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Abstract Objective Previous studies have shown that tumor mutation burden (TMB) in cancer is associated with prognosis. The purpose of this study is to identify TMB related genes in gastric cancer (GC) and to explore their prognostic value. Methods In our research, weighted gene coexpression network analysis (WGCNA) algorithm was used to cluster the most relevant TMB modules in the Cancer Genome Atlas (TCGA) database. Limma package was used to screen the differentially expressed genes, and the intersection was identified as hub genes. We used gene expression profiling interactive analysis (GEPIA) and survival algorithm to analyze the clinical characteristics and prognosis of hub genes in tumor and normal tissue samples of TCGA and Gene Expression Omnibus cohort respectively. We also used CIBERSORT algorithm to calculate the proportion of 22 tumor immune cells in the high and low expression subgroups of hub genes. In addition, we used gene set enrichment analysis (GSEA) to predict the biological function of hub genes. P 1, and mm > 0.8). We found that the expression of SCN7A in tumor tissues was lower than that in normal tissues, and its expression level was also related to overall survival rate and tumor stage. GSEA analysis showed that SCN7A low expression group was enriched with "DNA replication", "base extension repair" and "proteasome" gene sets in GC. In addition, we found that there were significant differences in the infiltration degree of 7 kinds of immune cells between the two groups. Conclusion TMB can indicate the prognosis of gastric cancer. SCN7A is a hub gene associated with TMB, and its low expression is associated with better prognosis.

Background: Esophageal squamous cell carcinoma (ESCC) has a poor prognosis and occurs with high frequency in China. In particular, Fujian is one of the high-incidence areas of ESCC in China and the somatic mutation profile of ESCC there remains unclear. Patients and methods: Whole-exome sequencing (WES) was performed in 49 matched ESCC tumor-normal specimens to examine the somatic mutation profiles. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between mutational profile and survival were derived from Cox regression model. Results: We constructed a preliminary somatic mutation profiling of ESCC in Fujian. Exome sequencing data showed that the main base substitutions in ESCC were C > T transformation (close to 50%), C > A and T > C transversion. The study identified 21 significantly mutated genes, including 8 driver genes and 11 predicted driver genes. Among the 19 driver or predicted driver genes, 9 are novel (OBSCN, PKHD1L1, FSIP2, HRNR, CUBN, CELSR3, SCN7A, TULP4, SRRM2) and 10 have been previously reported. Three mutational signatures were identified to be prevalent in ESCC including Signature_15, Signature_4 and Signature_6, of which Signature_15 was related to prognosis of ESCC (HR 2.81, 95% CI 1.30–6.05; p = 0.008). Survival analysis showed that SCN7A was correlated to overall survival with an HR of 2.76 (95% CI 0.96–7.90, p = 0.058). After controlling for confounding factors such as age, gender, stage and location, the correlation between SCN7A and survival was statistically significant based on multivariate COX regression analysis (HR 4.76, 95% CI 1.20–18.85; p = 0.026, padjust = 0.053). The tumor vascular invasion was associated with SCN7A of ESCC patients (p = 0.028). Conclusion: In summary, this study provided comprehensive analysis of the somatic mutation profiles of ESCC, and identified SCN7A and Signature_15 for the prognosis of ESCC for the first time. The findings might serve as a conceptual basis for molecular diagnosis and prevention of ESCC. [ABSTRACT FROM AUTHOR]

Objective: Previous studies have shown that tumor mutation burden (TMB) in cancer is associated with prognosis. The purpose of this study is to identify TMB related genes in gastric cancer (GC) and to explore their prognostic value.Methods: In our research, weighted gene coexpression network analysis (WGCNA) algorithm was used to cluster the most relevant TMB modules in the Cancer Genome Atlas (TCGA) database. Limma package was used to screen the differentially expressed genes, and the intersection was identified as hub genes. We used gene expression profiling interactive analysis (GEPIA) and survival algorithm to analyze the clinical characteristics and prognosis of hub genes in tumor and normal tissue samples of TCGA and Gene Expression Omnibus cohort respectively. We also used CIBERSORT algorithm to calculate the proportion of 22 tumor immune cells in the high and low expression subgroups of hub genes. In addition, we used gene set enrichment analysis (GSEA) to predict the biological function of hub genes. P < 0.05 was considered statistically significant.Results: In the TCGA cohort, TMB was significantly correlated with the clinical features of GC (P < 0.05). Through WGCNA and differential gene analysis, we identified SCN7A as the hub gene (P < 0.05, |log2fc|> 1, and mm > 0.8). We found that the expression of SCN7A in tumor tissues was lower than that in normal tissues, and its expression level was also related to overall survival rate and tumor stage. GSEA analysis showed that SCN7A low expression group was enriched with "DNA replication", "base extension repair" and "proteasome" gene sets in GC. In addition, we found that there were significant differences in the infiltration degree of 7 kinds of immune cells between the two groups.Conclusion: TMB can indicate the prognosis of gastric cancer. SCN7A is a hub gene associated with TMB, and its low expression is associated with better prognosis. [ABSTRACT FROM AUTHOR]

The SCN family as the encoded gens of sodium channels has been proven to participate in development of cancers including hepatocellular carcinoma (HCC), but the prognostic value of the SCN family is unclear. The results of the UALCAN database had showed that SCN2A/4A/5A/8A mRNA were highly expressed in tumour tissues, while SCN1A/7A/11A mRNA were expressed at low levels (p < 0.05), furthermore, the expression of SCN4A and SCN7A had the similar levels in microarray analysis result. The pan-tumour analysis showed that SCN7A expression was stably lower in tumours than SCN4A expression by TIMER. Both SCN4A and SCN7A were related to tumour grade, nodal metastatic status, histological subtype, patient race, individual cancer stages and TP53 mutation status to varying degrees. The Kaplan–Meier plotter demonstrated that high SCN4A mRNA expression was correlated with better overall survival (OS), disease-specific survival (DSS) and progression-free survival (PFS) and that high expression of SCN7A mRNA was associated with better OS; however, in Asians, higher SCN4A was correlated with better OS and DSS, and higher SCN7A was well correlated with better OS, recurrence-free survival (RFS), DSS and PFS. Analysis of data from cBioPortal showed that mutation of SCN7A was related to RFS and PFS. The protein expression of SCN4A and SCN7A had been detected by Immunohistochemistry. Univariate survival analysis revealed that high SCN7A protein expression was significantly linked to better OS (p = 0.001) and RFS (p = 0.003). Moreover, SCN7A displayed as an independent prognostic factor by multivariate analysis. In addition, a lower methylation level indicated a poor outcome. Pathway and functional enrichment analysis predicted a relationship between SCN7A and the PI3K pathway. In conclusion, there are significant and stable changes in SCN4A and SCN7A expression in HCC. SCN7A expression has better prognostic value and might participate in HCC progression. [ABSTRACT FROM AUTHOR]

The precise mechanisms underlying the detrimental effects of early life adversity (ELA) on adult mental health remain still elusive. To date, most studies have exclusively targeted neuronal populations and not considered neuron-glia crosstalk as a crucially important element for the integrity of stress-related brain function. Here, we have investigated the impact of ELA, in the form of a limited bedding and nesting material (LBN) paradigm, on a glial subpopulation with unique properties in brain homeostasis, the NG2+ cells. First, we have established a link between maternal behavior, activation of the offspring's stress response and heterogeneity in the outcome to LBN manipulation. We further showed that LBN targets the hippocampal NG2+ transcriptome with glucocorticoids being an important mediator of the LBN-induced molecular changes. LBN altered the NG2+ transcriptome and these transcriptional effects were correlated with glucocorticoids levels. The functional relevance of one LBN-induced candidate gene, Scn7a, could be confirmed by an increase in the density of voltage-gated sodium (Nav) channel activated currents in hippocampal NG2+ cells. Scn7a remained upregulated until adulthood in LBN animals, which displayed impaired cognitive performance. Considering that Nav channels are important for NG2+ cell-to-neuron communication, our findings provide novel insights into the disruption of this process in LBN mice.

Within an articulately characterized family of ion channels, the voltage-gated sodium channels, exists a black sheep, SCN7A (Nax). Nax, in contrast to members of its molecular family, has lost its voltage-gated character and instead rapidly evolved a new function as a concentration-dependent sensor of extracellular sodium ions and subsequent signal transducer. As it deviates fundamentally in function from the rest of its family, and since the bulk of the impressive body of literature elucidating the pathology and biochemistry of voltage-gated sodium channels has been performed in nervous tissue, reports of Nax expression and function have been sparse. Here, we investigate available reports surrounding expression and potential roles for Nax activity outside of nervous tissue. With these studies as justification, we propose that Nax likely acts as an early sensor that detects loss of tissue homeostasis through the pathological accumulation of extracellular sodium and/or through endothelin signaling. Sensation of homeostatic aberration via Nax then proceeds to induce pathological tissue phenotypes via promotion of pro-inflammatory and pro-fibrotic responses, induced through direct regulation of gene expression or through the generation of secondary signaling molecules, such as lactate, that can operate in an autocrine or paracrine fashion. We hope that our synthesis of much of the literature investigating this understudied protein will inspire more research into Nax not simply as a biochemical oddity, but also as a potential pathophysiological regulator and therapeutic target. [ABSTRACT FROM AUTHOR]

The sodium channel NaX (encoded by the SCN7A gene) was originally identified in the heart and skeletal muscle and is structurally similar to the other voltage‐gated sodium channels but does not appear to be voltage gated. Although NaX is expressed at high levels in cardiac and skeletal muscle, little information exists on the function of NaX in these tissues. Transcriptional profiling of ion channels in the heart in a subset of patients with Brugada syndrome revealed an inverse relationship between the expression of NaX and NaV1.5 suggesting that, in cardiac myocytes, the expression of these channels may be linked. We propose that NaX plays a role in excitation–contraction coupling based on our experimental observations. Here we show that in cardiac myocytes, NaX is expressed in a striated pattern on the sarcolemma in regions corresponding to the sarcomeric M‐line. Knocking down NaX expression decreased NaV1.5 mRNA and protein and reduced the inward sodium current (INa+) following cell depolarization. When the expression of NaV1.5 was knocked down, ~85% of the INa+ was reduced consistent with the observations that NaV1.5 is the main voltage‐gated sodium channel in cardiac muscle and that NaX likely does not directly participate in mediating the INa+ following depolarization. Silencing NaV1.5 expression led to significant upregulation of NaX mRNA. Similar to NaV1.5, NaX protein levels were rapidly downregulated when the intracellular [Ca2+] was increased either by CaCl2 or caffeine. These data suggest that a relationship exists between NaX and NaV1.5 and that NaX may play a role in excitation–contraction coupling. [ABSTRACT FROM AUTHOR]

Immunohistochemistry for several neurochemical substances was performed on the human incisive papilla and other oral structures. Sodium channel alpha subunit 7 (SCN7A) protein-immunoreactive (IR) Schwann cells and protein gene product 9.5 (PGP 9.5)-IR nerve fibers made nerve plexuses beneath the epithelium of the palate, including the incisive papilla, tongue, and lip. SCN7A immunoreactivity could also be detected in lamellated and nonlamellated capsules of corpuscle endings. Lamellated SCN7A-IR corpuscle endings were mostly restricted to the mucous and cutaneous lips. These endings had thick and spiral-shaped PGP 9.5-IR axons without ramification. Nonlamellated SCN7A-IR corpuscle endings were most numerous in the incisive papilla among the oral regions. On the basis of axonal morphology, the nonlamellated endings were divided into simple and complex types. PGP 9.5-IR terminal axons in the simple type ran straight or meandered with slight ramification, whereas those in the complex type were densely entangled with abundant ramification. Substance P (SP)-, calcitonin gene-related peptide (CGRP)-, and transient receptor potential cation channel subfamily V member 2 (TRPV2)-IR varicose fibers were rarely seen beneath the epithelium of oral structures. The present study indicates that the human incisive papilla has many low-threshold mechanoreceptors with nonlamellated capsules. SP-, CGRP-, and TRPV2-containing nociceptors may be infrequent in the incisive papilla and other oral regions. [ABSTRACT FROM AUTHOR]

Nax, an α-subunit of the sodium channel encoded by the SCN7A gene, has been deemed to be a sensor of the concentration of sodium in the brain and may be involved in salt intake behavior. We inferred that Nax/SCN7A may participate in the regulation of blood pressure and the pathogenesis of essential hypertension (EH). The present case-control study involving 615 hypertensives and 617 normotensives was performed to investigate the association between SCN7A polymorphisms and EH in the Northern Han Chinese population. The three common single nucleotide polymorphisms (SNPs) (rs3791251, rs6738031, rs7565062) in the exons of SCN7A were genotyped with the TaqMan assay. Significant association between SNP rs7565062 and EH was found under the addictive and dominant genetic models (P = 0.024, OR = 1.283, 95%CI [1.033-1.592]; P = 0.013, OR = 1.203, 95%CI [1.040-1.392]; respectively). The three SNPs were in close pair-wise linkage disequilibrium with each other and the haplotype analyses indicated that haplotype G-A-T was significantly associated with increased risk of EH (P = 0.023, OR = 1.290). In conclusion, our data showed that SNP rs7565062 of SCN7A was significantly associated with EH and the allele T of rs7565062 or the related haplotype G-A-T will be a genetic risk factor for EH in the Northern Han Chinese population. [ABSTRACT FROM AUTHOR]

Abstract: Bone pain is one of the most common complications in cancer patients with bone metastases, and has the most significant impact on quality of life for patients. Patients with bone cancer pain may be difficult to treat due to the poor understanding of the mechanisms; therefore, the mechanisms of bone cancer pain required elucidation for developing new therapeutics. Recent studies show that SCN7A/Nax channel serves as a sodium-level sensor of the body fluid that controls the Na-intake behavior by changing the excitability of neurons. In the current study, the expression of SCN7A/Nax and the excitability of primary sensory neurons in bone cancer pain rats were examined. The analgesic effects of knockdown SCN7A/Nax channel using RNAi lentivirus intrathecal treatment were evaluated with a behavioral test. The results showed that implantation of sarcoma induced ongoing and movement-evoked pain behaviors, whereas SCN7A/Nax knockdown prevented the onset of these hyperalgesia. Immunohistochemistry showed that SCN7A/Nax was located in the medium- to large-sized neurons in dorsal root ganglions (DRGs). The proportion of SCN7A/Nax-positive cells was significantly increased in DRGs ipsilateral to sarcoma implantation. Immunostaining results were further confirmed by Western blot and real time-polymerase chain reaction (RT-PCR) analyses. Recording from primary sensory neurons in excised rat dorsal root ganglias, we found that most of SCN7A/Nax-positive neurons exhibited subthreshold oscillations, depolarized resting membrane potential and more negative threshold of action potential. These electrophysiological changes of neurons increased ectopic spike discharge which was thought to be an important generator of chronic pain, however, the hyperexcitability was completely reversed by SCN7A/Nax knockdown. These results demonstrate that enhanced expression of SCN7A/Nax channel within distinct subpopulation of DRG neurons contributes to bone cancer pain by increasing the excitability of these neurons. These findings may lead to novel strategies for the treatment of bone cancer pain. [Copyright &y& Elsevier]

As the resolution of molecular cytogenetic methods continues to improve, it has become increasingly possible to refine genotype-phenotype correlations based upon gene involvement. We report three new patients with nonrecurrent deletions involving subbands of 2q24. These patients were referred for evaluation of developmental delay, but were found to have unique, nonoverlapping clinical features. Patient 1 presented with infantile seizures, microcephaly, and brain anomalies, along with facial dysmorphism, growth retardation, neuromuscular scoliosis, and later with developmental regression. Array comparative genomic hybridization (aCGH) detected an 8 Mb interstitial deletion encompassing the neuronal sodium channel (SCN) gene cluster. Patient 2 presented with growth retardation, congenital heart defect, and hypotonia. Patient 3 presented with developmental delay and behavioral problems. Patients 2 and 3 had no history of seizures, microcephaly, or brain anomalies and were found to have deletions of 2q24, ∼8 Mb and <500 kb respectively, centromeric to and outside the SCN cluster. It has been demonstrated that mutations and copy number variants (CNVs) affecting the SCN gene cluster result in severe, early-onset seizures. It is however, less clear whether haploinsufficiency of regions outside the SCN cluster may result in phenotypically recognizable and clinically significant features. We discuss additional dosage sensitive genes that may exist outside the SCN cluster. Our and published data indicate that 2q24 deletions not involving the SCN cluster are associated with fewer neurobehavioral problems, but may predispose to congenital malformations. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The Scn7a gene encodes for the specific sodium channel NaX, which is considered a primary determinant of sodium sensing in the brain. Only partial data exist describing the NaX distribution pattern and the cell types that express NaX in both the rat and mouse brain. To generate a global view of the sodium detection mechanisms in the two rodent brains, we combined NaX immunofluorescence with fluorescent cell markers to map and identify the NaX-expressing cell populations throughout the network involved in hydromin-eral homeostasis. Here, we designed an anti-NaX antibody targeting the interdomain 2-3 region of the NaX channel's α-subunit. In both the rat and mouse, NaX immunostaining was colocalized with vimentin positive cells in the median eminence and with magnocel-lular neurons immunopositive for neurophysin associated with oxytocin or vasopressin in both the supraoptic and paraventricular nuclei. NaX immunostaining was also detected in neurons of the area postrema. In addition to this common NaX expression pattern, several differences in NaX immunostaining for certain structures and cell types were found between the rat and mouse. NaX was present in both NeuN and vimentin positive cells in the subfornical organ and the vascular organ of the lamina terminalis of the rat whereas NaX was only colocalized with vimentin positive cells in the mouse circumventricular organs. In addition, NaX immunostaining was specifically observed in NeuN immunopositive cells in the median preoptic nucleus of the rat. Overall, this study characterized the NaX-expressing cell types in the network controlling hydromineral homeostasis of the rat and mouse. NaX expression pattern was clearly different in the nuclei of the lamina terminalis of the rat and mouse, indicating that the mechanisms involved in systemic and central Na+ sensing are specific to each rodent species. [ABSTRACT FROM AUTHOR]

The precise mechanisms underlying the detrimental effects of early life adversity (ELA) on adult mental health remain still elusive. To date, most studies have exclusively targeted neuronal populations and not considered neuron-glia crosstalk as a crucially important element for the integrity of stress-related brain function. Here, we have investigated the impact of ELA, in the form of a limited bedding and nesting material (LBN) paradigm, on a glial subpopulation with unique properties in brain homeostasis, the NG2+ cells. First, we have established a link between maternal behavior, activation of the offspring's stress response and heterogeneity in the outcome to LBN manipulation. We further showed that LBN targets the hippocampal NG2+ transcriptome with glucocorticoids being an important mediator of the LBN-induced molecular changes. LBN altered the NG2+ transcriptome and these transcriptional effects were correlated with glucocorticoids levels. The functional relevance of one LBN-induced candidate gene, Scn7a , could be confirmed by an increase in the density of voltage-gated sodium (Na v ) channel activated currents in hippocampal NG2+ cells. Scn7a remained upregulated until adulthood in LBN animals, which displayed impaired cognitive performance. Considering that Na v channels are important for NG2+ cell-to-neuron communication, our findings provide novel insights into the disruption of this process in LBN mice., Competing Interests: GW reported having received lecture/consultancy fees from H. Lundbeck A/S, Servier SA, Astra Zeneca AB, Eli Lilly A/S, Sun Pharma Pty Ltd, Pfizer Inc, Shire A/S, HB Pharma A/S, Arla Foods A.m. b.A., Alkermes Inc, and Mundipharma International Ltd., Janssen AB. All other authors report no biomedical financial interests or potential conflicts of interest. This manuscript has been posted on a preprint server., (© 2021 The Authors.)

The sodium channel Na X (encoded by the SCN7A gene) was originally identified in the heart and skeletal muscle and is structurally similar to the other voltage-gated sodium channels but does not appear to be voltage gated. Although Na X is expressed at high levels in cardiac and skeletal muscle, little information exists on the function of Na X in these tissues. Transcriptional profiling of ion channels in the heart in a subset of patients with Brugada syndrome revealed an inverse relationship between the expression of Na X and Na V 1.5 suggesting that, in cardiac myocytes, the expression of these channels may be linked. We propose that Na X plays a role in excitation-contraction coupling based on our experimental observations. Here we show that in cardiac myocytes, Na X is expressed in a striated pattern on the sarcolemma in regions corresponding to the sarcomeric M-line. Knocking down Na X expression decreased Na V 1.5 mRNA and protein and reduced the inward sodium current (I Na+ ) following cell depolarization. When the expression of Na V 1.5 was knocked down, ~85% of the I Na+ was reduced consistent with the observations that Na V 1.5 is the main voltage-gated sodium channel in cardiac muscle and that Na X likely does not directly participate in mediating the I Na+ following depolarization. Silencing Na V 1.5 expression led to significant upregulation of Na X mRNA. Similar to Na V 1.5, Na X protein levels were rapidly downregulated when the intracellular [Ca 2+ ] was increased either by CaCl 2 or caffeine. These data suggest that a relationship exists between Na X and Na V 1.5 and that Na X may play a role in excitation-contraction coupling., (© 2020 International Union of Biochemistry and Molecular Biology.)

The Scn7a gene encodes for the specific sodium channel Na(X), which is considered a primary determinant of sodium sensing in the brain. Only partial data exist describing the Na(X) distribution pattern and the cell types that express Na(X) in both the rat and mouse brain. To generate a global view of the sodium detection mechanisms in the two rodent brains, we combined Na(X) immunofluorescence with fluorescent cell markers to map and identify the Na(X)-expressing cell populations throughout the network involved in hydromineral homeostasis. Here, we designed an anti-Na(X) antibody targeting the interdomain 2-3 region of the Na(X) channel's α-subunit. In both the rat and mouse, Na(X) immunostaining was colocalized with vimentin positive cells in the median eminence and with magnocellular neurons immunopositive for neurophysin associated with oxytocin or vasopressin in both the supraoptic and paraventricular nuclei. Na(X) immunostaining was also detected in neurons of the area postrema. In addition to this common Na(X) expression pattern, several differences in Na(X) immunostaining for certain structures and cell types were found between the rat and mouse. Na(X) was present in both NeuN and vimentin positive cells in the subfornical organ and the vascular organ of the lamina terminalis of the rat whereas Na(X) was only colocalized with vimentin positive cells in the mouse circumventricular organs. In addition, Na(X) immunostaining was specifically observed in NeuN immunopositive cells in the median preoptic nucleus of the rat. Overall, this study characterized the Na(X)-expressing cell types in the network controlling hydromineral homeostasis of the rat and mouse. Na(X) expression pattern was clearly different in the nuclei of the lamina terminalis of the rat and mouse, indicating that the mechanisms involved in systemic and central Na(+) sensing are specific to each rodent species.