forms of collective cell migration, changes in neighboring cells (neighbor exchange, NE) are essential. In the axial mesoderm in zebrafish, for example, the notochord is established through cell movements known as convergence and extension (C&E), which involves NE. For NE to occur efficiently, the balance between cell-scale and supracellular stresses plays a crucial role, but the molecular basis of how these stresses are controlled remains unclear. In this study, we focused on Pcdh8/Paraxial protocadherin (PAPC), which is specifically suppressed in the region (notochord) where and at the time (early gastrula) when extensive C&E occurs. Forced expression of PAPCΔC (PAPC lacking its intracellular domain) persisted in the developing notochord and resulted in morphogenetic defects in zebrafish. PAPCΔC was found to downregulate NE in the notochord in a homophilic contact-dependent manner. By examining oil droplets inserted between cells, we revealed that while cell-scale stresses were apparently unaffected, the direction of bias in the supracellular stresses was stabilized by the introduction of PAPCΔC in the notochordal region. Taken together, our results suggest that suppression of PAPC in the notochord is required to modify supracellular stresses and provide the conditions in which NE occurs efficiently, thus promoting morphogenetic cell movements. [ABSTRACT FROM AUTHOR]

Cell motility increases the fitness of bacterial cells. Previous research focused on the transcriptional regulator CdsR, which represses cellular autolysis and promotes spore formation in Bacillus thuringiensis. However, the targets of CdsR are mostly unknown. Here, we reported a new function of CdsR in regulating cell motility. Mutation of cdsR results in increase of cell mobility, and a number of related genes were upregulated compared to wild type HD73. Thus, we investigated the transcription of the fla/che gene cluster, which involves in cell mobility and comprises eight operons/genes, including motAB1, cheY-yrhK, lamB-cheR, yaaR-fliG2, cheV-mogR, hag1, hag2, and yjbJ-flgG. Additionally, the motAB2 operon was discovered, which consists of homologs genes motA2 and motB2 that are like motA1 and motB1. Through promoter-lacZ fusion assays and EMSA experiments, it was discovered that CdsR directly regulates the motAB1, cheY-yrhK, lamB-cheR, yaaR-fliG2, cheV-mogR, hag1, hag2, yjbJ-flgG, and motAB2 operons by binding to their promoter regions. Importantly, it was confirmed that CdsR is a metalloregulator and the binding to promoter can be inhibited by Cu (II) ions. This research enhances our understanding of the regulation of cell mobility in B. thuringiensis. [ABSTRACT FROM AUTHOR]

Talin regulates crucial cellular functions, including cell adhesion and motility, and affects human diseases. Triggered by mechanical forces, talin plays crucial roles in facilitating the formation of focal adhesions and recruiting essential focal adhesion regulatory elements such as vinculin. The structural flexibility allows talin to fine-tune its signaling responses. This study presents our 2.7 Å cryoEM structures of talin, which surprisingly uncovers several auto-inhibitory states. Contrary to previous suggestions, our structures reveal that (1) the first and last three domains are not involved in maintaining talin in its closed state and are mobile, (2) the talin F-actin and membrane binding domain are loosely attached and thus available for binding, and (3) the main force-sensing domain is oriented with its vinculin binding sites ready for release. These structural snapshots offer insights and advancements in understanding the dynamic talin activation mechanism, which is crucial for mediating cell adhesion. Talin controls cell adhesion and motility, impacting disease. 2.7 Å cryoEM structures reveal mobile membrane and F-actin binding domains, and force-sensing readiness, providing insights into the dynamic activation of talin in mediating cell adhesion. [ABSTRACT FROM AUTHOR]

Background: Early embryogenesis is characterized by dramatic cell proliferation and movement. In most insects, early embryogenesis includes a phase called the uniform blastoderm, during which cells evenly cover the entirety of the egg. However, the embryo of the German cockroach, Blattella germanica, like those of many insects within the super order Polyneoptera, does not have a uniform blastoderm; instead, its first cells condense rapidly at the site of a future germband. We investigated early development in this species in order to understand how early gene expression is or is not conserved in these insect embryos with distinct early cell behaviors. Results: We present a detailed time series of nuclear division and distribution from fertilization through germband formation and report patterns of expression for the early patterning genes hunchback, caudal, and twist in order to understand early polarization and mesoderm formation. We show a detailed time course of the spatial expression of two genes involved in the segmentation cascade, hedgehog and even-skipped, and demonstrate two distinct dynamics of the segmentation process. Conclusions: Despite dramatic differences in cell distribution between the blastoderms of many Polyneopteran insects and those of more well-studied developmental models, expression patterns of early patterning genes are mostly similar. Genes associated with axis determination in other insects are activated relatively late and are probably not maternally deposited. The two phases of segmentation—simultaneous and sequential—might indicate a broadly conserved mode of morphological differentiation. The developmental time course we present here should be of value for further investigation into the causes of this distinct blastoderm type. [ABSTRACT FROM AUTHOR]

Background: Uveal melanoma (UM) is the most common primary intraocular tumour in adults, and approximately 50% of patients will develop metastasis. Epigenetic changes are a major factor in cancer progression. We aimed to determine whether methylation profiles could be altered using a DNA methyltransferase (DNMT) inhibitor in UM cell lines. Methods: Four primary and metastatic UM cell lines were treated with azacytidine and analysed for cell proliferation, colony formation, and BAP1 protein expression. Genomic and cell-free (cf)DNA methylation were compared. Results: In all cell lines, azacytidine treatment resulted in dose-dependent effects on proliferation, colony formation, and radiosensitivity. Methylation profiling revealed differences in methylation between cell lines according to BAP1 expression. Matched primary and metastatic cell lines showed very similar patterns. Alterations were seen in pathways known to be important in UM progression, such as PI3K/Akt and MAPK signaling, and in pathways involved in cancer progression, such as regulation of stemlike potential, cell motility, and invasion. These changes were maintained in genomic and cell-free DNA. Conclusions: This data suggests that DNMT inhibitors cause changes in UM cells that are maintained in cfDNA. The results suggest that targeting methylation in UM treatment and monitoring response to treatment using cfDNA methylation could be a valuable tool. [ABSTRACT FROM AUTHOR]

Repair of the damaged meniscus is a scientific challenge owing to the poor self-healing potential of the white area of the meniscus. Tissue engineering provides a new method for the repair of meniscus injuries. In this study, we explored the superiority of 2% hyaluronic acid chitin hydrogel in temperature sensitivity, in vitro degradation, biocompatibility, cell adhesion, and other biological characteristics, and investigated the advantages of hyaluronic acid (HA) and Transforming Growth Factor β1 (TGF-β1) in promoting cell proliferation and a matrix formation phenotype. The hydrogel loaded with HA and TGF-β1 promoted cell proliferation. The HA + TGF-β1 mixed group showed the highest glycosaminoglycan (GAG) content and promoted cell migration. Hydroxypropyl chitin (HPCH), HA, and TGF-β1 were combined to form a composite hydrogel with a concentration of 2% after physical cross-linking, and this was injected into a rabbit model of a meniscus full-thickness tear. After 12 weeks of implantation, the TGF-β1 + HA/HPCH composite hydrogel was significantly better than HPCH, HA/HPCH, TGF-β1 + HPCH, and the control group in promoting meniscus repair. In addition, the new meniscus tissue of the TGF-β1 + HA/HPCH composite hydrogel had a tissue structure and biochemical content similar to that of the normal meniscus tissue. [ABSTRACT FROM AUTHOR]

Dynamic changes in intracellular ultrastructure can be critical for the ability of organisms to acclimate to environmental conditions. Microalgae, which are responsible for ~50% of global photosynthesis, compartmentalize their Ribulose 1,5 Bisphosphate Carboxylase/Oxygenase (Rubisco) into a specialized structure known as the pyrenoid when the cells experience limiting CO2 conditions; this compartmentalization is a component of the CO2 Concentrating Mechanism (CCM), which facilitates photosynthetic CO2 fixation as environmental levels of inorganic carbon (Ci) decline. Changes in the spatial distribution of mitochondria in green algae have also been observed under CO2 limitation, although a role for this reorganization in CCM function remains unclear. We used the green microalga Chlamydomonas reinhardtii to monitor changes in mitochondrial position and ultrastructure as cells transition between high CO2 and Low/Very Low CO2 (LC/VLC). Upon transferring cells to VLC, the mitochondria move from a central to a peripheral cell location and orient in parallel tubular arrays that extend along the cell’s apico-basal axis. We show that these ultrastructural changes correlate with CCM induction and are regulated by the CCM master regulator CIA5. The apico-basal orientation of the mitochondrial membranes, but not the movement of the mitochondrion to the cell periphery, is dependent on microtubules and the MIRO1 protein, with the latter involved in membrane–microtubule interactions. Furthermore, blocking mitochondrial respiration in VLC-acclimated cells reduces the affinity of the cells for Ci. Overall, our results suggest that mitochondrial repositioning functions in integrating cellular architecture and energetics with CCM activities and invite further exploration of how intracellular architecture can impact fitness under dynamic environmental conditions. [ABSTRACT FROM AUTHOR]

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors, with high incidence and poor prognosis. Revealing mechanisms of ESCC progression and developing new therapeutic targets remains crucial. The aim of this study was to elucidate the molecular mechanism of miR‐30c‐5p in regulating the malignant progression of ESCC. Methods: TCGA, GEO, and other datasets were used to analyze the differential expression of miR‐30c‐5p in ESCC and adjacent tissues, and its impact on prognosis. Then the effects of miR‐30c‐5p on the proliferation, migration, and invasion of TE‐1 and Eca9706 cells were investigated through proliferation experiments, transwell and wounding healing assays. The regulatory mechanism of miR‐30c‐5p on the PI3K/AKT signaling pathway and its interaction in cancer progression were investigated through Western blots, dual‐luciferase reporter assay, and rescue experiments. Results: miR‐30c‐5p was significantly downregulated in ESCC tissue and represented a poor prognosis. miR‐30c‐5p mimic significantly inhibited the proliferation, migration, and invasion ability of ESCC, while miR‐30c‐5p inhibitor significantly promoted tumor cell progression. Through bioinformatic analysis and experimental results, miR‐30c‐5p interacted directly with PIK3CA mRNA and inhibited subsequent signaling pathway activation. PIK3CA activator could eliminate the inhibitory effects of miR‐30c‐5p mimic on the progression of ESCC, while PIK3CA inhibitors could rescue the promoting effect of miR‐30c‐5p inhibitor group cells. Conclusions: In summary, we found that miR‐30c‐5p inhibited the proliferation, invasion and migration of ESCC by inhibiting PI3K/AKT signaling pathway for the first time, and this study is expected to provide a novel insight and potential therapeutic target for managing ESCC. [ABSTRACT FROM AUTHOR]

In this paper, we investigate a chemotaxis system under homogeneous Neumann boundary conditions within a bounded domain with a smooth boundary. The system describes the movement of cells in response to two chemical signal substances: one acts as a chemoattractant, while the other serves as a chemorepellent, both produced by the cells. The system takes into account chemotactic sensitivity in the reaction movement when detecting these chemicals. Under certain assumptions, we demonstrate the existence of a unique global bounded classical solution for the proposed problem. To further understand the time evolution of the system's solutions, we conduct numerical experiments and analyze the dynamic properties of the L∞(Ω)$$ {L}&#x0005E;{\infty}\left(\Omega \right) $$ norm of the solutions with respect to variations in chemical production rates. [ABSTRACT FROM AUTHOR]

Keratin intermediate filaments confer structural stability to epithelial tissues, but the reason this simple mechanical function requires a protein family with 54 isoforms is not understood. During skin wound healing, a shift in keratin isoform expression alters the composition of keratin filaments. If and how this change modulates cellular functions that support epidermal remodeling remains unclear. We report an unexpected effect of keratin isoform variation on kinase signal transduction. Increased expression of wound-associated keratin 6A, but not of steady-state keratin 5, potentiated keratinocyte migration and wound closure without compromising mechanical stability by activating myosin motors to increase contractile force generation. These results substantially expand the functional repertoire of intermediate filaments from their canonical role as mechanical scaffolds to include roles as isoform-tuned signaling scaffolds that organize signal transduction cascades in space and time to influence epithelial cell state. [Display omitted] • During skin wound healing, the isoform composition of keratin filaments changes • Wound-associated keratin isoforms organize cellular signals to activate myosin • Keratin isoform-dependent signaling is separable from canonical mechanical function Nanes et al. explore why the seemingly simple mechanical function of keratin intermediate filaments requires a protein family with 54 isoforms. They find that skin wound healing triggers a change in keratin isoform expression not to alter force resistance but to organize signals activating myosin and promoting cell motility. [ABSTRACT FROM AUTHOR]

The cytoskeleton is essential for spatial and temporal organisation of a wide range of cellular and tissue‐level processes, such as proliferation, signalling, cargo transport, migration, morphogenesis, and neuronal development. Cytoskeleton research aims to study these processes by imaging, or by locally manipulating, the dynamics and organisation of cytoskeletal proteins with high spatiotemporal resolution: which matches the capabilities of optical methods. To date, no photoresponsive microtubule‐stabilising tool has united all the features needed for a practical high‐precision reagent: a low potency and biochemically stable non‐illuminated state; then an efficient, rapid, and clean photoresponse that generates a high potency illuminated state; plus good solubility at suitable working concentrations; and efficient synthetic access. We now present CouEpo, a photocaged epothilone microtubule‐stabilising reagent that combines these needs. Its potency increases approximately 100‐fold upon irradiation by violet/blue light to reach low‐nanomolar values, allowing efficient photocontrol of microtubule dynamics in live cells, and even the generation of cellular asymmetries in microtubule architecture and cell dynamics. CouEpo is thus a high‐performance tool compound that can support high‐precision research into many microtubule‐associated processes, from biophysics to transport, cell motility, and neuronal physiology. [ABSTRACT FROM AUTHOR]