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International Journal of Molecular... Aug 2023Cancer is one of the most difficult diseases for human beings to overcome. Its development is closely related to a variety of factors, and its specific mechanisms have... (Review)
Review
Cancer is one of the most difficult diseases for human beings to overcome. Its development is closely related to a variety of factors, and its specific mechanisms have been a hot research topic in the field of scientific research. The tropomyosin family (Tpm) is a group of proteins closely related to the cytoskeleton and actin, and recent studies have shown that they play an important role in various cancers, participating in a variety of biological activities, including cell proliferation, invasion, and migration, and have been used as biomarkers for various cancers. The purpose of this review is to explore the research progress of the Tpm family in tumorigenesis development, focusing on the molecular pathways associated with them and their relevant activities involved in tumors. PubMed and Web of Science databases were searched for relevant studies on the role of Tpms in tumorigenesis and development and the activities of Tpms involved in tumors. Data from the literature suggest that the Tpm family is involved in tumor cell proliferation and growth, tumor cell invasion and migration, tumor angiogenesis, tumor cell apoptosis, and immune infiltration of the tumor microenvironment, among other correlations. It can be used as a potential biomarker for early diagnosis, follow-up, and therapeutic response of some tumors. The Tpm family is involved in cancer in a close relationship with miRNAs and LncRNAs. Tpms are involved in tumor tissue invasion and migration as a key link. On this basis, is frequently used as a biomarker for various cancers. However, the specific molecular mechanism of its involvement in cancer progression has not been explained clearly, which remains an important direction for future research.
Topics: Humans; Tropomyosin; Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Actins; Tumor Microenvironment
PubMed: 37686101
DOI: 10.3390/ijms241713295 -
Anillin forms linear structures and facilitates furrow ingression after septin and formin depletion.Cell Reports Sep 2023During cytokinesis, a contractile ring consisting of unbranched filamentous actin (F-actin) and myosin II constricts at the cell equator. Unbranched F-actin is generated...
During cytokinesis, a contractile ring consisting of unbranched filamentous actin (F-actin) and myosin II constricts at the cell equator. Unbranched F-actin is generated by formin, and without formin no cleavage furrow forms. In Caenorhabditis elegans, depletion of septin restores furrow ingression in formin mutants. How the cleavage furrow ingresses without a detectable unbranched F-actin ring is unknown. We report that, in this setting, anillin (ANI-1) forms a meshwork of circumferentially aligned linear structures decorated by non-muscle myosin II (NMY-2). Analysis of ANI-1 deletion mutants reveals that its disordered N-terminal half is required for linear structure formation and sufficient for furrow ingression. NMY-2 promotes the circumferential alignment of the linear ANI-1 structures and interacts with various lipids, suggesting that NMY-2 links the ANI-1 network with the plasma membrane. Collectively, our data reveal a compensatory mechanism, mediated by ANI-1 linear structures and membrane-bound NMY-2, that promotes furrowing when unbranched F-actin polymerization is compromised.
Topics: Animals; Actins; Septins; Formins; Cytokinesis; Cell Membrane; Caenorhabditis elegans; Myosin Type II; Microfilament Proteins; Caenorhabditis elegans Proteins; Contractile Proteins
PubMed: 37665665
DOI: 10.1016/j.celrep.2023.113076 -
Archivum Immunologiae Et Therapiae... Aug 2023In recent years, the incidence of colorectal cancer (CRC) and breast cancer (BC) has increased worldwide and caused a higher mortality rate due to the lack of selective... (Review)
Review
In recent years, the incidence of colorectal cancer (CRC) and breast cancer (BC) has increased worldwide and caused a higher mortality rate due to the lack of selective anti-tumor therapies. Current chemotherapies and surgical interventions are significantly preferred modalities to treat CRC or BC in advanced stages but the prognosis for patients with advanced CRC and BC remains dismal. The immunotherapy technique of chimeric antigen receptor (CAR)-T cells has resulted in significant clinical outcomes when treating hematologic malignancies. The novel CAR-T therapy target antigens include GUCY2C, CLEC14A, CD26, TEM8/ANTXR1, PDPN, PTK7, PODXL, CD44, CD19, CD20, CD22, BCMA, GD2, Mesothelin, TAG-72, CEA, EGFR, B7H3, HER2, IL13Ra2, MUC1, EpCAM, PSMA, PSCA, NKG2D. The significant aim of this review is to explore the recently updated information pertinent to several novel targets of CAR-T for CRC, and BC. We vividly described the challenges of CAR-T therapies when treating CRC or BC. The immunosuppressive microenvironment of solid tumors, the shortage of tumor-specific antigens, and post-treatment side effects are the major hindrances to promoting the development of CAR-T cells. Several clinical trials related to CAR-T immunotherapy against CRC or BC have already been in progress. This review benefits academicians, clinicians, and clinical oncologists to explore more about the novel CAR-T targets and overcome the challenges during this therapy.
Topics: Humans; Female; Receptors, Chimeric Antigen; Breast Neoplasms; Immunotherapy, Adoptive; Colorectal Neoplasms; Cell- and Tissue-Based Therapy; Tumor Microenvironment; Cell Adhesion Molecules; Receptor Protein-Tyrosine Kinases; Microfilament Proteins; Receptors, Cell Surface; Receptors, Enterotoxin
PubMed: 37566162
DOI: 10.1007/s00005-023-00684-x -
British Journal of Cancer Dec 2023Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer, arising from resistance to androgen-deprivation therapies. However, the molecular...
BACKGROUND
Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer, arising from resistance to androgen-deprivation therapies. However, the molecular mechanisms associated with NEPC development and invasiveness are still poorly understood. Here we investigated the expression and functional significance of Fascin-1 (FSCN1), a pro-metastasis actin-bundling protein associated with poor prognosis of several cancers, in neuroendocrine differentiation of prostate cancer.
METHODS
Differential expression analyses using Genome Expression Omnibus (GEO) database, clinical samples and cell lines were performed. Androgen or antagonist's cellular treatments and knockdown experiments were used to detect changes in cell morphology, molecular markers, migration properties and in vivo tumour growth. Chromatin immunoprecipitation-sequencing (ChIP-Seq) data and ChIP assays were analysed to decipher androgen receptor (AR) binding.
RESULTS
We demonstrated that FSCN1 is upregulated during neuroendocrine differentiation of prostate cancer in vitro, leading to phenotypic changes and NEPC marker expression. In human prostate cancer samples, FSCN1 expression is restricted to NEPC tumours. We showed that the androgen-activated AR downregulates FSCN1 expression and works as a transcriptional repressor to directly suppress FSCN1 expression. AR antagonists alleviate this repression. In addition, FSCN1 silencing further impairs in vivo tumour growth.
CONCLUSION
Collectively, our findings identify FSCN1 as an AR-repressed gene. Particularly, it is involved in NEPC aggressiveness. Our results provide the rationale for the future clinical development of FSCN1 inhibitors in NEPC patients.
Topics: Humans; Male; Androgen Antagonists; Androgens; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Microfilament Proteins; Prostatic Neoplasms; Receptors, Androgen; Neuroendocrine Tumors
PubMed: 37875732
DOI: 10.1038/s41416-023-02449-x -
Nature Communications Oct 2023Cortactin coactivates Arp2/3 complex synergistically with WASP-family nucleation-promoting factors (NPFs) and stabilizes branched networks by linking Arp2/3 complex to...
Cortactin coactivates Arp2/3 complex synergistically with WASP-family nucleation-promoting factors (NPFs) and stabilizes branched networks by linking Arp2/3 complex to F-actin. It is poorly understood how cortactin performs these functions. We describe the 2.89 Å resolution cryo-EM structure of cortactin's N-terminal domain (Cort) bound to Arp2/3 complex. Cortactin binds Arp2/3 complex through an inverted Acidic domain (D20-V29), which targets the same site on Arp3 as the Acidic domain of NPFs but with opposite polarity. Sequences N- and C-terminal to cortactin's Acidic domain do not increase its affinity for Arp2/3 complex but contribute toward coactivation with NPFs. Coactivation further increases with NPF dimerization and for longer cortactin constructs with stronger binding to F-actin. The results suggest that cortactin contributes to Arp2/3 complex coactivation with NPFs in two ways, by helping recruit the complex to F-actin and by stabilizing the short-pitch (active) conformation, which are both byproducts of cortactin's core function in branch stabilization.
Topics: Actin-Related Protein 2-3 Complex; Cortactin; Actins; Wiskott-Aldrich Syndrome Protein; Actin-Related Protein 2; Actin-Related Protein 3
PubMed: 37898612
DOI: 10.1038/s41467-023-42229-y -
Cardiovascular Diabetology Oct 2023We investigated the association of high-sensitivity cardiac troponin (Hs-cTn) with all-cause and cardiovascular mortality in non-diabetic individuals.
Association between high sensitivity cardiac troponin and mortality risk in the non-diabetic population: findings from the National Health and Nutrition Examination Survey.
OBJECTIVE
We investigated the association of high-sensitivity cardiac troponin (Hs-cTn) with all-cause and cardiovascular mortality in non-diabetic individuals.
METHODS
This study included 10,393 participants without known diabetes and cardiovascular disease from the US National Health and Nutrition Examination Survey (NHANES). Serum Hs-cTnI and Hs-cTnT concentrations were measured. Prediabetes was defined as fasting blood glucose between 100 and 125 mg/dL or HbA1c between 5.7 and 6.4%. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality risk. Time-dependent receiver operating characteristics (tROC) curves were utilized to measure the predictive performance of the biomarkers. Net Reclassification Improvement (NRI) were calculated to estimate the improvement in risk classification for adding Hs-cTnT or Hs-cTnI to the standard models based on Framingham risk factors.
RESULTS
The mean age of the participants was 48.1 ± 19.1 years, with 53.3% being female and 25.8% being prediabetic. After multivariable adjustment, compared to those with Hs-cTnI concentration less than the limit of detection, the HRs (95% CIs) of the participants with Hs-cTnI concentration higher than the 99th upper reference limit were 1.74 (1.35, 2.24) for all-cause mortality and 2.10 (1.36, 3.24) for cardiovascular mortality. The corresponding HRs (95% CIs) for Hs-cTnT were 2.07 (1.53, 2.81) and 2.92 (1.47, 5.80) for all-cause and cardiovascular mortality. There was a significant interaction between prediabetes and Hs-cTnI on the mortality risk; a positive relationship was only observed in prediabetic individuals. No interaction was observed between prediabetes and Hs-cTnT on mortality risk. The Areas Under tROC indicated both Hs-cTnT and Hs-cTnI show better predictive performance in cardiovascular mortality than in all-cause mortality. NRI (95% CI) for adding Hs-cTnT to the standard model were 0.25 (0.21, 0.27) and 0.33 (0.26, 0.39) for all-cause and cardiovascular mortality. The corresponding NRI (95% CI) for Hs-cTnI were 0.04 (0, 0.06) and 0.07 (0.01, 0.13).
CONCLUSIONS
Elevated blood levels of Hs-cTnI and Hs-cTnT are associated with increased mortality. Measurement of Hs-cTnT in non-diabetic subjects, particularly those with prediabetes, may help identify individuals at an increased risk of cardiovascular disease and provide early and more intensive risk factor modification.
Topics: Humans; Female; Adult; Middle Aged; Aged; Male; Cardiovascular Diseases; Nutrition Surveys; Prediabetic State; Biomarkers; Troponin I; Troponin T
PubMed: 37904214
DOI: 10.1186/s12933-023-02003-2 -
Scientific Reports Jul 2023Focal segmental glomerulosclerosis (FSGS) is a common glomerular injury leading to end-stage renal disease. Monogenic FSGS is primarily ascribed to decreased podocyte...
Focal segmental glomerulosclerosis (FSGS) is a common glomerular injury leading to end-stage renal disease. Monogenic FSGS is primarily ascribed to decreased podocyte integrity. Variants between residues 184 and 245 of INF2, an actin assembly factor, produce the monogenic FSGS phenotype. Meanwhile, variants between residues 57 and 184 cause a dual-faceted disease involving peripheral neurons and podocytes (Charcot-Marie-Tooth CMT/FSGS). To understand the molecular basis for INF2 disorders, we compared structural and cytoskeletal effects of INF2 variants classified into two subgroups: One (G73D, V108D) causes the CMT/FSGS phenotype, and the other (T161N, N202S) produces monogenic FSGS. Molecular dynamics analysis revealed that all INF2 variants show distinct flexibility compared to the wild-type INF2 and could affect stability of an intramolecular interaction between their N- and C-terminal segments. Immunocytochemistry of cells expressing INF2 variants showed fewer actin stress fibers, and disorganization of cytoplasmic microtubule arrays. Notably, CMT/FSGS variants caused more prominent changes in mitochondrial distribution and fragmentation than FSGS variants and these changes correlated with the severity of cytoskeletal disruption. Our results indicate that CMT/FSGS variants are associated with more severe global cellular defects caused by disrupted cytoskeleton-organelle interactions than are FSGS variants. Further study is needed to clarify tissue-specific pathways and/or cellular functions implicated in FSGS and CMT phenotypes.
Topics: Humans; Microfilament Proteins; Glomerulosclerosis, Focal Segmental; Formins; Actins; Mutation; Cytoskeleton; Podocytes
PubMed: 37491439
DOI: 10.1038/s41598-023-38588-7 -
Genes Dec 2023MICAL2 is an actin-regulatory protein that functions through redox modification of actin. Nuclear localized MICAL2 triggers the disassembly of nuclear actin, which...
MICAL2 is an actin-regulatory protein that functions through redox modification of actin. Nuclear localized MICAL2 triggers the disassembly of nuclear actin, which subsequently leads to nuclear retention of the actin-binding transcriptional coregulator myocardin-related transcription factor-A (MRTF-A), which leads to the activation of serum response factor (SRF)/MRTF-A-dependent gene transcription. In this study, we show that the secreted signaling protein GAS6 (growth-arrest specific 6) and its cognate receptor Axl, a transmembrane tyrosine kinase, also induce the activation of SRF/MRTF-A and their downstream target genes. We find that serum-induced SRF/MRTF-A-dependent gene expression can be blocked, in part, by the inhibition of Axl signaling. Furthermore, we find that Gas6/Axl-induced SRF/MRTF-A-dependent transcription is dependent on MICAL2. Gas6/Axl promotes cell invasion, which is blocked by MICAL2 knockdown, suggesting that MICAL2 promotes cytoskeletal effects of the Gas6/Axl pathway. We find that Gas/6/Axl signaling promotes the nuclear localization of MICAL2, which may contribute to the ability of Gas6/SRF to augment SRF/MRTF-A-dependent gene transcription. The physiological significance of the Gas6/Axl-MICAL2 signaling pathway described here is supported by the marked gene expression correlation across a broad array of different cancers between and and , as well as the coexpression of these genes and the known SRF/MRTF-A target transcripts. Overall, these data reveal a new link between Gas6/Axl and SRF/MRTF-A-dependent gene transcription and link MICAL2 as a novel effector of the Gas6/Axl signaling pathway.
Topics: Transcription Factors; Actins; Signal Transduction; Transcription, Genetic
PubMed: 38137053
DOI: 10.3390/genes14122231 -
BMC Nephrology Jul 2023Studies reported that kelch-like protein 3 (KLHL3)-Cullin3(CUL3) E3 ligase ubiquitinated with-no-lysine kinase 4 (WNK4). Impaired WNK4 ubiquitination plays a key role in...
BACKGROUND
Studies reported that kelch-like protein 3 (KLHL3)-Cullin3(CUL3) E3 ligase ubiquitinated with-no-lysine kinase 4 (WNK4). Impaired WNK4 ubiquitination plays a key role in Familial hyperkalemic hypertension (FHHt, also called pseudohypoaldosteronism type II) which results from overaction of thiazide-sensitive sodium chloride cotransport (NCC). In addition, researchers have also found that dietary potassium deficiency activates NCC along the renal distal convoluted tubule (DCT). However, the underlying mechanism remains unclear about the relationship between potassium and WNK4.
METHODS
In the present study, we conducted in vitro and in vivo experiments to confirm that KLHL3-dependent WNK4 degradation is affected by potassium through the neddylation and autophagy pathway. In vitro, the WNK4 and KLHL3 plasmids were cotransfected into HEK293 cell lines by lipofectamine 2000, and then incubated with different potassium concentrations (1mmol/L and 10mmol/L) for 24 h, and further treated with MLN4924 or the autophagy inhibitor or both of MLN4924 and the autophagy inhibitor for another 24 h respectively. In vivo, we created mice that were fed with low or high potassium diets and then were injected MLN4924 in the experimental groups. The expression of WNK4, pWNK4, KLHL3, NEDD8, LC3 ,and P62 was detected by western blotting in vitro and vivo experiments.
RESULTS
We found that the abundance and phosphorylation of WNK4 increase when neddylation is inhibited both in vitro and vivo. Furthermore, the abundance of pWNK4, WNK4, NEDD8, and KLHL3 was increased in the low potassium (LK) group. Inhibiting autophagy can ameliorate the effect of potassium on the abundance and activity of WNK4 to some extent.
CONCLUSION
These findings suggest a complex regulation of potassium in the degradation of WNK4. Low potassium can activate WNK4, which may be related to neddylation and autophagy, but the mechanism needs to be further studied.
Topics: Animals; Humans; Mice; Adaptor Proteins, Signal Transducing; Autophagy; HEK293 Cells; Kidney Tubules, Distal; Microfilament Proteins; Potassium; Protein Serine-Threonine Kinases
PubMed: 37481568
DOI: 10.1186/s12882-023-03257-4 -
Brain, Behavior, and Immunity Nov 2023The pathophysiology of autism spectrum disorder (ASD) involves genetic and environmental factors. Mounting evidence demonstrates a role for the gut microbiome in ASD,...
BACKGROUND
The pathophysiology of autism spectrum disorder (ASD) involves genetic and environmental factors. Mounting evidence demonstrates a role for the gut microbiome in ASD, with signaling via short-chain fatty acids (SCFA) as one mechanism. Here, we utilize mice carrying deletion to exons 4-22 of Shank3 (Shank3) to model gene by microbiome interactions in ASD. We identify SCFA acetate as a mediator of gut-brain interactions and show acetate supplementation reverses social deficits concomitant with alterations to medial prefrontal cortex (mPFC) transcriptional regulation independent of microbiome status.
METHODS
Shank3 and wild-type (Wt) littermates were divided into control, Antibiotic (Abx), Acetate and Abx + Acetate groups upon weaning. After six weeks, animals underwent behavioral testing. Molecular analysis including 16S and metagenomic sequencing, metabolomic and transcriptional profiling were conducted. Additionally, targeted serum metabolomic data from Phelan McDermid Syndrome (PMS) patients (who are heterozygous for the Shank3 gene) were leveraged to assess levels of SCFA's relative to ASD clinical measures.
RESULTS
Shank3 mice were found to display social deficits, dysregulated gut microbiome and decreased cecal levels of acetate - effects exacerbated by Abx treatment. RNA-sequencing of mPFC showed unique gene expression signature induced by microbiome depletion in the Shank3 mice. Oral treatment with acetate reverses social deficits and results in marked changes in gene expression enriched for synaptic signaling, pathways among others, even in Abx treated mice. Clinical data showed sex specific correlations between levels of acetate and hyperactivity scores.
CONCLUSION
These results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.
Topics: Humans; Male; Female; Mice; Animals; Autism Spectrum Disorder; Nerve Tissue Proteins; Prefrontal Cortex; Acetates; Dietary Supplements; Microfilament Proteins
PubMed: 37657643
DOI: 10.1016/j.bbi.2023.08.020