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Forkhead box O (FOXO) transcription factors (TFs) are a subclass of the larger family of forkhead TFs. Mammalians express four members FOXO1, FOXO3, FOXO4, and FOXO6. The interest in FOXO function stems mostly from their observed role in determining lifespan, where in model organisms, increased FOXO activity results in extended lifespan. FOXOs act as downstream of several signaling pathway and are extensively regulated through post‐translational modifications. The transcriptional program activated by FOXOs in various cell types, organisms, and under various conditions has been described and has shed some light on what the critical transcriptional targets are in mediating FOXO function. At the cellular level, these studies have revealed a role for FOXOs in cell metabolism, cellular redox, cell proliferation, DNA repair, autophagy, and many more. The general picture that emerges hereof is that FOXOs act to preserve equilibrium, and they are important for cellular homeostasis. Here, we will first briefly summarize the general knowledge of FOXO regulation and possible functions. We will use genomic stability to illustrate how FOXOs ensure homeostasis. Genomic stability is critical for maintaining genetic integrity, and therefore preventing disease. However, genomic mutations need to occur during lifetime to enable evolution, yet their accumulation is believed to be causative to aging. Therefore, the role of FOXO in genomic stability may underlie its role in lifespan and aging. Finally, we will come up with questions on some of the unknowns in FOXO function, the answer(s) to which we believe will further our understanding of FOXO function and ultimately may help to understand lifespan and its consequences. [ABSTRACT FROM AUTHOR]

Snakehead vesiculovirus (SHVV), a strain of negative-stranded RNA viruses extracted from sick snakehead fish (Ophicephalus striatus), may pose a threat to the health of snakehead fish. Previous research has proved that the replication of SHVV can be significantly inhibited by glutamine starvation. To study how glutamine starvation inhibits SHVV replication, channel catfish ovary (CCO) cells with SHVV cultivated in the glutamine-free medium or the complete medium were used to investigate the differentially expressed proteins (DEPs). The results showed that 124 up-regulated and 246 down-regulated proteins were involved in many viral replication physiological processes, such as autophagy, post-translational modifications machinery, and functional pathways, including the PI3K-Akt signaling pathway and mTOR signaling pathway. Furthermore, a few proteins, such as Akt and Hsp90, which have been confirmed to be involved in the replication of RNA viruses, were also significantly differentially expressed. Taken together, our study demonstrated that glutamine starvation affects various functional pathways and the expression of some key proteins related to RNA viral replication, which will benefit future studies on the replication mechanisms of SHVV and the prevention of SHVV infection. [ABSTRACT FROM AUTHOR]

Translationally controlled tumor protein (TCTP) is a multifunctional protein that plays a wide variety of physiological and pathological roles, including as a cytoplasmic repressor of Na,K-ATPase, an enzyme pivotal in maintaining Na+ and K+ ion gradients across the plasma membrane, by binding to and inhibiting Na,K-ATPase. Studies with transgenic mice overexpressing TCTP (TCTP-TG) revealed the pathophysiological significance of TCTP in the development of systemic arterial hypertension. Overexpression of TCTP and inhibition of Na,K-ATPase result in the elevation of cytoplasmic Ca2+ levels, which increases the vascular contractility in the mice, leading to hypertension. Furthermore, studies using an animal model constructed by multiple mating of TCTP-TG with apolipoprotein E knockout mice (ApoE KO) indicated that TCTP-induced hypertension facilitates the severity of atherosclerotic lesions in vivo. This review attempts to discuss the mechanisms underlying TCTP-induced hypertension and related diseases gleaned from studies using genetically altered animal models and the potential of TCTP as a target in the therapy of hypertension-related pathological conditions. [ABSTRACT FROM AUTHOR]

Fetuin-A is a liver derived plasma protein showing highest serum concentrations in utero, preterm infants, and neonates. Fetuin-A is also present in cerebrospinal fluid (CSF). The origin of CSF fetuin-A, blood-derived via the blood-CSF barrier or synthesized intrathecally, is presently unclear. Fetuin-A prevents ectopic calcification by stabilizing calcium and phosphate as colloidal calciprotein particles mediating their transport and clearance. Thus, fetuin-A plays a suppressive role in inflammation. Fetuin-A is a negative acute-phase protein under investigation as a biomarker for multiple sclerosis (MS). Here we studied the association of pediatric inflammatory CNS diseases with fetuin-A glycosylation and phosphorylation. Paired blood and CSF samples from 66 children were included in the study. Concentration measurements were performed using a commercial human fetuin-A/AHSG ELISA. Of 60 pairs, 23 pairs were analyzed by SDS-PAGE following glycosidase digestion with PNGase-F and Sialidase-AU. Phosphorylation was analyzed in 43 pairs by Phos-TagTM acrylamide electrophoresis following alkaline phosphatase digestion. Mean serum and CSF fetuin-A levels were 0.30 ± 0.06 mg/ml and 0.644 ± 0.55 μg/ml, respectively. This study showed that serum fetuin-A levels decreased in inflammation corroborating its role as a negative acute-phase protein. Blood-CSF barrier disruption was associated with elevated fetuin-A in CSF. A strong positive correlation was found between the CSF fetuin-A/serum fetuin-A quotient and the CSF albumin/serum albumin quotient, suggesting predominantly transport across the blood-CSF barrier rather than intrathecal fetuin-A synthesis. Sialidase digestion showed increased asialofetuin-A levels in serum and CSF samples from children with neuroinflammatory diseases. Desialylation enhanced hepatic fetuin-A clearance via the asialoglycoprotein receptor thus rapidly reducing serum levels during inflammation. Phosphorylation of fetuin-A was more abundant in serum samples than in CSF, suggesting that phosphorylation may regulate fetuin-A influx into the CNS. These results may help establish Fetuin-A as a potential biomarker for neuroinflammatory diseases. [ABSTRACT FROM AUTHOR]

Eubacterium limosum is an acetogen that can produce butyrate along with acetate as the main fermentation end-product from methanol, a promising C1 feedstock. Although physiological characterization of E. limosum B2 during methylotrophy was previously performed, the strain was cultured in a semi-defined medium, limiting the scope for further metabolic insights. Here, we sequenced the complete genome of the native strain and performed adaptive laboratory evolution to sustain growth on methanol mineral medium. The evolved population significantly improved its maximal growth rate by 3.45-fold. Furthermore, three clones from the evolved population were isolated on methanol mineral medium without cysteine by the addition of sodium thiosulfate. To identify mutations related to growth improvement, the whole genomes of wild-type E. limosum B2, the 10th, 25th, 50th, and 75th generations, and the three clones were sequenced. We explored the total proteomes of the native and the best evolved clone (n°2) and noticed significant differences in proteins involved in gluconeogenesis, anaplerotic reactions, and sulphate metabolism. Furthermore, a homologous recombination was found in subunit S of the type I restriction-modification system between both strains, changing the structure of the subunit, its sequence recognition and the methylome of the evolved clone. Taken together, the genomic, proteomic and methylomic data suggest a possible epigenetic mechanism of metabolic regulation. [ABSTRACT FROM AUTHOR]

Aberrant activation of hepatocyte growth factor (HGF) and its receptor c-Met axis promotes tumor growth. Therefore, many clinical trials have been conducted. A phase 3 trial investigating a monoclonal antibody targeting HGF in combination with fluoropyrimidine-based chemotherapy had to be terminated prematurely; however, the reason behind the failure remains poorly defined. In this study, we investigated the influence of HGF on the antineoplastic effects of 5-fluorouracil (5-FU), a fluoropyrimidine, in HepG2 cells. HGF suppressed the proliferative activity of cells concomitantly treated with 5-FU more robustly as compared to that of cells treated with 5-FU alone, and markedly increased the expression of uridine phosphorylase 1 (UPP1). Intracellular concentration of 5-fluorouridine, an initial anabolite of 5-FU catalyzed by UPP1, was increased by HGF. Interestingly, erlotinib enhanced HGF-induced increase in UPP1 mRNA; in contrast, gefitinib suppressed it. Furthermore, erlotinib suppressed HGF-increased phosphorylation of the epidermal growth factor receptor at the Tyr1173 site involved in downregulation of extracellular signal-regulated kinase (Erk) activation, and enhanced the HGF-increased phosphorylation of Erk. Collectively, these findings suggest that inhibition of the HGF/c-Met axis diminishes the effects of fluoropyrimidine through downregulation of UPP1 expression. Therefore, extreme caution must be exercised in terms of patient safety while offering chemotherapy comprising fluoropyrimidine concomitantly with inhibitors of the HGF/c-Met axis. [ABSTRACT FROM AUTHOR]

Oncogenic fusion genes have emerged as successful targets in several malignancies, such as chronic myeloid leukemia and lung cancer. Fusion of the fibroblast growth receptor 3 and the transforming acidic coiled coil containing protein—FGFR3-TACC3 fusion—is prevalent in 3–4% of human glioblastoma. The fusion protein leads to the constitutively activated kinase signaling of FGFR3 and thereby promotes cell proliferation and tumor progression. The subgroup of FGFR3-TACC3 fusion-positive glioblastomas presents with recurrent clinical and histomolecular characteristics, defining a distinctive subtype of IDH-wildtype glioblastoma. This review aims to provide an overview of the available literature on FGFR3-TACC3 fusions in glioblastoma and possible implications for actual clinical practice. [ABSTRACT FROM AUTHOR]

Traditionally, fetuin-A embodies the prototype anti-calcification protein in the blood, preventing cardiovascular calcification. Low serum fetuin-A is generally associated with mineralization dysbalance and enhanced mortality in end stage renal disease. Recent evidence indicates that fetuin-A is a crucial factor moderating tissue inflammation and fibrosis, as well as a systemic indicator of acute inflammatory disease. Here, the expanded function of fetuin-A is discussed in the context of mineralization and inflammation biology. Unbalanced depletion of fetuin-A in this context may be the critical event, triggering a vicious cycle of progressive calcification, inflammation, and tissue injury. Hence, we designate fetuin-A as tissue chaperone and propose the potential use of exogenous fetuin-A as prophylactic agent or emergency treatment in conditions that are associated with acute depletion of endogenous protein. [ABSTRACT FROM AUTHOR]

Ym1 is a rodent-specific chitinase-like protein (CLP) lacking catalytic activity, whose cellular origins are mainly macrophages, neutrophils and other cells. Although the detailed function of Ym1 remains poorly understood, Ym1 has been generally recognized as a fundamental feature of alternative activation of macrophages in mice and hence one of the prevalent detecting targets in macrophage phenotype distinguishment. Studies have pointed out that Ym1 may have regulatory effects, which are multifaceted and even contradictory, far more than just a mere marker. Allergic lung inflammation, parasite infection, autoimmune diseases, and central nervous system diseases have been found associations with Ym1 to varying degrees. Thus, insights into Ym1's role in diseases would help us understand the pathogenesis of different diseases and clarify the genuine roles of CLPs in mammals. This review summarizes the information on Ym1 from the gene to its expression and regulation and focuses on the association between Ym1 and diseases. [ABSTRACT FROM AUTHOR]

Wnt signaling is essential during animal development and regeneration, but also plays an important role in diseases such as cancer and diabetes. The canonical Wnt signaling pathway is one of the most conserved signaling cascades in the animal kingdom, with the T‐cell factor/lymphoid enhancer factor (TCF/LEF) proteins being the major mediators of Wnt/β‐catenin‐regulated gene expression. In comparison with invertebrates, vertebrates possess a high diversity of TCF/LEF family genes, implicating this as a possible key change to Wnt signaling at the evolutionary origin of vertebrates. However, the precise nature of this diversification is only poorly understood. The aim of this study is to clarify orthology, paralogy, and isoform relationships within the TCF/LEF gene family within chordates via in silico comparative study of TCF/LEF gene structure, molecular phylogeny, and gene synteny. Our results support the notion that the four TCF/LEF paralog subfamilies in jawed vertebrates (gnathostomes) evolved via the two rounds of whole‐genome duplications that occurred during early vertebrate evolution. Importantly, gene structure comparisons and synteny analysis of jawless vertebrate (cyclostome) TCFs suggest that a TCF7L2‐like form of gene structure is a close proxy for the ancestral vertebrate structure. In conclusion, we propose a detailed evolutionary path based on a new pre‐whole‐genome duplication vertebrate TCF gene model. This ancestor gene model highlights the chordate and vertebrate innovations of TCF/LEF gene structure, providing the foundation for understanding the role of Wnt/β‐catenin signaling in vertebrate evolution. [ABSTRACT FROM AUTHOR]

Introduction: Neuropathic pain initiates an interplay of pathways, involving MAP kinases and NFκB-signaling, leading to expression of immune response factors and activation and inactivation of proteins via phosphorylation. Neuropathic pain models demonstrated that spinal cord stimulation (SCS) may provide analgesia by modulating gene and protein expression in neuroinflammatory processes. A differential target multiplexed programming (DTMP) approach was more effective than conventional SCS treatments at modulating these. This work investigated the effect of DTMP and low rate SCS (LR-SCS) on proteins associated with MAP kinases and NFκB-signaling relevant to neuroinflammation. Methods: Animals subjected to the spared nerve injury model (SNI) of neuropathic pain were treated continuously (48h) with either DTMP or LR-SCS. No-SNI and No-SCS groups were included as controls. Proteomics and phosphoproteomics of stimulated spinal cord tissues were performed via liquid chromatography/tandem mass spectrometry. Proteins were identified from mass spectra using bioinformatics. Expression levels and fold changes (No-SCS/No-SNI and SCS/No-SCS) were obtained from spectral intensities. Results: Analyses identified 7192 proteins, with 1451 and 705 significantly changed by DTMP and LR-SCS, respectively. Eighty-one proteins, including MAP kinases, facilitating NFκB-signaling as part of inflammatory processes were identified. The pain model significantly increased expression levels of complement pathway-related proteins (LBP, NRG1, APP, CFH, C3, C5), which were significantly reversed by DTMP. Expression levels of other complement pathway-related proteins (HMGB1, S100A8, S100A9, CRP, C4) were decreased by DTMP, although not significantly affected by SNI. Other proteins (ORM1, APOE, NG2, CNTF) involved in NFκB-signaling were increased by SNI and decreased by DTMP. Expression levels of phosphorylated protein kinases involved in NFκB-signaling (including MAP kinases, PKC, MARK1) were affected by the pain model and reverse modulated by DTMP. LR-SCS modulated inflammatory-related proteins although to a lesser extent than DTMP. Conclusion: Proteomic analyses support the profound effect of the DTMP approach on neuroinflammation via MAP kinases and NFκB-mediated signaling to alleviate neuropathic pain. [ABSTRACT FROM AUTHOR]

Periodontal disorders are among the most widespread chronic illnesses globally which impact the tooth-supporting tissues and have a multitude of ramifications for one's quality of life. The purpose of periodontal diagnostic methods is to offer meaningful information to clinicians about the type, location, and severity of periodontal disease so that disease monitoring and therapy may be established. Due to a lack of proper molecular diagnostic tools, their early detection is still difficult. Proteomics, the promising new "omics", has become an important complementary tool to genomics providing novel information and greater insight into biology. The value of multidimensional peptide resolving approaches in the characterisation of complicated proteomes cannot be overstated and thus can very much be used as diagnostic biomarkers in periodontal world. Since proteomics is considered more intricate and complicated than genomics, the sound and rich facts of proteins concerned in periodontitis can be applied in the analysis, avoidance and management of periodontal diseases. Despite several novel protein markers being recently enlisted by discovery proteomics through various methods such as Enzyme Linked Immunosorbent Assay (ELISA), immunoassays with Mass Spectroscopy (MS), Protein Topography and Migration Analysis platform (ProtoMap), Matrix Assisted Laser Desorption (MALDI) etc., their routine diagnostic application is hampered by the lack of validation platforms that can rapidly, accurately and simultaneous quantify multiple proteins in large populations. Furthermore, saliva contains a non invasively collected store of clinically relevant biomarkers, which, if properly employed, might aid in early illness detection and monitoring. Hence, in this context, this review aims to discuss the unravelling field of proteomics in brief and the scientific sphere of its development from laboratory to clinical practice and its implications in the field of periodontology. [ABSTRACT FROM AUTHOR]

Facilitation of fear extinction is a desirable action for the drugs to treat fear-related diseases, such as posttraumatic stress disorder (PTSD). We previously reported that a selective agonist of the δ-opioid receptor (DOP), KNT-127, facilitates contextual fear extinction in mice. However, its site of action in the brain and the underlying molecular mechanism remains unknown. Here, we investigated brain regions and cellular signaling pathways that may mediate the action of KNT-127 on fear extinction. Twenty-four hours after the fear conditioning, mice were reexposed to the conditioning chamber for 6 min as extinction training (reexposure 1). KNT-127 was microinjected into either the basolateral nucleus of the amygdala (BLA), hippocampus (HPC), prelimbic (PL), or infralimbic (IL) subregions of the medial prefrontal cortex, 30 min before reexposure 1. Next day, mice were reexposed to the chamber for 6 min as memory testing (reexposure 2). KNT-127 that infused into the BLA and IL, but not HPC or PL, significantly reduced the freezing response in reexposure 2 compared with those of control. The effect of KNT-127 administered into the BLA and IL was antagonized by pretreatment with a selective DOP antagonist. Further, the effect of KNT-127 was abolished by local administration of MEK/ERK inhibitor into the BLA, and PI3K/Akt inhibitor into the IL, respectively. These results suggested that the effect of KNT-127 was mediated by MEK/ERK signaling in the BLA, PI3K/Akt signaling in the IL, and DOPs in both brain regions. Here, we propose that DOPs play a role in fear extinction via distinct signaling pathways in the BLA and IL. [ABSTRACT FROM AUTHOR]

Background: Resveratrol, a well-known natural compound and nutrient, activates the deacetylation ability of SIRT1, demonstrating p53-dependent apoptosis functions in many diseases. However, the nascent proteomic fluctuation caused by resveratrol is still unclear. Objective: In this study, we investigated the effect of resveratrol on the nascent proteome and transcriptome initiated by SIRT1 activation, and we explored the mechanism of resveratrol in HEK 293T cells. Methods: Bioorthogonal noncanonical amino acid tagging (BONCAT) is a method used to metabolically label nascent proteins. In this strategy, L-azidohomoalanine (AHA) was used to replace methionine (Met) under different conditions. Taking advantage of the click reaction between AHA and terminal alkyne- and disulfide-functionalized agarose resin (TAD resin), we were able to efficiently separate stimulation responsive proteins from the pre-existing proteome. Resveratrol responsive proteins were identified by Liquid Chromatograph- Mass Spectrometer/Mass Spectrometer (LC-MS/MS). Furthermore, changes in mRNA levels were analyzed by transcriptome sequencing. Results: Integrational analysis revealed a resveratrol response in HEK 293T cells and showed that Hsp60 was downregulated at both the nascent protein and mRNA levels. Knockdown of SIRT1 and Hsp60 provides evidence that resveratrol downregulated Hsp60 through SIRT1 and that Hsp60 decreased p53 through the Akt pathway. Conclusions: This study revealed dynamic changes in the nascent proteome and transcriptome in response to resveratrol in HEK 293T cells and demonstrated that resveratrol downregulates Hsp60 by activating SIRT1, which may be a possible mechanism by which resveratrol prevents p53-dependent apoptosis by regulating Hsp60. [ABSTRACT FROM AUTHOR]

The stringent response is critical for the survival of Mycobacterium tuberculosis (Mtb) under nutrient starvation. The mechanism is mediated by a GTP pyrophosphokinase known as Rel, containing N‐terminal synthetase and hydrolase domains and C‐terminal regulatory domains, which include the TGS domain (ThrRS, GTPase, and SpoT proteins) that has been proposed to activate the synthetase domain via interaction with deacylated tRNA. Here, we present the NMR solution structure of the Mtb Rel TGS domain (MtRel TGS), consisting of five antiparallel β‐strands and one helix–loop–helix motif. The interaction of MtRel TGS with deacylated tRNA is shown, indicating the critical amino acids of MtRel TGS in tRNA binding, and presenting the first structural evidence of MtRel TGS binding to deacylated tRNA in solution in the absence of the translational machinery. [ABSTRACT FROM AUTHOR]

The synaptonemal complex (SC) is a supramolecular protein scaffold that mediates chromosome synapsis and facilitates crossing over during meiosis. In mammals, SC proteins are generally assumed to have no other function. Here, we show that SC protein TEX12 also localises to centrosomes during meiosis independently of chromosome synapsis. In somatic cells, ectopically expressed TEX12 similarly localises to centrosomes, where it is associated with centrosome amplification, a pathology correlated with cancer development. Indeed, TEX12 is identified as a cancer-testis antigen and proliferation of some cancer cells is TEX12-dependent. Moreover, somatic expression of TEX12 is aberrantly activated via retinoic acid signalling, which is commonly disregulated in cancer. Structure-function analysis reveals that phosphorylation of TEX12 on tyrosine 48 is important for centrosome amplification but not for recruitment of TEX12 to centrosomes. We conclude that TEX12 normally localises to meiotic centrosomes, but its misexpression in somatic cells can contribute to pathological amplification and dysfunction of centrosomes in cancers. Sandhu et al. report that the synaptonemal complex (SC) protein, TEX12, localises to centrosomes independently of the SC during meiosis. They also show that it provokes centrosome amplification in somatic cells, a pathology associated with cancer development. [ABSTRACT FROM AUTHOR]

Pellino‐2 is an E3 ubiquitin ligase that mediates intracellular signaling in innate immune pathways. Most studies of endogenous Pellino‐2 have been performed in macrophages, but none in nonimmune cells. Using yeast two‐hybrid screening and co‐immunoprecipitation, we identified six novel interaction partners of Pellino‐2, with various localizations: insulin receptor substrate 1, NIMA‐related kinase 9, tumor necrosis factor receptor‐associated factor 7, cyclin‐F, roundabout homolog 1, and disheveled homolog 2. Pellino‐2 showed cytoplasmic localization in a wide range of nonimmune cells under physiological potassium concentrations. Treatment with the potassium ionophore nigericin resulted in nuclear localization of Pellino‐2, which was reversed by the potassium channel blocker tetraethylammonium. Live‐cell imaging revealed intracellular migration of GFP‐tagged Pellino‐2. In summary, Pellino‐2 interacts with proteins at different cellular locations, taking part in dynamic processes that change its intracellular localization influenced by potassium efflux. [ABSTRACT FROM AUTHOR]

Novel genetic variants for donkey milk lysozyme and β-lactoglobulins I and II have been identified by the combined use of peptide mass mapping and sequencing by tandem mass spectrometry in association with database searching. The novel donkey lysozyme variant designated as lysozyme B (Mr 14,631 Da) differed in three amino acid exchanges, N49 → D, Y52 → S, and S61 → N, from the previously published sequence. Three novel genetic variants for donkey β-lactoglobulins were identified. One of them is a type β-lactoglobulin I with three amino acid exchanges at E36 → S, S97 → T, and V150 → I (β-lactoglobulin I B, Mr 18,510 Da). The two others are type β-lactoglobulins II with two amino acid exchanges at C110 → P and M118 → T (β-lactoglobulin II B, Mr 18,227 Da) and with three amino acid exchanges at D96 → E, C110 → P, and M118 → T (β-lactoglobulin II C, Mr 18,241 Da). All these primary structures are closely related to those of homologous proteins in horse milk (percent identity >96%). [ABSTRACT FROM AUTHOR]

Background: Gastric cancer (GC) is one of the most common malignancies, molecular mechanism of which is still not clear. Aberrant expression of tumor-associated genes is the major cause of tumorigenesis. DBF4 is an important factor in cancers, although there is yet no report on its function and molecular mechanism in GC. Methods: The expression of DBF4 in tumor tissues or cells of GC was detected by qRT-PCR and western blotting. Gastric cancer cell line MGC-803 and AGS were transfected with DBF4 siRNA or overexpression vector to detect the function of DBF4 in proliferation, migration and the sensitivity to 5-Fu with CCK-8 assay, colony formation assay, transwell assay, and wound healing assay. miR-30a was found to be the regulator of DBF4 by online bioinformatics software and confirmed with qRT-PCR, western blot and dual-luciferase reporter assays. Results: In our study, increased expression of DBF4 in GC tissues was first identified through The Cancer Genome Atlas (TCGA) and later confirmed using specimens from GC patients. Furthermore, functional experiments were applied to demonstrate that DBF4 promotes cell proliferation and migration in GC cell lines, moreover weakens the sensitivity of MGC803 and AGS cells to 5-Fu. We further demonstrated that miR-30a showed significantly lower expression in GC cells and inhibited the expression of DBF4 through 3ʹ-UTR suppression. Furthermore, rescue experiments revealed that the miR-30a-DBF4 axis regulated the GC cell proliferation, migration and the sensitivity to 5-Fu. The important composition in tumor microenvironment, lactate, may be the primary factor that suppressed miR-30a to strengthen the expression of DBF4. Conclusions: Taken together, our study was the first to identify DBF4 as a regulator of cell proliferation and migration in GC. Furthermore, our study identified the lactate-miR-30a-DBF4 axis as a crucial regulator of tumor progression and the tumor sensitivity to 5-Fu, which maybe serve useful for the development of novel therapeutic targets. [ABSTRACT FROM AUTHOR]

The voltage-dependent anion channels (VDACs) are the most abundant proteins present on the outer mitochondrial membrane. They serve a myriad of functions ranging from energy and metabolite exchange to highly debatable roles in apoptosis. Their role in molecular transport puts them on the center stage as communicators between cytoplasmic and mitochondrial signaling events. Beyond their general role as interchangeable pores, members of this family may exhibit specific functions. Even after nearly five decades of their discovery, their role in plant systems is still a new and rapidly emerging field. The information on biochemical regulation of VDACs is limited. Various interacting proteins and post-translational modifications (PTMs) modulate VDAC functions, amongst these, phosphorylation is quite noticeable. In this review, we have tried to give a glimpse of the recent advancements in the biochemical/interactional regulation of plant VDACs. We also cover a critical analysis on the importance of PTMs in the functional regulation of VDACs. Besides, the review also encompasses numerous studies which can identify VDACs as a connecting link between Ca2+ and reactive oxygen species signaling in special reference to the plant systems. [ABSTRACT FROM AUTHOR]

Proton pumps create a proton motif force and thus, energize secondary active transport at the plasma nmembrane and endomembranes of the secretory pathway. In the plant cell, the dominant proton pumps are the plasma membrane ATPase, the vacuolar pyrophosphatase (V-PPase), and the vacuolar-type ATPase (V-ATPase). All these pumps act on the cytosolic pH by pumping protons into the lumen of compartments or into the apoplast. To maintain the typical pH and thus, the functionality of the cytosol, the activity of the pumps needs to be coordinated and adjusted to the actual needs. The cellular toolbox for a coordinated regulation comprises 14-3-3 proteins, phosphorylation events, ion concentrations, and redox-conditions. This review combines the knowledge on regulation of the different proton pumps and highlights possible coordination mechanisms. [ABSTRACT FROM AUTHOR]

Background: Invadopodia are actin-based cell-membrane protrusions associated with the extracellular matrix degradation accompanying cancer invasion. The elucidation of the molecular mechanisms leading to invadopodia formation and activity is central for the prevention of tumor spreading and growth. Protein tyrosine kinases such as Src are known to regulate invadopodia assembly, little is however known on the role of protein tyrosine phosphatases in this process. Among these enzymes, we have selected the tyrosine phosphatase Shp1 to investigate its potential role in invadopodia assembly, due to its involvement in cancer development. Methods: Co-immunoprecipitation and immunofluorescence studies were employed to identify novel substrate/s of Shp1AQ controlling invadopodia activity. The phosphorylation level of cortactin, the Shp1 substrate identified in this study, was assessed by immunoprecipitation, in vitro phosphatase and western blot assays. Short interference RNA and a catalytically-dead mutant of Shp1 expressed in A375MM melanoma cells were used to evaluate the role of the specific Shp1-mediated dephosphorylation of cortactin. The anti-invasive proprieties of glycerophosphoinositol, that directly binds and regulates Shp1, were investigated by extracellular matrix degradation assays and in vivo mouse model of metastasis. Results: The data show that Shp1 was recruited to invadopodia and promoted the dephosphorylation of cortactin at tyrosine 421, leading to an attenuated capacity of melanoma cancer cells to degrade the extracellular matrix. Controls included the use of short interference RNA and catalytically-dead mutant that prevented the dephosphorylation of cortactin and hence the decrease the extracellular matrix degradation by melanoma cells. In addition, the phosphoinositide metabolite glycerophosphoinositol facilitated the localization of Shp1 at invadopodia hence promoting cortactin dephosphorylation. This impaired invadopodia function and tumor dissemination both in vitro and in an in vivo model of melanomas. Conclusion: The main finding here reported is that cortactin is a specific substrate of the tyrosine phosphatase Shp1 and that its phosphorylation/dephosphorylation affects invadopodia formation and, as a consequence, the ability of melanoma cells to invade the extracellular matrix. Shp1 can thus be considered as a regulator of melanoma cell invasiveness and a potential target for antimetastatic drugs. 831JMZGwFCMXv4_eLWR3W6 Video abstract [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatocellular carcinoma (HCC) is a fatal disease characterized by vast molecular heterogeneity. Although major advances in tumour genetics has led to the identification of new biomarkers, the prognosis of patients with HCC remains dismal. Methods: Quantitative reverse‐transcription polymerase chain reaction (qRT‐PCR) and western blot (WB) were used to evaluate meiosis‐specific nuclear structural 1 (MNS1) expression in HCC cells. Immunohistochemistry staining was used to evaluate MNS1 expression in HCC tissues. Clinical significance of MNS1 was evaluated by Cox regression analysis. Transwell assays were conducted to assess cells migration ability. Cell counting kit‐8 and colony formation assays were performed to detect cells proliferation ability. NOD/SCID/γc(null) (NOG) mice model was adopted to investigate functions of MNS1 in vivo. Results: The expression of MNS1, which is elevated in most HCC tissues, correlated with poor survival in HCC patients. Functional experiments revealed the oncogenic role of MNS1, which promotes HCC growth and metastasis through AKT‐dependent modulation of β‐catenin. β‐Catenin expression was crucial for MNS1's oncogenic effects. MNS1 indirectly translocated β‐catenin from the cytoplasm to the nucleus via the MNS1‐GSK3β axis. Conclusions: MNS1 promotes HCC growth and metastasis via activating PI3K/AKT signalling and may serve as an important prognostic biomarker as well as potential novel therapeutic target for HCC. [ABSTRACT FROM AUTHOR]

The two lipocalins, β-lactoglobulin (βLg) and glycodelin (Gd), are possibly the most closely related members of the large and widely distributed lipocalin family, yet their functions appear to be substantially different. Indeed, the function of β-lactoglobulin, a major component of ruminant milk, is still unclear although neonatal nutrition is clearly important. On the other hand, glycodelin has several specific functions in reproduction conferred through distinct, tissue specific glycosylation of the polypeptide backbone. It is also associated with some cancer outcomes. The glycodelin gene, PAEP , reflecting one of its names, progestagen-associated endometrial protein, is expressed in many though not all primates, but the name has now also been adopted for the β-lactoglobulin gene (HGNC, www.genenames.org). After a general overview of the two proteins in the context of the lipocalin family, this review considers the properties of each in the light of their physiological functional significance, supplementing earlier reviews to include studies from the past decade. While the biological function of glycodelin is reasonably well defined, that of β-lactoglobulin remains elusive. [ABSTRACT FROM AUTHOR]

Nuclear proteins are crucial in cells and are greatly linked to various biological functions. Abnormal expression of nuclear proteins is associated with many diseases ranging from inflammation to cancer. However, it remains challenging to detect nuclear proteins in single cells because of their low abundance and complex subcellular environment. Herein, we report a subcellular-resolved plasmonic immunosandwich assay (srPISA), for probing nucleus-enriched proteins in single living cells with minimal disruption. We demonstrated the specific extraction and ultrasensitive detection capabilities of the srPISA by probing low-copy-number nuclear telomerase in single living cells and further compared the telomerase expression levels in these single cells. Additionally, we showed the subcellular resolving capability of the srPISA by probing the spatial distribution of smad2 in the nucleus and cytoplasm of single living cells. We found that smad2 was expressed both in the nucleus and the cytoplasm, but showed different expression levels. Moreover, smad2 distributed more homogeneously in the nucleus than in the cytoplasm. Finally, the srPISA of nuclear telomerase in cell division strongly verified that the subcellular analytical results obtained by the srPISA are reliable. Overall, the srPISA approach allowed specific extraction and ultrasensitive detection of target low-copy-number proteins at the subcellular level, providing a unique and powerful single cell analysis tool for cell biology studies. [ABSTRACT FROM AUTHOR]

Deficiency of ASM (acid sphingomyelinase) causes the lysosomal storage Niemann-Pick disease (NPD). Patients with NPD type B may develop progressive interstitial lung disease with frequent respiratory infections. Although several investigations using the ASM-deficient (ASMKO) mouse NPD model revealed inflammation and foamy macrophages, there is little insight into the pathogenesis of NPD-associated lung disease. Using ASMKO mice, we report that ASM deficiency is associated with a complex inflammatory phenotype characterized by marked accumulation of monocyte-derived CD11b+ macrophages and expansion of airspace/alveolar CD11c+ CD11b+ macrophages, both with increased size, granularity, and foaminess. Both the alternative and classical pathways were activated, with decreased in situ phagocytosis of opsonized (Fc-coated) targets, preserved clearance of apoptotic cells (efferocytosis), secretion of Th2 cytokines, increased CD11c+/CD11b+ cells, and more than a twofold increase in lung and plasma proinflammatory cytokines. Macrophages, neutrophils, eosinophils, and noninflammatory lung cells of ASMKO lungs also exhibited marked accumulation of chitinase-like protein Ym1/2, which formed large eosinophilic polygonal Charcot-Leyden-like crystals. In addition to providing insight into novel features of lung inflammation that may be associated with NPD, our report provides a novel connection between ASM and the development of crystal- associated lung inflammation with alterations in macrophage biology. [ABSTRACT FROM AUTHOR]

Fetuin-A is an inhibitor of ectopic calcification that is expressed mainly in hepatocytes and is secreted into the circulation after posttranslational processing, including glycosylation and phosphorylation. The molecular weight (MW) of fully modified fetuin-A (FM-fetuin-A) is approximately 60 kDa in an immunoblot, which is much higher than the estimated MW by amino acid sequence. Under conditions of calcification stress such as advanced stage chronic kidney disease, fetuin-A prevents calcification by forming colloidal complexes, which are referred to as calciprotein particles (CPP). Since the significance of CPP in this process is unclear, we investigated the effect of synthetic secondary CPP on the level of FM-fetuin-A in HepG2 cells. Secondary CPP increased the level of FM-fetuin-A in dose- and time-dependent manners, but did not affect expression of mRNA for fetuin-A. Treatment with O- and/or N-glycosidase caused a shift of the 60 kDa band of FM-fetuin-A to a lower MW. Preincubation with brefeldin A, an inhibitor of transport of newly synthesized proteins from the endoplasmic reticulum to the Golgi apparatus, completely blocked the secondary CPP-induced increase in FM-fetuin-A. Treatment with BAPTA-AM, an intracellular calcium chelating agent, also inhibited the CPP-induced increase in the FM-fetuin-A level. Secondary CPP accelerate posttranslational processing of fetuin-A in HepG2 cells. [ABSTRACT FROM AUTHOR]

The stringent response, regulated by the bifunctional (p)ppGpp synthetase/hydrolase Rel in mycobacteria, is critical for long‐term survival of the drug‐tolerant dormant state of Mycobacterium tuberculosis. During amino acid starvation, MtRel senses a drop in amino acid concentration and synthesizes the messengers pppGpp and ppGpp, collectively called (p)ppGpp. Here, we investigate the role of the regulatory 'Aspartokinase, Chorismate mutase and TyrA' (ACT) domain in MtRel. Using NMR spectroscopy approaches, we report the high‐resolution structure of dimeric MtRel ACT which selectively binds to valine out of all other branched‐chain amino acids tested. A set of MtRel ACT mutants were generated to identify the residues required for maintaining the head‐to‐tail dimer. Through NMR titrations, we determined the crucial residues for binding of valine and show structural rearrangement of the MtRel ACT dimer in the presence of valine. This study suggests the direct involvement of amino acids in (p)ppGpp accumulation mediated by MtRel independent to interactions with stalled ribosomes. Database Structural data are available in the PDB database under the accession number 6LXG. [ABSTRACT FROM AUTHOR]

Adhesive structures between cells and with the surrounding matrix are essential for the development of multicellular organisms. In addition to providing mechanical integrity, they are key signalling centres providing feedback on the extracellular environment to the cell interior, and vice versa. During development, mitosis and repair, cell adhesions must undergo extensive remodelling. Post-translational modifications of proteins within these complexes serve as switches for activity. Tyrosine phosphorylation is an important modification in cell adhesion that is dynamically regulated by the protein tyrosine phosphatases (PTPs) and protein tyrosine kinases. Several PTPs are implicated in the assembly and maintenance of cell adhesions, however, their signalling functions remain poorly defined. The PTPs can act by directly dephosphorylating adhesive complex components or function as scaffolds. In this review, we will focus on human PTPs and discuss their individual roles in major adhesion complexes, as well as Hippo signalling. We have collated PTP interactome and cell adhesome datasets, which reveal extensive connections between PTPs and cell adhesions that are relatively unexplored. Finally, we reflect on the dysregulation of PTPs and cell adhesions in disease. [ABSTRACT FROM AUTHOR]

Neutrophils (PMNs) are innate immune cells with primary roles in inflammation and in host defense against infections. Both inflammatory and tumor angiogenesis are modulated by a sequential, coordinated production of angiogenic factors such as vascular endothelial growth factors (VEGFs), angiopoietins, hepatocyte growth factor (HGF), and chemokines. These factors are produced by several immune cells, including PMNs. Activation of cannabinoid receptor type‐1 (CB1) and ‐2 (CB2) has been suggested as a new strategy to modulate in vitro and in vivo angiogenesis. We sought to investigate whether activation of CB1 and CB2 by CB agonists modulate LPS‐mediated angiogenic activity of human PMNs. Highly purified PMNs were isolated from buffy coats of healthy donors. Cells were stimulated with CB1 and CB2 agonists/antagonists alone and/or in combination with LPS. Angiogenic factors in cell‐free supernatants were measured by ELISA. The modulation of activation markers of PMNs by CB agonists was evaluated by flow cytometry. Angiogenesis in vitro was measured as tube formation by optical microscopy. Endothelial cell permeability was assessed by an in vitro vascular permeability assay. LPS‐activated PMNs released VEGF‐A, CXCL8, and HGF. Preincubation of PMNs with low concentrations of CB1 and CB2 agonists inhibited VEGF‐A release induced by LPS, but did not affect CXCL8 and HGF production. The effects of CB agonists on VEGF‐A release induced by LPS were reversed by preincubation with CB antagonists. CB agonists modulated in vitro angiogenesis and endothelial permeability induced by supernatants of LPS‐activated PMNs through the reduction of VEGF‐A. Neutrophils play a central role in the control of bacterial infections and in the outcome of sepsis. The latter condition is associated with an increase in circulating levels of VEGF‐A. We demonstrated that low concentrations of CB agonists inhibit VEGF‐A release from LPS‐activated PMNs. These results suggest that CB agonists might represent a novel therapeutic strategy in patients with sepsis. [ABSTRACT FROM AUTHOR]

Neutrophils are the most prevalent leukocytes in the human body. They have a pivotal role in the innate immune response against invading bacterial and fungal pathogens, while recent emerging evidence also demonstrates their role in cancer progression and anti-tumor responses. The efficient execution of many neutrophil effector responses requires the presence of β 2 integrins, in particular CD11a/CD18 or CD11b/CD18 heterodimers. Although extensively studied at the molecular level, the exact signaling cascades downstream of β 2 integrins still remain to be fully elucidated. In this review, we focus mainly on inside-out and outside-in signaling of these two β 2 integrin members expressed on neutrophils and describe differences between various neutrophil stimuli with respect to integrin activation, integrin ligand binding, and the pertinent differences between mouse and human studies. Last, we discuss how integrin signaling studies could be used to explore the therapeutic potential of targeting β 2 integrins and the intracellular signaling cascade in neutrophils in several, among other, inflammatory conditions in which neutrophil activity should be dampened to mitigate disease. [ABSTRACT FROM AUTHOR]

The development of functionally selective or biased ligands is a promising approach towards drugs with less side effects. Biased ligands for G protein-coupled receptors can selectively induce G protein activation or β-arrestin recruitment. The consequences of this selective action on cellular functions, however, are not fully understood. Here, we investigated the impact of five biased and balanced dopamine D2 receptor agonists and antagonists on the global protein expression in HEK293T cells by untargeted nanoscale liquid chromatography–tandem mass spectrometry. The proteome analysis detected 5290 protein groups. Hierarchical clustering and principal component analysis based on the expression levels of 1462 differential proteins led to a separation of antagonists and balanced agonist from the control treatment, while the biased ligands demonstrated larger similarities to the control. Functional analysis of affected proteins revealed that the antagonists haloperidol and sulpiride regulated exocytosis and peroxisome function. The balanced agonist quinpirole, but not the functionally selective agonists induced a downregulation of proteins involved in synaptic signaling. The β-arrestin-preferring agonist BM138, however, regulated several proteins related to neuron function and the dopamine receptor-mediated signaling pathway itself. The G protein-selective partial agonist MS308 influenced rather broad functional terms such as DNA processing and mitochondrial translation. [ABSTRACT FROM AUTHOR]

The retrieval of fear memory induces two opposite memory process, i.e., reconsolidation and extinction. Brief retrieval induces reconsolidation to maintain or enhance fear memory, while prolonged retrieval extinguishes this memory. Although the mechanisms of reconsolidation and extinction have been investigated, it remains unknown how fear memory phases are switched from reconsolidation to extinction during memory retrieval. Here, we show that an extracellular signal-regulated kinase (ERK)-dependent memory transition process after retrieval regulates the switch of memory phases from reconsolidation to extinction by preventing induction of reconsolidation in an inhibitory avoidance (IA) task in male mice. First, the transition memory phase, which cancels the induction of reconsolidation, but is insufficient for the acquisition of extinction, was identified after reconsolidation, but before extinction phases. Second, the reconsolidation, transition, and extinction phases after memory retrieval showed distinct molecular and cellular signatures through cAMP responsive element binding protein (CREB) and ERK phosphorylation in the amygdala, hippocampus, and medial prefrontal cortex (mPFC). The reconsolidation phase showed increased CREB phosphorylation, while the extinction phase displayed several neural populations with various combinations of CREB and/or ERK phosphorylation, in these brain regions. Interestingly, the three memory phases, including the transition phase, showed transient ERK activation immediately after retrieval. Most importantly, the blockade of ERK in the amygdala, hippocampus, or mPFC at the transition memory phase disinhibited reconsolidation-induced enhancement of IA memory. These observations suggest that the ERK-signaling pathway actively regulates the transition of memory phase from reconsolidation to extinction and this process functions as a switch that cancels reconsolidation of fear memory. [ABSTRACT FROM AUTHOR]

In contrast to most bacteria, the mycobacterial F1FO‐ATP synthase (α3:β3:γ:δ:ε:a:b:b':c9) does not perform ATP hydrolysis‐driven proton translocation. Although subunits α, γ and ε of the catalytic F1‐ATPase component α3:β3:γ:ε have all been implicated in the suppression of the enzyme's ATPase activity, the mechanism remains poorly defined. Here, we brought the central stalk subunit ε into focus by generating the recombinant Mycobacterium smegmatis F1‐ATPase (MsF1‐ATPase), whose 3D low‐resolution structure is presented, and its ε‐free form MsF1αβγ, which showed an eightfold ATP hydrolysis increase and provided a defined system to systematically study the segments of mycobacterial ε's suppression of ATPase activity. Deletion of four amino acids at ε's N terminus, mutant MsF1αβγεΔ2‐5, revealed similar ATP hydrolysis as MsF1αβγ. Together with biochemical and NMR solution studies of a single, double, triple and quadruple N‐terminal ε‐mutants, the importance of the first N‐terminal residues of mycobacterial ε in structure stability and latency is described. Engineering ε's C‐terminal mutant MsF1αβγεΔ121 and MsF1αβγεΔ103‐121 with deletion of the C‐terminal residue D121 and the two C‐terminal ɑ‐helices, respectively, revealed the requirement of the very C terminus for communication with the catalytic α3β3‐headpiece and its function in ATP hydrolysis inhibition. Finally, we applied the tools developed during the study for an in silico screen to identify a novel subunit ε‐targeting F‐ATP synthase inhibitor. [ABSTRACT FROM AUTHOR]

Fibrosis is a pathological process characterized by accumulation of fibrous connective tissue in organs, leading to organ malfunction and failure. At the cellular level, tissue injury or cellular stress results in aberrant and/or sustained fibroblast "activation" leading to excessive extracellular matrix (ECM) accumulation and remodeling, as well as abnormal crosstalk with other cell types. Fibroblast functions within the fibrotic milieu are broad and complex, but among the most prominent are regulation of tissue architecture via modulation of ECM deposition and synthesis, and production of, activation of, and response to growth factors. Thus, both integrins and growth factor receptors (GFRs) play critical roles in fibroblast orchestration of tissue remodeling. However, the interplay between integrins and GFRs in this context is not fully understood. Their interaction has been described for other diseases, such as cancer. Here, we review the literature relevant to integrin/GFR interactions in the context of fibrosis, classify the known interactions into broad categories, and discuss research opportunities that may yield novel therapeutic targets for a broad range of debilitating chronic diseases. [ABSTRACT FROM AUTHOR]

Background The hepatokine fetuin-A, released by the human liver, promotes pro-inflammatory effects of perivascular fat. The involvement of inflammation in type 2 diabetes mellitus (T2DM) can affect the kidney and contribute to the development of diabetic kidney disease. Therefore we examined the association of urinary fetuin-A protein fragments with renal damage in T2DM patients. Methods Urinary peptides of 1491 individuals using proteome data available from the human urine proteome database were analysed. Prediction of proteases involved in urinary peptide generation was performed using the Proteasix tool. Results We identified 14 different urinary protein fragments that belong to the region of the connecting peptide (amino acid 301–339) of the total fetuin-A protein. Calpains (CAPN1 and CAPN2), matrix metalloproteinase and pepsin A-3 were identified as potential proteases that were partially confirmed by previous in vitro studies. Combined fetuin-A peptides (mean of amplitudes) were significantly increased in T2DM patients with kidney disease and to a lesser extent with cardiovascular risk. Furthermore, fetuin-A peptide levels displayed a significant negative correlation with baseline estimated glomerular filtration rate (eGFR) values (r  = −0.316, P < 0.0001) and with the slope (%) of eGFR per year (r  = −0.096, P = 0.023). A multiple regression model including fetuin-A peptide and albuminuria resulted in a significantly improved correlation with eGFR (r  = −0.354, P < 0.0001) compared with albuminuria, indicating an added value of this novel biomarker. Conclusions The urinary proteome analysis demonstrated the association of fetuin-A peptides with impaired kidney function in T2DM patients. Furthermore, fetuin-A peptides displayed early signs of kidney damage before albuminuria appeared and therefore can be used as markers for kidney disease detection. [ABSTRACT FROM AUTHOR]

The ability of Mycobacteria to overcome oxidative stress is of paramount importance for its survival within the host. One of the key enzymes that are involved in protecting the bacterium from reactive oxygen species is the catalase‐peroxidase (KatG). However, in strains resistant to the antibiotic isoniazid, KatG is rendered ineffective, which is associated with an increased expression of alkylhydroperoxide reductase subunit C (AhpC). Mycobacterial AhpC possesses a unique helical displacement when compared to its bacterial counterparts. Here, via mutagenesis studies, we demonstrate the importance of this helix for redox modulation of the catalytic activity of AhpC. Along with structural insights from crystallographic data, the impact of critical residues on the structure and flexibility of the helix and on AhpC oligomerization is described. [ABSTRACT FROM AUTHOR]

Staphylococcus aureus is one of the main causative agent of infections acquired in both community and hospital environment. In this context, photodynamic therapy (PDT) consists in using a photosensitizer that, activated by light, evokes the formation of reactive oxygen species (ROS), which lead to the death of microorganisms due to oxidative damage; it is useful tool since this action, harmful to pathogens, does not significantly injure human cells. In view of this, this work proposes a more in-depth study on the use of resveratrol (RSV) as a possible photosensitizer. It was observed, in the intradermal infection model in animals' ear dermis, that photoactivated resveratrol promotes an increase in myeloperoxidase expression with reduced bacterial load in the draining lymph node. Besides that, the draining lymph node of the animals treated with photoactivated RSV controls inflammation through IL-10 production. These are pioneers data and this work being a pilot study; then, other works must be conducted with the objective of elucidate the photoactivated resveratrol mechanism of action. [ABSTRACT FROM AUTHOR]

Background: Colon cancer (CC) is a common malignant cancer. Recently, circFNDC3B was found to exert biological function in multiple cancers. However, it was unclear whether the potential protein encoded by circFNDC3B is involved in carcinogenesis of CC. Methods: We used Sanger sequence and RNase R digestion assay to confirm the existence of circFNDC3B, and quantitative real-time PCR was used to evaluate the circRNA's expression. Then fluorescence in situ hybridization (FISH) was performed to study location of circFNDC3B. The identification of protein encoded by circFNDC3B was performed using LC-MS/MS. The function of circFNDC3B-218aa on proliferation, invasion and migration were assessed by CCK8 assays, colony formation assays, transwell assays, wound-healing assays and animal experiments. RNA-sequencing and western blot were used to identify the gene regulated by circFNDC3B-218aa. Finally, glucose metabolism-related assays were performed to further investigate function of circFNDC3B-218aa. Results: CircFNDC3B was localized mostly in the cytoplasm, and was decreased in CC cell lines and tissues. The patients with low circFNDC3B expression had a shorter OS (P = 0.0014) than patients with high expression. Moreover, circFNDC3B inhibited the proliferation, invasion and migration of CC cells. Next, we identified that circFNDC3B could encode a novel protein circFNDC3B-218aa. Furthermore, circFNDC3B-218aa, not circFNDC3B, inhibited the proliferation, invasion and migration of CC. Additionally, the in vivo experiments implied that up-regulated circFNDC3B-218aa exhibited an inhibitory effect on CC progression. By RNA-sequencing, western blot and glucose metabolism-related assays, we found that circFNDC3B-218aa inhibited the expression of Snail, and subsequently promoted the tumor-suppressive effect of FBP1 in CC. Conclusions: The novel circFNDC3B-218aa may serve as a tumor suppressive factor and potential biomarker which may supply the potential therapeutic target for CC. [ABSTRACT FROM AUTHOR]