• Genetic variants
• HBV-related hepatocellular carcinoma
• NLRP3 inflammasome
• Overall survival

• Humans
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/virology
• Liver Neoplasms/genetics
• Liver Neoplasms/mortality
• Liver Neoplasms/virology
• Polymorphism, Single Nucleotide
• NLR Family, Pyrin Domain-Containing 3 Protein/genetics
• Female
• Male
• Middle Aged
• Hepatitis B virus
• Hepatitis B/complications
• Quantitative Trait Loci
• Inflammasomes/genetics
• Nerve Tissue Proteins/genetics
• Prognosis
• Survival Rate
• Aged
• Adult

• 2023GXNSFBA026091 the Joint Project on Regional High-Incidence Diseases Research of Guangxi Natural Science Foundation
• AB18050020 the Key Research and Development Project of Guangxi
• GXMUYSF202121 the Youth Science Foundation of Guangxi Medical University
• 2021KY0099 Youth and Middle-aged Scientific and Technological Innovation Leading Talents Program of the Corps
• GKE-KF202007 Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education
• D17011 Overseas Expertise Introduction Center for Discipline Innovation of Food Nutrition and Human Health (111 Center)
• the Key Research and Development Project of Guangxi

• Amyloid precursor protein
• Amyloid β
• Metabolic disease

• Amyloid beta-Peptides/metabolism
• Amyloid beta-Protein Precursor/metabolism
• Animals
• Humans
• Metabolic Diseases/metabolism

The significance of cysteine cathepsins for the liberation of thyroid hormones from the precursor thyroglobulin was previously shown by in vivo and in vitro studies. Cathepsin L is most important for thyroglobulin processing in mice. The present study aims at specifying the possible contribution of its closest relative, cysteine cathepsin L2/V, to thyroid function. Immunofluorescence analysis on normal human thyroid tissue revealed its predominant localization at the apical plasma membrane of thyrocytes and within the follicle lumen, indicating the secretion of cathepsin V and extracellular tasks rather than its acting within endo-lysosomes. To explore the trafficking pathways of cathepsin V in more detail, a chimeric protein consisting of human cathepsin V tagged with green fluorescent protein (GFP) was stably expressed in the Nthy-ori 3-1 thyroid epithelial cell line. Colocalization studies with compartment-specific markers and analyses of post-translational modifications revealed that the chimeric protein was sorted into the lumen of the endoplasmic reticulum and subsequently transported to the Golgi apparatus, while being N-glycosylated. Immunoblotting showed that the chimeric protein reached endo-lysosomes and it became secreted from the transduced cells. Astonishingly, thyroid stimulating hormone (TSH)-induced secretion of GFP-tagged cathepsin V occurred as the proform, suggesting that TSH upregulates its transport to the plasma membrane before it reaches endo-lysosomes for maturation. The proform of cathepsin V was found to be reactive with the activity-based probe DCG-04, suggesting that it possesses catalytic activity. We propose that TSH-stimulated secretion of procathepsin V is the default pathway in the thyroid to enable its contribution to thyroglobulin processing by extracellular means.

• cysteine cathepsins
• green fluorescent protein tagging
• protein trafficking
• secretion
• thyroid epithelial cells
• thyroid stimulating hormone

• Cysteine cathepsins
• Non-canonical trafficking
• Nuclear forms
• Proliferation-promoting
• Thyroid cancer

• Cathepsins/genetics
• Cell Nucleus/genetics
• Cysteine Endopeptidases/genetics
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• Lysosomes/genetics
• Thyroid Epithelial Cells/metabolism
• Thyroid Gland/metabolism
• Thyroid Neoplasms/genetics
• Thyroid Neoplasms/pathology

• AML1/ETO+
• amyloid precursor protein
• matrix metalloproteinase-2
• microRNA-144
• migration

• Aging
• Alzheimer disease
• Amyloid precursor protein
• Amyloidogenic pathway
• Cancer
• Non- amyloidogenic pathway

• Amyloid precursor protein
• Breast cancer
• Cancer subtype
• Immunohistochemistry
• Nodal metastatsis
• Patient survival

• Adult
• Aged
• Aged, 80 and over
• Female
• Humans
• Middle Aged
• Young Adult
• Amyloid beta-Protein Precursor/adverse effects
• Breast Neoplasms/complications
• Breast Neoplasms/psychology
• Prognosis

• Health and Medical Research Fund of Hong Kong

• ADP-ribosylation factor (ARF)
• ELMO1
• FE65
• Ras-related C3 botulinum toxin substrate 1 (Rac1)
• amyloid precursor protein (APP)
• amyloid β A4 precursor protein-binding family B member 1
• guanine nucleotide exchange factor (GEF)
• neurite outgrowth

Amyloid precursor protein (APP) has been reported to be highly expressed in acute myeloid leukemia (AML)1-eight-twenty one (ETO)-positive AML. In the present study, the clinical and prognostic significance of APP expression was assessed in 65 patients with AML1-ETO-positive AML using reverse transcription-quantitative polymerase chain reaction. The patients were divided into an APP-high expression (APP-H) group (n=32) and an APP-low expression (APP-L) group (n=33) according to the cut-off value of APP relative expression, which was calculated by receiver operating characteristic curve analysis. It was observed that C-KIT mutations (14/32 vs. 3/33, P=0.009), white blood cell count (median, 23.2×10⁹ vs. 12.4×10⁹ cells/l; P=0.011) and bone marrow cellularity (median, 91.0 vs. 84.0%; P=0.039) and incidence of extramedullary leukemia (11/32 vs. 3/33, P=0.013) were all significantly increased in the APP-H group compared with the APP-L group. Furthermore, significantly lower rate of cumulative two-cycle complete remission (83.9 vs. 100%, P=0.016), major molecular remission following two courses of consolidation (34.5 vs. 71.4%, P=0.005), and poorer relapse-free survival (RFS) (33.5±5.2% vs. 76.3±6.9%, P<0.001) and overall survival (OS) (44.5±7.0% vs. 81.9±5.8%, P=0.002) were associated with APP overexpression. Multivariate analysis revealed that APP overexpression was a significant adverse factor affecting both RFS and OS. Taken together, these data suggest that APP may be correlated with C-KIT mutations and involved in leukemia cell proliferation, and its overexpression has an adverse effect on the prognosis in AML1-ETO-positive AML.

• AML1-ETO
• acute myeloid leukemia
• amyloid precursor protein
• clinical significance
• prognosis

The purpose of this study was to find disease-associated genes and potential mechanisms in head and neck squamous cell carcinoma (HNSCC) with deoxyribonucleic acid microarrays. The gene expression profiles of GSE6791 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were obtained with packages in R language and STRING constructed protein–protein interaction (PPI) network of the DEGs with combined score >0.8. Subsequently, module analysis of the PPI network was performed by Molecular Complex Detection plugin and functions and pathways of the hub gene in subnetwork were studied. Finally, overall survival analysis of hub genes was verified in TCGA HNSCC cohort. A total of 811 DEGs were obtained, which were mainly enriched in the terms related to extracellular matrix (ECM)–receptor interaction, ECM structural constituent, and ECM organization. A PPI network was constructed, consisting of 401 nodes and 1,254 edges and 15 hub genes with high degrees in the network. High expression of 4 genes of the 15 genes was associated with poor OS of patients in HNSCC, including PSMA7, ITGA6, ITGB4, and APP. Two significant modules were detected from the PPI network, and the enriched functions and pathways included proteasome, ECM organization, and ECM–receptor interaction. In conclusion, we propose that PSMA7, ITGA6, ITGB4, and APP may be further explored as potential biomarkers to aid HNSCC diagnosis and treatment.

• function and pathway analysis
• head and neck squamous cell carcinoma
• interaction network
• prognostic biomarkers

• RNA-sequencing
• miRNA
• notch signaling pathway
• pneumonia
• protein-protein interaction
• target

The nervous system is now recognized to be a relevant component of the tumor microenvironment. Receptors for neuropeptides and neurotransmitters have been identified in breast cancer. However, very little is known about the role of neurogenes in regulating breast cancer progression. Our purpose was to identify neurogenes associated with breast cancer tumorigenesis with a potential to be used as biomarker and/or targets for treatment. We used three databases of human genes: GeneGo, GeneCards and Eugenes to generate a list of 1266 relevant neurogenes. Then we used bioinformatics tools to interrogate two published breast cancer databases SAGE and MicMa (n=96) and generated a list of 7 neurogenes that are differentially express among breast cancer subtypes. The clinical potential was further investigated using the GOBO database (n=1881). We identified 6 neurogenes that are differentially expressed among breast cancer subtypes and whose expression correlates with prognosis. Histamine receptor1 (HRH1), neuropilin2 (NRP2), ephrin-B1 (EFNB1), neural growth factor receptor (NGFR) and amyloid precursor protein (APP) were differentially overexpressed in basal and HER2-enriched tumor samples and syntaxin 1A (STX1A) was overexpressed in HER2-enriched and luminal B tumors. Analysis of HRH1, NRP2, and STX1A expression using the GOBO database showed that their expression significantly correlated with a shorter overall survival (p < 0.0001) and distant metastasis-free survival (p < 0.0001). In contrast, elevated co-expression of NGFR, EFNB1 and APP was associated with longer overall (p < 0.0001) and metastasis-free survival (p < 0.0001). We propose that HRH1, NRP2, and STX1A can be used as prognostic biomarkers and therapeutic targets for basal and HER2-enriched breast cancer subtypes.

• breast cancer
• neurogenes
• neuropeptides
• neurotransmitters
• tumor microenvironment

miRNAs (microRNAs) are a set of endogenous and small non-coding RNAs which specifically induce degradation of target mRNAs or inhibit protein translation to control gene expression. Obviously, aberrant miRNA expression in human cells will lead to a serious of changes in protein-protein interaction network (PPIN), thus to activate or inactivate some pathways related to various diseases, especially carcinogenesis. In this study, we systematically constructed the miRNA-regulated co-expressed protein-protein interaction network (CePPIN) for 17 cancers firstly. We investigated the topological parameters and functional annotation for the proteins in CePPIN, especially for those miRNA targets. We found that targets regulated by more miRNAs tend to play a more important role in the forming process of cancers. We further elucidated the miRNA regulation rules in PPIN from a more systematical perspective. By GO and KEGG pathway analysis, miRNA targets are involved in various cellular processes mostly related to cell cycle, such as cell proliferation, growth, differentiation, etc. Through the Pfam classification, we found that miRNAs belonging to the same family tend to have targets from the same family which displays the synergistic function of these miRNAs. Finally, the case study on miR-519d and miR-21-regulated sub-network was performed to support our findings.

• Platelets
• RAGE
• Thrombosis
• Tumor cell
• Tumor microenvironment

• Amyloid beta-Peptides/metabolism
• Biomarkers, Tumor
• Blood Platelets/physiology
• Cell Communication/physiology
• HMGB1 Protein/metabolism
• Humans
• Leukocyte L1 Antigen Complex/metabolism
• Ligands
• Neoplasms/diagnosis
• Neoplasms/physiopathology
• Neoplasms/therapy
• Paracrine Communication/physiology
• Platelet Activation/physiology
• Receptor for Advanced Glycation End Products/physiology
• Transforming Growth Factor beta/metabolism
• Tumor Microenvironment/physiology

• Alzheimer's disease
• amyloid precursor protein
• cell surface receptors
• signaling.

• Alternative splicing
• Amyloid beta precursor protein
• Colorectal cancer
• Numb homolog
• Vascular endothelial growth factor A

• Adenocarcinoma/genetics
• Adenocarcinoma/pathology
• Alternative Splicing
• Amplified Fragment Length Polymorphism Analysis
• Amyloid beta-Protein Precursor/genetics
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/pathology
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Membrane Proteins/genetics
• Nerve Tissue Proteins/genetics
• Polymorphism, Restriction Fragment Length
• RNA, Messenger/genetics
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Vascular Endothelial Growth Factor A/genetics

Amyloid-β precursor protein (APP) is a highly conserved single transmembrane protein that has been linked to Alzheimer disease. Recently, the increased expression of APP in multiple types of cancers has been reported where it has significant correlation with the cancer cell proliferation. However, the function of APP in the pathogenesis of breast cancer has not previously been determined. In this study, we studied the pathological role of APP in breast cancer and revealed its potential mechanism.

The expression level of APP in multiple breast cancer cell lines was measured by Western blot analysis and the breast cancer tissue microarray was utilized to analyze the expression pattern of APP in human patient specimens. To interrogate the functional role of APP in cell growth and apoptosis, the effect of APP knockdown in MDA-MB-231 cells were analyzed. Specifically, multiple signal transduction pathways and functional alterations linked to cell survival and motility were examined in in vivo animal model as well as in vitro cell culture with the manipulation of APP expression.

We found that the expression of APP is increased in mouse and human breast cancer cell lines, especially in the cell line possessing higher metastatic potential. Moreover, the analysis of human breast cancer tissues revealed a significant correlation between the level of APP and tumor development. Knockdown of APP (APP-kd) in breast cancer cells caused the retardation of cell growth in vitro and in vivo, with both the induction of p27^kip1 and caspase-3-mediated apoptosis. APP-kd cells also had higher sensitivity to treatment of chemotherapeutic agents, TRAIL and 5-FU. Such anti-tumorigenic effects shown in the APP-kd cells partially came from reduced pro-survival AKT activation in response to IGF-1, leading to activation of key signaling regulators for cell growth, survival, and pro-apoptotic events such as GSK3-β and FOXO1. Notably, knock-down of APP in metastatic breast cancer cells limited cell migration and invasion ability upon stimulation of IGF-1.

The present data strongly suggest that the increase of APP expression is causally linked to tumorigenicity as well as invasion of aggressive breast cancer and, therefore, the targeting of APP may be an effective therapy for breast cancer.

• Amyloid precursor protein
• Cell proliferation
• Copper
• Prostate cancer

• Amino Acid Sequence
• Amyloid beta-Protein Precursor/chemistry
• Amyloid beta-Protein Precursor/metabolism
• Binding Sites
• Brain Neoplasms/metabolism
• Brain Neoplasms/pathology
• Brain Neoplasms/secondary
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Copper/administration & dosage
• Dose-Response Relationship, Drug
• Humans
• Male
• Molecular Sequence Data
• Prostatic Neoplasms/metabolism
• Prostatic Neoplasms/pathology
• Protein Binding
• Protein Structure, Tertiary

• 14845 Cancer Research UK

• Amyloid precursor protein
• Epithelial–mesenchymal transition
• Metalloproteinase
• Prostate cancer

Neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and frontotemporal dementias (FTD), are considered distinct entities, however, there is increasing evidence of an overlap from the clinical, pathological and genetic points of view. All neurodegenerative diseases are characterized by neuronal loss and death in specific areas of the brain, for example, hippocampus and cortex for AD, midbrain for PD, frontal and temporal lobes for FTD. Loss of neurons is a relatively late event in the progression of neurodegenerative diseases that is typically preceded by other events such as metabolic changes, synaptic dysfunction and loss, neurite retraction, and the appearance of other abnormalities, such as axonal transport defects. The brain’s ability to compensate for these dysfunctions occurs over a long period of time and results in late clinical manifestation of symptoms, when successful pharmacological intervention is no longer feasible. Currently, diagnosis of AD, PD and different forms of dementia is based primarily on analysis of the patient’s cognitive function. It is therefore important to find non-invasive diagnostic methods useful to detect neurodegenerative diseases during early, preferably asymptomatic stages, when a pharmacological intervention is still possible. Altered expression of microRNAs (miRNAs) in many disease states, including neurodegeneration, and increasing relevance of miRNAs in biofluids in different pathologies has prompted the study of their possible application as neurodegenerative diseases biomarkers in order to identify new therapeutic targets. Here, we review what is known about the role of miRNAs in the pathogenesis of neurodegeneration and the possibilities and challenges of using these small RNA molecules as a signature for neurodegenerative conditions.

• Alzheimer’s-autism continuum
• anabolic hypothesis
• cranial volume
• neurite overgrowth

• R01 AG018379 NIA NIH HHS
• R01 AG018884 NIA NIH HHS

Introduction. The biological role of amyloid precursor protein (APP) is not well understood, especially in testicular germ cell tumors (TGCTs). Therefore, we aimed to investigate the immunoreactivity (IR) and expression of APP in TGCTs and evaluated its clinical relevance. Materials and Methods. We performed an analysis of immunohistochemistry and mRNA expression of APP in 64 testicular specimens and 21 snap-frozen samples obtained from 1985 to 2004. We then evaluated the association between APP expression and clinicopathological status in TGCTs. Results. Positive APP IR was observed in 9.8% (4/41) of seminomatous germ cell tumors (SGCTs) and 39.1% (9/23) of nonseminomatous germ cell tumors (NGCTs). NGCTs showed significantly more cases of positive IR (P = 0.00870) and a higher mRNA expression level compared with those of SGCTs (P = 0.0140). Positive APP IR was also significantly associated with α-fetoprotein (αFP) elevation (P = 0.00870) and venous invasion (P = 0.0414). Conclusion. We observed an elevated APP expression in TGCTs, especially in NGCTs. APP may be associated with a more aggressive cancer in TGCTs.

• Adult
• Amyloid beta-Protein Precursor/antagonists & inhibitors
• Amyloid beta-Protein Precursor/genetics
• Amyloid beta-Protein Precursor/metabolism
• Blotting, Western
• Cell Adhesion
• Cell Movement
• Cell Proliferation
• Core Binding Factor Alpha 2 Subunit/genetics
• Female
• Humans
• In Situ Hybridization, Fluorescence
• Leukemia, Myeloid, Acute/genetics
• Leukemia, Myeloid, Acute/metabolism
• Leukemia, Myeloid, Acute/pathology
• Leukemic Infiltration/pathology
• Male
• Matrix Metalloproteinase 2/genetics
• Matrix Metalloproteinase 2/metabolism
• Neoplasm Invasiveness
• Oncogene Proteins, Fusion/genetics
• Prognosis
• RNA, Messenger/genetics
• RNA, Small Interfering/genetics
• RUNX1 Translocation Partner 1 Protein
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Tumor Cells, Cultured
• Young Adult

Recognition of overlapping molecular signaling activated by a chemical trigger of cancer and neurodegeneration is new, but the path to this discovery has been long and potholed. Six conferences (1962–1972) examined the puzzling neurotoxic and carcinogenic properties of a then-novel toxin [cycasin: methylazoxymethanol (MAM)-β-d-glucoside] in cycad plants used traditionally for food and medicine on Guam where a complex neurodegenerative disease plagued the indigenous population. Affected families showed combinations of amyotrophic lateral sclerosis (ALS), parkinsonism (P), and/or a dementia (D) akin to Alzheimer’s disease (AD). Modernization saw declining disease rates on Guam and remarkable changes in clinical phenotype (ALS was replaced by P-D and then by D) and in two genetically distinct ALS-PDC-affected populations (Kii-Japan, West Papua-Indonesia) that used cycad seed medicinally. MAM forms DNA lesions – repaired by O⁶-methylguanine methyltransferase (MGMT) – that perturb mouse brain development and induce malignant tumors in peripheral organs. The brains of young adult MGMT-deficient mice given a single dose of MAM show DNA lesion-linked changes in cell-signaling pathways associated with miRNA-1, which is implicated in colon, liver, and prostate cancers, and in neurological disease, notably AD. MAM is metabolized to formaldehyde, a human carcinogen. Formaldehyde-responsive miRNAs predicted to modulate MAM-associated genes in the brains of MGMT-deficient mice include miR-17-5p and miR-18d, which regulate genes involved in tumor suppression, DNA repair, amyloid deposition, and neurotransmission. These findings marry cycad-associated ALS-PDC with colon, liver, and prostate cancer; they also add to evidence linking changes in microRNA status both to ALS, AD, and parkinsonism, and to cancer initiation and progression.

• ALS-PDC
• Alzheimer disease
• BMAA
• DNA damage
• amyotrophic lateral sclerosis
• colon cancer
• formaldehyde
• methylazoxymethanol

• Animals
• Anti-Inflammatory Agents, Non-Steroidal/pharmacology
• Carcinoma/metabolism
• Forkhead Box Protein O3
• Forkhead Transcription Factors/metabolism
• Humans
• Oncogenes/physiology
• Phosphatidylinositol 3-Kinases/metabolism
• Proto-Oncogene Proteins c-akt/metabolism
• Rats
• Signal Transduction/drug effects
• Signal Transduction/physiology
• Sulindac/analogs & derivatives
• Sulindac/pharmacology
• Thyroid Neoplasms/metabolism
• Tumor Cells, Cultured

• Adenocarcinoma/genetics
• Alternative Splicing
• Amyloid beta-Protein Precursor/genetics
• Base Sequence
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• Carcinoma, Non-Small-Cell Lung/genetics
• Carcinoma, Non-Small-Cell Lung/metabolism
• Carcinoma, Non-Small-Cell Lung/pathology
• Case-Control Studies
• Cell Line, Tumor
• Cell Proliferation
• Colonic Neoplasms/genetics
• Colonic Neoplasms/metabolism
• Exons
• Female
• Gene Expression Profiling
• Gene Knockdown Techniques
• Humans
• Lung Neoplasms/genetics
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Male
• Membrane Proteins/antagonists & inhibitors
• Membrane Proteins/genetics
• Microfilament Proteins/genetics
• Nerve Tissue Proteins/antagonists & inhibitors
• Nerve Tissue Proteins/genetics
• Oligonucleotide Array Sequence Analysis
• Organ Specificity
• Pregnancy
• RNA, Messenger/genetics
• RNA, Neoplasm/genetics
• RNA, Small Interfering/genetics
• Receptors, Notch/metabolism
• Signal Transduction
• Vascular Endothelial Growth Factor A/genetics

• MOP-67011 Canadian Institutes of Health Research

• Animals
• Biomarkers, Tumor/analysis
• Cell Line, Tumor
• Clusterin
• Cysteine-Rich Protein 61
• DNA-Binding Proteins
• Humans
• Mice
• Mice, SCID
• Neoplasm Proteins/analysis
• Neoplasm Proteins/metabolism
• Phosphoproteins
• Phosphopyruvate Hydratase
• Proteomics/methods
• Quaternary Ammonium Compounds
• RNA-Binding Proteins
• Thyroid Neoplasms/chemistry
• Thyroid Neoplasms/diagnosis
• Transplantation, Heterologous
• Tumor Suppressor Proteins
• Nucleolin

• Canadian Institutes of Health Research

• tumor suppressor
• neurodegeneration
• cancer
• park2

• Animals
• Autophagy/genetics
• Cell Cycle/genetics
• DNA Repair/genetics
• Humans
• Mitochondria/genetics
• Mitochondria/metabolism
• Neoplasms/genetics
• Neoplasms/metabolism
• Neoplasms/pathology
• Neurodegenerative Diseases/genetics
• Neurodegenerative Diseases/metabolism
• Neurodegenerative Diseases/pathology

• R01 NS086875 NINDS NIH HHS
• T32 CA009685 NCI NIH HHS

• Animals
• Animals, Genetically Modified
• Chromosomes, Artificial, Bacterial
• Comparative Genomic Hybridization/methods
• Disease Models, Animal
• Genes, Tumor Suppressor
• Humans
• In Situ Hybridization, Fluorescence
• Melanoma/genetics
• Oligonucleotide Array Sequence Analysis/methods
• Oncogenes
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics
• Reproducibility of Results
• Rhabdomyosarcoma/genetics
• Zebrafish/genetics
• Zebrafish/metabolism

• R01 CA111560 NCI NIH HHS
• R01-CA111560 NCI NIH HHS