Erb-b2 Receptor Tyrosine Kinase Research Articles

Transcriptome Profiling Reveals Novel Candidate Genes Related to Hippocampal Dysfunction in SREBP-1c Knockout Mice.

Lipid homeostasis is an important component of brain function, and its disturbance causes several neurological disorders, such as Huntington’s, Alzheimer’s, and Parkinson’s diseases as well as mood disorders. Sterol regulatory element-binding protein-1c (SREBP-1c) is a key modulatory molecule involved in lipid homeostasis in the central nervous system. However, little is known about the biological effects of SREBP-1c in the brain. Our previous study uncovered that mice deficient in SREBP-1c exhibit schizophrenia-like behaviors. To investigate whether there are novel molecular mechanisms involved in the neurological aberrations caused by SREBP-1c deficiency, we analyzed the transcriptomes of the hippocampus of SREBP-1c knockout (KO) mice and wild-type mice. We found seven differentially expressed genes (three up-regulated and four down-regulated genes) in the hippocampus of SREBP-1c KO mice. For further verification, we selected the three most significantly changed genes: glucagon-like peptide 2 receptors (GLP2R) involved in hippocampal neurogenesis and neuroplasticity as well as in cognitive impairments; necdin (NDN) which is related to neuronal death and neurodevelopmental disorders; and Erb-B2 receptor tyrosine kinase 4 (ERBB4) which is a receptor for schizophrenia-linked protein, neuregulin-1. The protein levels of GLP2R and NDN were considerably decreased, but the level of ERBB4 was significantly increased in the hippocampus of SREBP-1c KO mice. However, further confirmation is warranted to establish the translatability of these findings from this rodent model into human patients. We suggest that these data provide novel molecular evidence for the modulatory role of SREBP-1c in the mouse hippocampus.

RNA Sequencing for Gene Expression Profiles in Peripheral Blood Mononuclear Cells with Ankylosing Spondylitis RNA.

Several previous studies have attempted to investigate the regulatory mechanisms underlying gene expression in ankylosing spondylitis (AS). However, the specific molecular pathways underlying this condition remain unclear. Previous research used next-generation RNA sequencing to identify a series of differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) when compared between patients with AS and healthy controls, thus implying that these DEGs may be related to AS. Furthermore, by screening these DEGS, it may be possible to facilitate clinical diagnosis and optimize treatment strategies. In order to test this hypothesis, we recruited 15 patients with AS and 15 healthy controls. We randomly selected five subjects from each group of patients for RNA sequencing analysis. Sequence reads were generated by an Illumina HiSeq2500 platform and mapped on to the human reference genome using HISAT2. We successfully identified 973 significant DEGs (p < 0.05) in PBMCs. When compared with controls, 644 of these genes were upregulated (with a fold change (FC) > 2) in AS patients and 329 were downregulated (FC < 0.5). Our analysis identified numerous genes related to immune response. Gene Ontology (GO) analysis indicated that these DEGs were significantly related to the positive regulation of epidermal growth factor-activated receptor activity, the positive regulation of the ERBB (erb-b2 receptor tyrosine kinase) signaling pathway, the differentiation of trophoblast giant cells, oxygen transport, immune-related pathways, and inflammation-related pathways. The DEGs were also closely related to the TNF and NF-κB signaling pathways. Six DEGs were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) curve analysis indicated that IL6 may represent a useful biomarker for diagnosing AS. The development of new biomarkers may help us to elucidate the specific mechanisms involved in the development and progression of AS.

ERBB4 promotes the progression of inflammatory breast cancer through regulating PDGFRA.

BackgroundThe regulatory roles of human epidermal growth factor receptor [erb-b2 receptor tyrosine kinase 4 (ERBB)] family in tumors was received widespread attention. Although ERBB4 was crucial regulator in metastasis of malignant tumors, the exact mechanism of ERBB4 in inflammatory breast cancer (IBC) remains unclarified.MethodsIn this study, we collected IBC tissues and cell lines, and explored the expression levels of ERBB4 and platelet-derived growth factor receptor alpha (PDGFRA) using real-time quantitative polymerase chain reaction (RT-PCR), immunohistochemistry (IHC) and western blot assays. Furthermore, cell viability with ERBB4 silencing in SUM149 cells was examined by MTT assay and cell migration and invasion were detected by transwell assay.ResultsThe data indicated thatERBB4abolishing dramatically depressed capacity of proliferation, migration and invasion of IBC cells. Moreover, PDGFRA was an important factor for the function of ERBB4 and PDGFRA overexpression could, at least, partly rescue the ERBB4 silencing-mediated inhibition in proliferation and metastasis of IBC cells.ConclusionsTake together, we verified the first time that ERBB4 promoted the progression of IBC through regulating PDGFRA. Thus, inhibition of ERBB4 might be a novel therapeutic candidate against IBC.

The efficacy of afatinib in patients with HER2 mutant non-small cell lung cancer: a meta-analysis.

BackgroundErb-b2 receptor tyrosine kinase 2 (ErbB2/HER2) mutation has been found in approximately 2–4% of non-small cell lung cancer (NSCLC) patients and has been identified as one of carcinogenic mutations. Afatinib, a member of irreversible HER family inhibitor, has been investigated by a number of literatures, yet whose therapeutic efficiency remains uncertain in NSCLC with HER2 mutation. To elucidate the clinical efficacy and safety of afatinib in treating HER2 mutant NSCLC, we integrated and reanalyzed the data from current available studies.MethodsWe conducted a systematic literature search for published articles regarding afatinib treating HER2-mutant lung cancer. Eight studies met the inclusion and exclusion criteria. The main outcomes were the objective response rate (ORR) and disease control rate (DCR).ResultsNinety-five patients with HER2 mutations were identified from eight studies. The pooled ORR was 21% (95% CI: 11–34%) and the pooled DCR was 66% (95% CI: 57–76%). The patients harboring A775-G776ins YVMA mutation, the most common subtype of HER2 exon 20 mutation, derived greater clinical benefit. Most adverse events were grade 1–2, except a case of fatal acute renal injury, possibly related to afatinib.ConclusionsAfatinib monotherapy demonstrated frustrating anti-tumor activity with tolerable toxicity in HER2 mutant NSCLC. Based on current available data, we do not recommend the regular application of afatinib in NSCLC with HER2 mutations unless the response heterogeneity with specific genomic variant of HER2 mutation was further clarified.

Clinical importance of neuregulin-4 and its receptor ErbB4 in periodontal disease pathogenesis.

The aim of this clinical trial was to evaluate the levels of Neuregulin-4 (Nrg4), Erb-b2 receptor tyrosine kinase 4 (ErbB4), interleukin (IL)-6, IL-10, nitric oxide synthase (NOS)-2, and arginase (Arg)-1 in periodontal health and disease. This study includes systemically healthy 20 periodontally healthy (H), 20 gingivitis (G), 20 stage II periodontitis (P1), and 20 stage III periodontitis (P2) subjects. Periodontal clinical measurements and samples of gingival crevicular fluid (GCF) and serum were obtained at baseline and 4weeks after non-surgical periodontal treatment (NSPT). Enzyme-linked immunosorbent assay (ELISA) was used to determine ErbB4, Nrg4, IL-6, IL-10, NOS2, and Arg1 levels in all samples. GCF ErbB4 and Nrg4 total amounts and IL-6/IL-10 ratio were significantly higher in G, P1, and P2 groups than H group. Serum NOS2 levels were significantly lower, whereas serum Arg1 levels were higher in H group than the others. The GCF levels of ErbB4 and Nrg4 were significantly decreased after NSPT in G, P1, and P2 groups. Additionally, the GCF levels of ErbB4 and Nrg4 were positively correlated with all clinical parameters and IL-6/IL-10 ratio. Nrg4 and its receptor ErbB4 might have crucial roles in the pathogenesis of periodontal disease. These results should be verified with future prospective studies to further clarify the exact role of those biomarkers.

Intrinsic Genetic and Transcriptomic Patterns Reflect Tumor Immune Subtypes Facilitating Exploring Possible Combinatory Therapy.

The classification of immune subtypes was based on immune signatures highlighting the tumor immuno-microenvironment. It was found that immune subtypes associated with mutation and expression patterns in the tumor. How the intrinsic genetic and transcriptomic alterations contribute to the immune subtypes and how to select drug combinations from both targeted drugs and immune therapeutic drugs according to different immune subtypes are still not clear. Through statistical analysis of genetic alterations and transcriptional profiles of breast invasive carcinoma (BRCA) samples, we found significant differences in the number of somatic missense mutations and frameshift deletions among the different immune subtypes. The high mutation load for somatic missense mutations and frameshift deletions may be explained by the high frequency of mutations and high expression of DNA double-strand break repair pathway genes. Extensive analysis of signaling pathways in both the genetic and transcriptomic levels reveals significantly altered pathways such as tumor protein Tumor Protein P53 (TP53) and receptor tyrosine kinase (RTK)/RAS signaling pathways among different subtypes. Drug targets in the signaling pathways such as mitogen-activated protein kinase kinase kinase 1 (MAP3K1) and Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) show genetic alteration in specific subtypes, which may be potential targets for patients of a specific subtype. More drug targets which show transcriptional difference among immune subtypes were discovered, such as cyclin-dependent kinase (CDK)4, CDK6, Erb-B2 receptor tyrosine kinase 2 (ERBB2), etc. Moreover, differences in functional activity between tumor growth and immune-related pathways also elucidate the extrinsic factors of differences in prognosis and suggest potential drug combinations for different immune subtypes. These results help to explain how intrinsic alterations are associated with the immune subtypes and provide clues for possible combination therapy for different immune subtypes.

Small Non-Coding RNA Profiling Identifies miR-181a-5p as a Mediator of Estrogen Receptor Beta-Induced Inhibition of Cholesterol Biosynthesis in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, representing the most aggressive breast cancer (BC) subtype with limited treatment options due to a lack of estrogen receptor alpha (ERα), progesterone receptor (PR), and Erb-B2 receptor tyrosine kinase 2 (HER2/neu) expression. Estrogen receptor beta (ERβ) is present in a fraction of TNBC patients, where its expression correlates with improved patient outcomes, supported by the fact that it exerts oncosuppressive effects in TNBC cell models in vitro. ERβ is involved in microRNA-mediated regulation of gene expression in hormone-responsive BC cells and could mediate its actions through small noncoding RNAs (sncRNAs) in TNBCs also. To verify this possibility, smallRNA sequencing was performed on three ERβ-expressing cell lines from different TNBC molecular subtypes. Several sncRNAs resulted modulated by ERβ, with a subset being regulated in a tumor subtype-independent manner. Interestingly, sncRNA profiling of 12 ERβ+and 32 ERβ− primary TNBC biopsies identified 7 microRNAs, 1 PIWI-interacting RNA (piRNA), and 1 transfer RNA (tRNA) differentially expressed in ERβ+ compared to ERβ− tumors and cell lines. Among them, miR-181a-5p was found to be overexpressed in ERβ+ tumors and predicted target key components of the cholesterol biosynthesis pathway previously found to be inhibited by ERβ in TNBC cells.

The kinase PERK represses translation of the G-protein–coupled receptor LGR5 and receptor tyrosine kinase ERBB3 during ER stress in cancer cells

As a branch of the unfolded protein response, protein kinase R-like endoplasmic reticulum kinase (PERK) represses global translation in response to endoplasmic reticulum (ER) stress. This pathophysiological condition is associated with the tumor microenvironment in cancer. Previous findings in our lab have suggested that PERK selectively represses translation of some mRNAs, but this possibility awaits additional investigation. In this study, we show that a stem-cell marker protein, leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), is rapidly depleted in colon cancer cells during ER stress, an effect that depended on the PERK-mediated translational repression. Indeed, the PERK inhibition led to the accumulation of premature, underglycosylated forms of LGR5, which were produced only at low levels during proper PERK activation. Unlike the mature LGR5 form, which is constitutively degraded regardless of PERK activation, the underglycosylated LGR5 exhibited a prolonged half-life and accumulated inside the cells without being expressed on the cell surface. We also found that Erb-B2 receptor tyrosine kinase 3 (ERBB3) is subjected to a similarly-regulated depletion by PERK, whereas the epidermal growth factor receptor (EGFR), stress-inducible heat-shock protein family A (Hsp70) member 5 (HSPA5), and anterior gradient 2 protein-disulfide isomerase family member (AGR2) were relatively. insensitive to the PERK-mediated repression of translation. These results indicate that LGR5 and ERBB3 are targets for PERK-mediated translational repression during ER stress.

Neuregulin‐4 Limits Pro‐Inflammatory Cytokine Production in Macrophages

BackgroundPro‐inflammatory macrophages are critical mediators of intestinal inflammation. Over‐aggressive responses from these cells, including elevated cytokine release and prolonged persistence in tissue, may contribute to inflammatory bowel disease. We have previously found that the ErbB4 receptor tyrosine kinase is induced on macrophages by pro‐inflammatory stimulation, and that treatment with the ErbB4‐specific ligand neuregulin‐4 (NRG4) reduces macrophage numbers through apoptosis and ameliorates colitis. This suggests that macrophage‐expressed ErbB4 limits colonic inflammation, but the impact of NRG4/ErbB4 on cytokine regulation in these cells remains untested. We hypothesized that ErbB4 inhibits pro‐inflammatory cytokine production in macrophages.MethodsTo test the role of ErbB4 in regulating cytokine expression, we generated bone‐marrow derived macrophages from mice lacking ErbB4 in cells of myeloid lineage (LysMCre/ErbB4FF) or sex‐matched littermate controls, and activated with IFN□/LPS (pro‐inflammatory M1) or IL‐4 (anti‐inflammatory M2). To test the role of NRG4, we treated activated cells with recombinant ligand at 100 ng/ml for 24 hours, harvesting cells before the onset of NRG4‐induced apoptosis to compare functional effects on cytokine expression. RNA was collected and analyzed for cytokines by qPCR.ResultsPro‐inflammatory M1 activation of macrophages induced NRG4 expression 11‐fold (p=0.01). M1 macrophages from LysMCre/ErbB4FF mice expressed elevated levels of TNF (32% higher, p=0.02) and CXCL1 (69% higher, p=0.01) versus M1 macrophages from littermate controls. No differences in expression were seen in anti‐inflammatory M2 macrophages. NRG4 treatment led to reduced TNF (31% lower, p=0.005) and IL‐1β (16% lower, p=0.01) in M1 macrophages from wild‐type mice.Summary/ConclusionNRG4 reduces pro‐inflammatory cytokine production in macrophages through its receptor, ErbB4. This work suggests that ErbB4 signaling in macrophages drives an anti‐inflammatory feedback loop to limit colonic inflammation.Support or Funding InformationNIH 2R01DK095004‐06A1 (Frey); Crohn's and Colitis Foundation (Frey and Schumacher)

The ErbB3 receptor tyrosine kinase regulates expression of Notch target genes and intestinal stem cell markers.

BackgroundStem cell‐driven regeneration of the intestinal epithelium is important for recovery of damage from insults including inflammation, chemotherapy, and radiation. This process is controlled through tight regulation of intestinal stem cells (ISCs). Our lab has previously reported that intestine‐specific knockout of the receptor tyrosine kinase ErbB3 leads to precocious development of Paneth cells and increased Paneth cell numbers in mice the mouse intestinal epithelium. Since Paneth cells can play a supportive role for ISCs, we tested the hypothesis that altered ErbB3 signaling results in changes in the ISC compartment.MethodsWe crossed ErbB3flox/flox mice with mice expressing villin promoter‐driven Cre to generate an intestinal epithelial‐specific ErbB3 knockout mouse model (ErbB3‐IEKO). Ileal samples were collected from these mice, fixed, and embedded in paraffin for immunostaining. Tissue samples from the ileum were also processed for RNA and protein for qPCR and immunoblots. Samples were probed for Notch target genes and Notch ligands due to the importance of Notch signaling in maintaining the intestinal stem cell compartment. Enteroids were generated from ileum of C57Bl/6 mice and treated with the ErbB3 ligand Nrg‐1β. To activate and inactivate Notch experimentally, enteroids and HT29 cells were treated with valproic acid (VPA) and the γ‐secretase inhibitor DAPT respectively.ResultsqPCR of ErbB3‐IEKO ileum showed increased expression of Lgr5 (rapid‐cycling ISCs) and Bmi1 (facultative ISCs or secretory progenitors capable of regenerating ISCs). Ileal sections also showed increased numbers of Lgr5+ cells by in situ hybridization, and western blots showed increased protein levels of Bmi1 in ErbB3‐IEKO ileum. qPCR of ErbB3‐IEKO ileum showed increased expression of Notch target genes Hey1, Hey2, and Heyl, as well as expression of Notch ligands Dll1, Jag1, and Jag2. Enteroids treated with Nrg‐1β had decreased expression of Hey1, Lgr5, and Bmi1. Enteroids and HT29 cells treated with VPA to activate Notch had decreased expression of ErbB3 RNA; this was abrogated by DAPT treatment.ConclusionErbB3 negatively regulates expression of Lgr5 and Bmi1, markers for fast‐cycling and quiescent ISCs, respectively, indicating a possible role for ErbB3 in the ISC niche. Furthermore, ErbB3 and Notch appear to negatively regulate one another, suggesting a possible mechanism for ErbB3’s effects on ISCs and intestinal cell differentiation.Support or Funding InformationThis work was supported by NIH award R01DK095004.

EGF-Containing Membrane-Bound Mucins: A Hidden ErbB2 Targeting Pathway?

Membrane-bound mucins belong to a heterogeneous family of large O-glycoproteins involved in numerous cancers and inflammatory diseases of the epithelium. Some of them are also involved in protein-protein interactions, with receptor tyrosine kinase ErbB2, and fundamental and clinical data showed that these complexes have a detrimental impact on cancer outcome, thus raising interest in therapeutic targeting. This paper aims to demonstrate that MUC3, MUC4, MUC12, MUC13, and MUC17 have a common evolutionary origin and share a common structural organization with EGF-like and SEA domains. Theoretical structure-function relationship analysis of the conserved domains indicated that the studied membrane-bound mucins share common biological properties along with potential specific functions. Finally, the potential druggability of these complexes is discussed, revealing ErbB2-related pathways of cell signaling to be targeted.

Long Non-Coding RNA Cancer Susceptibility 9 (CASC9) Up-Regulates the Expression of ERBB2 by Inhibiting miR-193a-5p in Colorectal Cancer.

BackgroundEmerging studies have reported that long non-coding RNAs (lncRNAs) were crucial regulators in the progression of colorectal cancer (CRC). LncRNA susceptibility 9 (CASC9) was involved in several cancers; however, its role in CRC remains unknown.MethodsRT-PCR was done to probe the expression of CASC9 and miR-193a-5p in CRC samples. CRC cell lines (HCT116 and SW480) were used as cell models. The biological influence of CASC9 on cancer cells was studied using CCK-8 assay, Transwell assay and TUNEL assay in vitro, and subcutaneous xenotransplanted tumor model in vivo. Interaction between CASC9 and miR-193a-5p was investigated by bioinformatics analysis, RT-PCR, and luciferase reporter assay. The expression level of the downstream gene of miR-193a-5p, erb-b2 receptor tyrosine kinase 2 (ERBB2), was tested by Western blot.ResultsCASC9 was significantly up-regulated in CRC samples, while miR-193a-5p was markedly down-regulated. Overexpression of CASC9 promoted viability, migration and invasion of CRC cells, while overexpression of miR-193a-5p had the opposite effect. CASC9 could down-regulate miR-193a-5p via sponging it, and there was a negative relevancy between CASC9 and miR-193a-5p in CRC samples. CASC9 also enhanced the expression levels of ERBB2, while this effect could be reversed by co-transfection with miR-193a-5p.ConclusionCASC9, an oncogenic lncRNA, was abnormally up-regulated in CRC tissues, and it could indirectly modulate the expression of ERBB2 via reducing the expression level of miR-193a-5p.

Investigating the Homotypic and Heterotypic Interactions of ErbB Receptor Tyrosine Kinases

Human epidermal growth factor receptor family (HER1-4 or ErbB1-4) is vital to cellular homeostasis, and any dysregulation of the receptors leads to serious diseases such as cancer. HER family receptors share similar structures: a ligand-binding extracellular domain, transmembrane domain, juxtamembrane domain, kinase domain, and a C-terminal tail. HER2 has an extracellular domain with an intrinsically closed conformation that does not bind to ligands, and HER3 has a catalytically inactive kinase domain. HER family receptors form an asymmetric dimer to activate the downstream signaling upon ligand binding. With their structural features and their roles in tumorigenesis, researchers have vastly studied EGFR homodimerization and HER1-HER2/ HER2-HER3 heterodimerization as therapeutic targets. However, collective understanding on the communication and the regulation of the HER family network is still elusive due to the difficulties of quantitative assessments of direct receptor-receptor interactions. Here we use pulsed interleaved excitation fluorescence cross correlation spectroscopy (PIE-FCCS) to assess the direct homotypic and heterotypic receptor-receptor interactions of the HER family in live cells before and after ligand stimulation. PIE-FCCS allows us to evaluate the receptor-receptor interactions with quantitative dynamic parameters such as diffusion coefficient, density, binding affinity, and degree of protein co-localization. Accompanied by biochemical functional assays, this study will shed light on the regulatory effect of HER family interactions on downstream signaling.

The Pharmacogenomics "Side-effect" of TP53/EGFR in Non-small Cell Lung Cancer Accompanied with Atorvastatin Therapy: A Functional Network Analysis.

Atorvastatin belongs to the group of statins and is the leading drug for hypercholesterolemia treatment. Although, its anticancer effects are highly appreciated, its properties are still unclear. The aim of this study was to explore the underlying anticancer mechanisms induced by atorvastatin and enlarge the potential target in non-small cell lung cancer. Target genes of atorvastatin were collected by the DrugBank database. Prediction of interaction between primary targets and secondary targets was performed, and protein-protein interaction network was constructed though the STRING. Then, KEGG pathway enrichment analysis was performed with WebGestalt and ClueGO, including the pathways in non-small cell lung cancer. Furthermore, a genomic alteration analysis of the selected seed genes of atorvastatin benefit and non-small cell lung cancer pathway was conducted by cBioPortal. Finally, a survival analysis with the selected seed genes in lung cancer (lung adenocarcinoma, lung squamous cell carcinoma) was conducted using Kaplan-Meier (KM) plotter. To identify seed genes, 65 potential candidate genes were screened as targets for atorvastatin using STRING with DrugBank database, while the KEGG pathway was enriched to get the overlap match of pathways in non-small cell lung cancer. Then 4 seed genes, Epidermal Growth Factor Receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (ERBB2), AKT serine/threonine kinase 1 (AKT1) and tumor protein p53 (TP53), were selected and their genomic alternation were evaluated by cBioPortal. Survival analysis found that TP53 and EGFR showed a significant correlation (log rank P = 3e-07 and 0.023) with lung adenocarcinoma and lung squamous cell carcinoma, according to the KM analysis. Gene-phenotype connectivity for atorvastatin in non-small cell lung cancer was identified using functional/activity network analysis method, and our findings demonstrated that TP53 and EGFR could be the potential targets in cancer patients with atorvastatin therapy.

Clinicopathological characteristics and genetic analysis of pulmonary carcinoid tumors: A single-center retrospective cohort study and literature review.

Pulmonary carcinoid tumors, including typical and atypical carcinoids, are well-differentiated neuroendocrine tumors (NETs) that represent 1–2% of all lung cancer cases. In the present study, all cases of well-differentiated NETs diagnosed at Tianjin Medical University General Hospital (Tianjin, China) between 2006 and 2016 were reviewed, and 20 pulmonary carcinoid cases were identified. The clinical features of these cases were summarized, and the results of pathological and imaging examinations were collated. As a low-grade malignant pulmonary neoplasm, the molecular biological mechanism of pulmonary carcinoids is yet to be elucidated. To investigate the underlying molecular mechanisms behind pulmonary carcinoids and to determine an effective molecular targeted therapeutic strategy, next-generation sequencing (NGS) was performed using tissue samples from six patients to determine additional molecular biological characteristics that may help guide targeted therapy. A total of 27 somatic mutations in 21 genes were detected. Of note, mutations in the KIT proto-oncogene receptor tyrosine kinase, Erb-B2 receptor tyrosine kinase 4, MET proto-oncogene receptor tyrosine kinase and insulin-like growth factor 1 genes occurred in two out of six cases. Since treatments for advanced carcinoids are relatively ineffective, molecular profiling may contribute to the identification of novel treatments. In addition, the literature on mutations in pulmonary carcinoids was reviewed and available clinical information and features of this tumor type were summarized.

LncRNA TMPO-AS1 facilitates the proliferation and metastasis of NSCLC cells by up-regulating ERBB2 via sponging miR-204-3p.

Introduction:This study aims at probing into the expression and biological function of long non-coding RNA (lncRNA) TMPO-AS1 in non-small cell lung cancer (NSCLC), and exploring its regulatory role for miR-204-3p and erb-b2 receptor tyrosine kinase 2 (ERBB2).Methods:In this study, paired NSCLC samples were collected, and the expression levels of TMPO-AS1, miR-204-3p and ERBB2 were examined by quantitative real-time polymerase chain reaction (qRT-PCR); proliferative ability and colony formation ability were detected by CCK-8 assay and plate colony formation assay, respectively; flow cytometry was performed to detect the effect of TMPO-AS1 on apoptosis; Transwell assay was used to detect the changes of migration and invasion; qRT-PCR and Western blot were utilised to analyse the changes of miR-204-3p and ERBB2 regulated by TMPO-AS1; luciferase reporter gene assay and RNA immunoprecipitation assay were employed to determine the regulatory relationship between TMPO-AS1 and miR-204-3p.Results:We demonstrated that TMPO-AS1 was significantly up-regulated in cancerous tissues of NSCLC samples, and positively correlated with the expression of ERBB2, while negatively correlated with miR-204-3p. After transfection of TMPO-AS1 shRNAs into NSCLC cells, the malignant phenotypes of NSCLC cells were significantly inhibited, while overexpression of TMPO-AS1 had opposite effects; TMPO-AS1 was also demonstrated to regulate the expression of miR-204-3p by sponging it, and indirectly modulate the expression of ERBB2.Conclusion:Collectively, we conclude that TMPO-AS1 has the potential to be the ‘ceRNA’ to regulate the expression of ERBB2 by sponging miR-204-3p in NSCLC.

Genomic Profiling and Clinicopathological Characteristics of Neuroendocrine Tumors of the Lung in East Asian Patients.

In recent years, the genomic landscape of neuroendocrine tumors (NETs) of the lung has been investigated. However, more data are necessary to elucidate the heterogeneous nature of NETs, especially in East Asian patients. A total of 64 patients who underwent surgical resection for lung NETs [26 typical or atypical carcinoid tumors, 21 large-cell neuroendocrine carcinomas (LCNECs), and 19 small-cell lung carcinomas (SCLCs)] were enrolled, and samples from 46 patients were subjected to targeted next-generation sequencing. Co-mutations of tumor protein p53 (TP53) and RB transcriptional corepressor 1 (RB1) were detected in 15%, 42%, and 93% of carcinoid tumors, LCNECs, and SCLCs, respectively. Oncogenic or targetable genetic alterations identified in this study included mutations of KRAS proto-oncogene (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), ALK receptor tyrosine kinase (ALK), mitogen-activated protein kinase kinase 1 (MAP2K1), and isocitrate dehydrogenase 1 (IDH1), as well as amplifications of erb-b2 receptor tyrosine kinase 2 (ERBB2), fibroblast growth factor receptor 1 (FGFR1), CD274 molecule (CD274), and MYCN proto-oncogene (MYCN). These alterations were more frequently found in high-grade NETs than in carcinoid tumors (33.3% vs. 7.7%). Programmed cell death-ligand 1 expression was strongly associated with the LCNEC subtype among NETs (p=0.002). The mutational status of TP53 and RB1 was significantly associated with NET subtypes in East Asian patients. Targeted therapy or immunotherapy may serve as a treatment option in a subset of patients with high-grade NETs.

Expression of Periostin in Cancer-associated Fibroblasts in Mammary Cancer in Female Dogs.

Mammary neoplasms, like breast neoplasms in women, are one of the most common tumours in female dogs. Cancer-associated fibroblasts (CAFs) found in the tumour stroma play a role in angiogenesis and increase cell migration, contributing to tumour growth and progression, as well as metastasis. The aim of our work was to determine the level of periostin (POSTN) expression in CAFs in mammary tumours of female dogs. The research material consisted of 77 carcinomas and 24 adenomas of the mammary ridge in female dogs. Immunohistochemistry tests were performed using antibodies directed against the antigens POSTN, Ki-67, ERB-B2 receptor tyrosine kinase 2 (HER2), vimentin, and alpha smooth muscle actin (αSMA). Expression of POSTN at the mRNA level was determined using real-time polymerase chain reaction methods in 20 cases of mammary neoplasms. Expression of POSTN in CAFs was observed in 92% of mammary cancer samples and in 25% of mammary adenoma samples in female dogs. A statistically significant increase in POSNT expression in CAFs was found in the carcinomas compared with mammary adenomas in female dogs. Expression of POSTN in CAFs in mammary carcinomas in female dogs positively correlated with the histological malignancy grade of tumours and the expression of Ki-67 proliferative antigen. Our results suggest a role of POSTN on the pathogenesis of mammary tumours in female dogs. Moreover, POSTN may prove to be a useful marker in the evaluation of cancerous stroma of mammary tumours in female dogs, and may have prognostic significance.

Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity

Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity

HER2 Status in Molecular Subtypes of Urothelial Carcinoma of the Renal Pelvis and Ureter.

Erb-b2 receptor tyrosine kinase 2 (ERBB2, also known as HER2) gene amplification or protein overexpression occurs in certain types of urothelial carcinomas. Molecular pathologic classification of urinary bladder cancer using immunohistochemistry has identified basal and luminal subtypes with differing prognoses, but the HER2 status of these subtypes has not been investigated. In addition, research on urothelial carcinoma of the renal pelvis and ureter (UCRPU) has not progressed because of its rarity, though its prognosis is worse than that of bladder cancer. In this study, we evaluated the clinical significance of HER2 status in molecular subtypes of UCRPU. HER2 status (protein overexpression and/or gene amplification) and molecular subtyping were determined for 148 cases of UCRPU (83 and 65 cases in the renal pelvis and ureter, respectively), using immunohistochemistry and fluorescent in situ hybridization, and compared with clinicopathologic factors. Subtype analysis revealed that the cases were 46% basal and 54% luminal. HER2 protein overexpression and/or gene amplification was observed in 14% of UCRPU cases and was significantly more frequent in the luminal subtype than in the basal (22% vs. 4%; P= .0030). Univariate analysis showed that the overall survival of patients with HER2-positive UCRPU was significantly shorter than those with HER2-negative tumors. HER2 protein overexpression and gene amplification were specifically observed in the luminal subtype of UCRPU, suggesting that these cases may respond to HER2-targeted therapies like trastuzumab.