Notch Signaling Pathway Research Articles

Protective Effects of Gastrodin Against Gentamicin-Induced Vestibular Damage by the Notch Signaling Pathway.

Gentamicin is a broad-spectrum antibiotic commonly used in clinical practice. However, the drug causes side effects of ototoxicity, leading to disruption in balance functionality. This study investigated the effect of gastrodin, a prominent compound present in Gastrodia, and the underlying mechanism on the development of gentamicin-induced vestibular dysfunction. Wild-type C57BL/6 mice were randomly assigned to three groups: control, gentamicin, and gentamicin + gastrodin groups. The extent of gentamicin-induced vestibular impairment was assessed through a series of tests including the swimming test, contact righting reflex test, and air-righting reflex. Alterations in vestibular hair cells were monitored through immunofluorescence assay, and cellular apoptosis was observed using TUNEL staining. The mRNA and protein expression of Notch1, Jagged1, and Hes1 was quantified through qRT-PCR, immunofluorescence, and western blot analyses. Gentamicin treatment led to pronounced deficits in vestibular function and otolith organ hair cells in mice. Nevertheless, pretreatment with gastrodin significantly alleviated these impairments. Additionally, the Notch signaling pathway was activated by gentamicin in the utricle, contributing to a notable increase in the expression levels of apoptosis-associated proteins. By contrast, gastrodin treatment effectively suppressed the Notch signaling pathway, thereby mitigating the occurrence of apoptosis. Collectively, these findings underscore the crucial role of gastrodin in safeguarding against gentamicin-induced vestibular dysfunction through the modulation of the Notch signaling pathway. This study suggests the potential of gastrodin as a promising therapeutic agent for preventing vestibular injuries.

Non-coding RNAs as Key Regulators of the Notch Signaling Pathway in Glioblastoma: Diagnostic, Prognostic, and Therapeutic Targets.

Glioblastoma multiforme (GBM) is a highly invasive brain malignancy originating from astrocytes, accounting for approximately 30% of central nervous system malignancies. Despite advancements in therapeutic strategies including surgery, chemotherapy, and radiopharmaceutical drugs, the prognosis for GBM patients remains dismal. The aggressive nature of GBM necessitates the identification of molecular targets and the exploration of effective treatments to inhibit its proliferation. The Notch signaling pathway, which plays a critical role in cellular homeostasis, becomes deregulated in GBM, leading to increased expression of pathway target genes such as MYC, Hes1, and Hey1, thereby promoting cellular proliferation and differentiation. Recent research has highlighted the regulatory role of non-coding RNAs (ncRNAs) in modulating Notch signaling by targeting critical mRNA expression at the post-transcriptional or transcriptional levels. Specifically, various types of ncRNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been shown to control multiple target genes and significantly contribute to the carcinogenesis of GBM. Furthermore, these ncRNAs hold promise as prognostic and predictive markers for GBM. This review aims to summarize the latest studies investigating the regulatory effects of ncRNAs on the Notch signaling pathway in GBM.

Mechanism of Shashen-Maidong herb pair in treating hepatocellular carcinoma using network pharmacology and experimental validation

Ethnopharmacological relevanceHepatocellular carcinoma (HCC) is among the most prevalent malignant tumors globally and represents a significant public health issue worldwide. Immune cell dysfunction is the crucial factor for the formation of immunosuppression microenvironment of HCC. Glehnia littoralis (A.Gray) F.Schmidt ex Miq. (Shashen) and Ophiopogon japonicus (Thunb.) Ker Gawl. (Maidong) are classic herb pair in traditional Chinese medicine (TCM) of nourishing Yin, and is widely applied in the treatment of HCC and possesses multiple immunomodulatory functions. However, the role of the the Shashen-Maidong herb pair (SS-MD) for the management of HCC and the potential mechanisms has not been explicated. Aim of the studyThe purpose of the research is to investigate the potential mechanism of the SS-MD herb pair for the management of HCC. Materials and methodsThe known components of the SS-MD herb pair were preliminarily identified using UPLC-Q-Orbitrap-MS/MS. The active ingredients of SS-MD herb pair in treating HCC were screened by constructing herb-component-target network, and the key therapeutic targets were explored by constructing a protein-protein interaction (PPI) network. The binding affinity of the key targets and components were validated through molecular docking and molecular dynamics simulations. GO biological function and KEGG pathway analyses were operated to elucidate the potential mechanisms of the SS-MD herb pair for the management of HCC. And the mechanism was verified in the tumor bearing mice model and cell co-culture experiments. ResultsNetwork pharmacology prediction revealed 39 active components and 138 targets of the SS-MD herb pair for the treatment of HCC. KEGG analysis mainly focused on Notch signaling pathway and Apoptosis signaling pathway. The targets were enriched in biological functions of lymphocyte effector function and lymphocyte apoptosis. In vivo and in vitro experiments proved that the SS-MD herb pair can improve the proportion of CD8+T cells in the HCC immune microenvironment, regulate its subgroup distribution. SS-MD herb pair promoted CD8+T cells to secrete IL-2, TNF-α, IFN-γ, Granzyme B and Perforin, and inhibited apoptosis by regulating Notch signaling pathway. ConclusionsThis study identified the key components, targets, and signaling pathways of the SS-MD herb pair, confirm that SS-MD herb pair play an immunomodulatory role in treating HCC, provides theoretical support for the collaborative treatment of HCC with TCM.

PLGA-Loaded Nedaplatin (PLGA-NDP) Inhibits 7,12-Dimethylbenz[a]anthracene (DMBA) Induced Oral Carcinogenesis via Modulating Notch Signaling Pathway and Induces Apoptosis in Experimental Hamster Model.

The present study is designed to evaluate the nanotherapeutic efficacy of prepared PLGA-loaded Nedaplatin (PLGA-NDP) against 7,12-dimethyl benz(a)anthracene (DMBA)-induced experimental oral carcinogenesis in hamster buccal pouch (HBP) model. The buccal pouch of golden Syrian hamsters was painted with 0.5% DMBA in liquid paraffin three times a week for 14 weeks, ultimately leading to the development of oral squamous cell carcinoma (OSCC). Oral administration of PLGA-NDP (preinitiation) and Cisplatin delivery (5 mg/kg b.wt) started 1 week before the carcinogen exposure and continued on alternative days. Post-administration of PLGA-NDP (5 mg/kg b.wt) started 2 days after carcinogen (DMBA) induction until the end of the experiment. After the 14th week, we observed that DMBA-painted hamsters exhibited tumor formation, morphological alterations, and well-differentiated OSSC in addition to the responsive molecular proteins during oral carcinogenesis. Furthermore, immunoblotting analysis demonstrated that PLGA-NDP inhibits Notch signaling, as evidenced by downregulation of Bcl-Xl, Bcl-2, p21, PGE2, HGF, and CXCL12 proteins, and upregulation of p53 and Bax. This apoptotic response is crucial for PLGA-NDP to induce apoptosis. In addition, RT-PCR results showed that PLGA-NDP nanoparticles play a downregulatory role in the therapeutic action of the notch signaling gene (Notch1, Notch 2, Hes1, Hey1, and Jagged1) at the mRNA transcription level in HBP carcinoma. Taken together, these data indicate that PLGA-NDP is a potent inhibitor of oral carcinogenesis and the expansion of cells that specifically target the Notch signaling pathway indicates that obstructing Notch signaling could potentially serve as a new and innovative therapeutic approach for oral squamous cell carcinoma (OSCC).

Anti-inflammatory Effects of Vagus Nerve Stimulation Are Mediated by the Notch Signaling Pathway during Sepsis-Associated AKI

Anti-inflammatory Effects of Vagus Nerve Stimulation Are Mediated by the Notch Signaling Pathway during Sepsis-Associated AKI

The toxic effects of exposure to fibrous and fragmented microplastic in juvenile rockfish based on two omics approach

Although the hazards of environmental microplastics (MPs) are well known, it is unclear which of their characteristics have the greatest effects on organism. We investigated the toxic effects of oral administration according to physical properties, including the shape of fragmented polyethylene terephthalate (PET) (FrPET) and fibrous PET (FiPET) MPs. After 72 h of exposure, apoptosis and phagocytic activity varied significantly among juvenile rockfish (Sebastes schlegeli) exposed to both FrPET and FiPET. The levels of immune-related genes and hepatic metabolic activity also increased after exposure to both shapes of MPs, but the variation in responses was greater in fish exposed to FiPET compared with those exposed to FrPET. The transcriptomic and metabolomics analysis results indicated that the maintenance and homeostasis of immune system was affected by oral exposure to FrPET and FiPET. The amino acid metabolic processes were identified in rockfish exposed to FrPET, but the notch signaling pathway were evident in the FiPET exposure group. Metabolomics analysis revealed that oral ingestion of MP fibers led to a stronger inflammatory response and greater oxidative stress in juvenile rockfish. These results can be used to understand environmentally dominant MP toxic effects such as type, size, shapes, as well as to prioritize ecotoxicological management.

Activating Invasion and Metastasis in Small Cell Lung Cancer: Role of the Tumour Immune Microenvironmentand Mechanisms of Vasculogenesis, Epithelial-Mesenchymal Transition, Cell Migration, and Organ Tropism.

Small cell lung cancer (SCLC) harbours the most aggressive phenotype of all lung cancers to correlate with its bleak prognosis. The aggression of SCLC is partially attributable to its strong metastatic tendencies. The biological processes facilitating the metastasis in SCLC are still poorly understood and garnering a deeper understanding of these processes may enable the exploration of additional targets against this cancer hallmark in the treatment of SCLC. This narrative review will discuss the proposed molecular mechanisms by which the cancer hallmark of activating invasion and metastasis is featured in SCLC through important steps of the metastatic pathway, and address the various molecular targets that may be considered for therapeutic intervention. The tumour immune microenvironment plays an important role in facilitating immunotherapy resistance, whilst the poor infiltration of natural killer cells in particular fosters a pro-metastatic environment in SCLC. SCLC vasculogenesis is achieved through VEGF expression and vascular mimicry, and epithelial-mesenchymal transition is facilitated by the expression of the transcriptional repressors of E-cadherin, the suppression of the Notch signalling pathway and tumour heterogeneity. Nuclear factor I/B, selectin and B1 integrin hold important roles in SCLC migration, whilst various molecular markers are expressed by SCLC to assist organ-specific homing during metastasis. The review will also discuss a recent article observing miR-1 mRNA upregulation as a potential therapeutic option in targeting the metastatic activity of SCLC. Treatment of SCLC remains a clinical challenge due to its recalcitrant and aggressive nature. Amongst the many hallmarks used by SCLC to enable its aggressive behaviour, that of its ability to invade surrounding tissue and metastasise is particularly notable and understanding the molecular mechanisms in SCLC metastasis can identify therapeutic targets to attenuate SCLC aggression and improve mortality.

The activation of the Notch signaling pathway by UBE2C promotes the proliferation and metastasis of hepatocellular carcinoma

UBE2C, a ubiquitin-conjugating enzyme, functions as an oncogene in different types of human cancers. Nonetheless, the exact influence of UBE2C on the development of HCC via regulation of ubiquitination remains uncertain. Here, we found that UBE2C displayed elevated levels of expression in HCC and was associated with an unfavorable prognosis, as evidenced by the analysis of the TCGA database and the examination of clinical specimens. The role of UBE2C in HCC revealed its ability to promote the growth and metastasis of HCC. Mechanistically, UBE2C activated Notch signaling, as evidenced by the upregulation of N1ICD and Hes1, crucial components of the Notch pathway, and activation of the RBP-JK luciferase reporter by UBE2C. Finally, rescue experiments demonstrated that the oncogenic role of UBE2C was eliminated through treatment with the Notch inhibitor DAPT, while overexpression of N1ICD alleviated the anticarcinogenic impact of knockdown of UBE2C. Altogether, the results of our study indicate that UBE2C plays a role in the activation of Notch signaling and could potentially serve as a viable target for therapeutic interventions in HCC.

Targeting glioblastoma with a brain-penetrant drug that impairs brain tumor stem cells via NLE1-Notch1 complex

Brain tumor stem cells (BTSCs) are a population of self-renewing malignant stem cells that play an important role in glioblastoma tumor hierarchy and contribute to tumor growth, therapeutic resistance, and tumor relapse. Thus, targeting of BTSCs within the bulk of tumors represents a crucial therapeutic strategy. Here, we report that edaravone is a potent drug that impairs BTSCs in glioblastoma. We show that edaravone inhibits the self-renewal and growth of BTSCs harboring a diverse range of oncogenic mutations without affecting non-oncogenic neural stem cells. Global gene expression analysis revealed that edaravone significantly alters BTSC transcriptome and attenuates the expression of a large panel of genes involved in cell cycle progression, stemness, and DNA repair mechanisms. Mechanistically, we discovered that edaravone directly targets Notchless homolog 1 (NLE1) and impairs Notch signaling pathway, alters the expression of stem cell markers, and sensitizes BTSC response to ionizing radiation (IR)-induced cell death. Importantly, we show that edaravone treatment in preclinical models delays glioblastoma tumorigenesis, sensitizes their response to IR, and prolongs the lifespan of animals. Our data suggest that repurposing of edaravone is a promising therapeutic strategy for patients with glioblastoma.

Anti-Cancer Effects of the Pandanus tectorius Parkinson Extract: Reduction of YAP and TAZ Levels via Inhibition of the Hippo and Notch Signaling Pathways

Anti-Cancer Effects of the <i>Pandanus tectorius</i> Parkinson Extract: Reduction of YAP and TAZ Levels via Inhibition of the Hippo and Notch Signaling Pathways

Prognostic value of PLEKHA4 and its correlation with tumor-infiltrating immune cells in breast cancer: a comprehensive study based on bioinformatics and clinical analysis validation.

Pleckstrin homology containing family A, number 4 (PLEKHA4) plays a role in a number of biological processes in human cells, including cell polarization, growth, and proliferation. However, the relationship between PLEKHA4 expression and survival in breast cancer (BC) remains unclear. The aim of this study is to investigate the potential of PLEKHA4 as a prognostic indicator in BC. We obtained gene expression profiles of BC and normal tissues from the Tumor Immune Estimation Resource (TIMER), UALCAN web. Immunohistochemistry (IHC) staining was performed to investigate the protein expression and prognostic value of PLEKHA4 in BC patients. The prognostic value was analyzed using Kaplan-Meier curve analysis and Cox regression analysis in R software after downloading The Cancer Genome Atlas (TCGA) databases. The correlations between PLEKHA4 and tumor immune infiltrates were investigated via gene set variation analysis (GSVA). Signaling pathways related to PLEKHA4 expression were identified by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Both bioinformatics and IHC results showed that PLEKHA4 was expressed at low levels in BC tissues compared with the adjacent tissues. Furthermore, the expression of PLEKHA4 was negatively correlated with ages (χ2=6.394, P=0.01), molecular subtype (χ2=15.606, P=0.001), lymph node metastasis (χ2=13.753, P=0.004), tumor-node-metastasis (TNM) stage (χ2=22.616, P<0.001). Kaplan-Meier curves implicated low expression of PLEKHA4 was associated with worse survival of BC patients [hazard ratio (HR) =0.46, P=0.01]. Cox regression models showed that low PLEKHA4 expression could be an independent risk factor for BC (HR =0.911, P=0.006). The results of gene set enrichment analysis (GSEA) showed that cell cycle, Notch signaling pathway, nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway, and Rho GTPases were highly enriched in the low PLEKHA4 expression group, as identified by GO and KEGG. Additionally, in BC, PLEKHA4 expression displayed a positive correlation with the infiltration of natural killer (NK) cells (P<0.001), CD8+ T cells (P<0.001), B cells (P<0.001), neutrophils (P<0.001), and dendritic cells (DCs) (P<0.001). The findings indicate that PLEKHA4 is an independent prognostic biomarker associated with key signaling pathways and immune infiltration in BC. Targeting PLEKHA4 may contribute to improving immunotherapy for BC.

Notch-1 regulates collective breast cancer cell migration by controlling intercellular junction and cytoskeletal organization.

Pathological observations show that cancer cells frequently invade the surrounding normal tissue in collective rather than individual cell migration. However, general principles governing collective cell migration remain to be discovered. Different from individual cell migration, we demonstrated that the Notch-1-activation reduced collective cells speed and distances. In particular, Notch-1-activation induced cellular cytoskeletal remodelling, strengthened the intercellular junctions and cell-matrix adhesions. Mechanistically, Notch-1 activation prevented the phosphorylation of GSK-3β and the translocation of cytoplasmic free β-catenin to the nucleus, which increased E-cadherin expression and tight intercellular junctions. Moreover, Notch-1 signalling also activated the RhoA/ROCK pathway, promoting reorganization of F-actin and contractile forces produced by myosin. Further, Notch-1 activation increased cell adhesion to the extracellular substrate, which inhibited collective cell migration. These findings highlight that cell adhesions and cell-cell junctions contribute to collective cell migration and provide new insights into mechanisms of the modulation of Notch-1 signalling pathway on cancer cell malignancy.

MicroRNA-124a promoted the differentiation of bone marrow mesenchymal stem cells into neurons through Notch signal pathway

This study investigated the possible mechanisms of microRNA-124a on the differentiation of bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanism. β-Thiol ethanol induced Notch1 mRNA expression, microRNA-124a inhibitor reduced the effects of β-thiol ethanol on Notch1 mRNA expression in BMSCs. Baicalin induced Hes1 mRNA expression, and microRNA-124a inhibitor reduced the effects of baicalin on Hes1 mRNA expression in BMSCs. Si-Notch1 suppressed Hes1 mRNA expression in BMSCs. Baicalin increased the effects of Notch1 on Hes1 mRNA expression in BMSCs. Si-Notch1 increased cell growth of BMSCs. Baicalin reduced the effects of si-Notch1 on cell growth and the differentiation of BMSCs. We demonstrated that microRNA-124a promoted the differentiation of BMSCs into neurons through Notch/Hes1 signal pathway.

Single-cell transcriptomics reveals e-cigarette vapor-induced airway epithelial remodeling and injury

BackgroundIn recent years, e-cigarettes have been used as alternatives among adult smokers. However, the impact of e-cigarette use on human bronchial epithelial (HBE) cells remains controversial.MethodsWe collected primary HBE cells of healthy nonsmokers and chronic obstructive pulmonary disease (COPD) smokers, and analyzed the impact of e- cigarette vapor extract (ECE) or cigarette smoke extract (CSE) on HBE cell differentiation and injury by single-cell RNA sequencing, immunostaining, HE staining, qPCR and ELISA. We obtained serum and sputum from healthy non- smokers, smokers and e-cigarette users, and analyzed cell injury markers and mucin proteins.ResultsECE treatment led to a distinct differentiation program of ciliated cells and unique patterns of their cell–cell communications compared with CSE. ECE treatment caused increased Notch signaling strength in a ciliated cell subpopulation, and HBE cell remodeling and injury including hypoplasia of ciliated cells and club cells, and shorter cilia. ECE-induced hypoplasia of ciliated cells and shorter cilia were ameliorated by the Notch signaling inhibition.ConclusionsThis study reveals distinct characteristics in e-cigarette vapor-induced airway epithelial remodeling, pointing to Notch signaling pathway as a potential targeted intervention for e-cigarette vapor-caused ciliated cell differentiation defects and cilia injury. In addition, a decrease in SCGB1A1 proteins is associated with e- cigarette users, indicating a potential lung injury marker for e-cigarette users.

Characterization of Endothelial Cell Subclusters in Localized Scleroderma Skin with Single-Cell RNA Sequencing Identifies NOTCH Signaling Pathway

Localized scleroderma (LS) is an autoimmune disease characterized by inflammation and fibrosis, leading to severe cutaneous manifestations such as skin hardening, tightness, discoloration, and other textural changes that may result in disability. While LS shares similar histopathologic features and immune-fibroblast interactions with systemic sclerosis (SSc), its molecular mechanisms remain understudied. Endothelial cells (EC) are known to play a crucial role in SSc but have not been investigated in LS. Single-cell RNA sequencing (scRNA-seq) now allows for detailed examination of this cell type in the primary organ of interest for scleroderma, the skin. In this study, we analyzed skin-isolated cells from 27 LS patients (pediatric and adult) and 17 healthy controls using scRNA-seq. Given the known role of EC damage as an initial event in SSc and the histologic and clinical skin similarities to LS, we focused primarily on endothelial cells. Our analysis identified eight endothelial subclusters within the dataset, encompassing both disease and healthy samples. Interaction analysis revealed that signaling from diseased endothelial cells was predicted to promote fibrosis through SELE interaction with FGFBP1 and other target genes. We also observed high levels of JAG in arterial endothelial cells and NOTCH in capillary endothelial cells, indicating the activation of a signaling pathway potentially responsible for epidermal abnormalities and contributing to LS pathogenesis. In summary, our scRNA-seq analysis identified potential disease-propagating endothelial cell clusters with upregulated pathways in LS skin, highlighting their importance in disease progression.

Abstract C100: Defining the role of Hedgehog, Notch, and Wnt signaling pathways in aggressive lethal prostate cancer of Hispanic men

Abstract Background: Hispanic American (HA) men with prostate cancer (PC) are more likely to have more aggressive and advanced diseases and greater mortality rates compared to non-Hispanic white (NHW) men. Resistance to the current anticancer therapy is the major hurdle that leads to poor clinical outcomes. Hedgehog, Notch, and Wnt signaling pathways play a crucial role in development, progression, and resistance to the various anticancer therapies. Here, we characterized the enrichment of Hedgehog, Notch, and Wnt signaling pathways and molecular tumors differences between HA and NHW patients. Methods: Our data consist of 88 PC tumors samples (HA=34, NHW=54) obtained from treatment-naive metastatic hormone-sensitive prostate cancer (mHSPC) that were analyzed by next-generation sequencing (592, NextSeq; Whole Exome Sequencing, NovaSeq) and Whole Transcriptome Sequencing (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). Pathway enrichment was determined by Gene Set Enrichment Analysis (GSEA, Broad Institute) by measurable TPM (transcripts per kilobase million). The medical records were reviewed in a deidentified fashion for clinical features. Statistical significance was determined using chi-square and Mann-Whitney U (p&amp;lt;0.05). Results: HA PC had enrichment of Hedgehog signaling (NES: 1.45, FDR=0.04), Notch signaling (NES: 1.41, FDR=0.07), and Wnt/β-catenin signaling (NES: 1.38, FDR=0.11) pathways compared to NHW tumors. HA tumors had higher expression of genes (HES1, Notch1, WNT1, WNT2; FC:1.1-2.5) associated with crosstalk between Hedgehog, Notch, and Wnt/β- catenin signaling pathways (all p&amp;lt;0.05). Moreover, HA tumors had higher expression of stemness (ALDH1A2, ALDH1A1, PROM1; FC: 1.7-3.0), drug efflux (ABCC1, ABCB1; FC: 1.1- 1.5), epithelial to mesenchymal transition (EMT) (TWIST1, MMP2; FC: 1.1-1.5), cell cycle (CCND2; FC: 1.2), inhibition of apoptosis (BIRC2, XIAP; FC: 1.1) and epigenetic (EP300, TET1, TET2; FC: 1.3-1.4) related genes compared to NHW tumors (all p&amp;lt;0.05). HA PC had higher frequency of Hedgehog and Wnt/β-catenin associated SPOP (16% vs 6.6%, p=0.2) and CTNNB1 (12% vs 2.2%, p=0.1) mutation compared to NHW PC. Conclusion: These results demonstrate that tumors from HA patients had enrichment of oncogenic Hedgehog, Notch, and Wnt/β-catenin signaling pathways, higher expression of stemness, drug efflux, EMT, cell cycle, inhibition of apoptosis and epigenetic-related genes, and mutations directly involved in activating the Hedgehog and Wnt/β-catenin signaling pathways. Together, these findings suggest that tumors from HA patients are enriched for gene signatures that promote cancer progression and therapy resistance. Additional research on collaboration and crosstalk between Hedgehog, Notch, and Wnt/β-catenin signaling pathways may help in designing better therapeutic strategies for HA men with mHSPC. Citation Format: Alejandro Recio-Boiles, Sachin Kumar Deshmukh, Ricardo J. Estrada-Mendizabal, Kenneth Barker, Sharon Wu, Joanne Xiu, Milan Radovich, Elisabeth I. Heath, Rana McKay, Juan Chipollini, Cynthia K. Miranti. Defining the role of Hedgehog, Notch, and Wnt signaling pathways in aggressive lethal prostate cancer of Hispanic men [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr C100.

Protein tyrosine phosphatase non-receptor II: A possible biomarker of poor prognosis and mediator of immune evasion in hepatocellular carcinoma.

The incidence of primary liver cancer is increasing year by year. In 2022 alone, more than 900000 people were diagnosed with liver cancer worldwide, with hepatocellular carcinoma (HCC) accounting for 75%-85% of cases. HCC is the most common primary liver cancer. China has the highest incidence and mortality rate of HCC in the world, and it is one of the malignant tumors that seriously threaten the health of Chinese people. The onset of liver cancer is occult, the early cases lack typical clinical symptoms, and most of the patients are already in the middle and late stage when diagnosed. Therefore, it is very important to find new markers for the early detection and diagnosis of liver cancer, improve the therapeutic effect, and improve the prognosis of patients. Protein tyrosine phosphatase non-receptor 2 (PTPN2) has been shown to be associated with colorectal cancer, triple-negative breast cancer, non-small cell lung cancer, and prostate cancer, but its biological role and function in tumors remain to be further studied. To combine the results of relevant data obtained from The Cancer Genome Atlas (TCGA) to provide the first in-depth analysis of the biological role of PTPN2 in HCC. The expression of PTPN2 in HCC was first analyzed based on the TCGA database, and the findings were then verified by immunohistochemical staining, quantitative real-time polymerase chain reaction (qRT-PCR), and immunoblotting. The value of PTPN2 in predicting the survival of patients with HCC was assessed by analyzing the relationship between PTPN2 expression in HCC tissues and clinicopathological features. Finally, the potential of PTPN2 affecting immune escape of liver cancer was evaluated by tumor immune dysfunction and exclusion and immunohistochemical staining. The results of immunohistochemical staining, qRT-PCR, and immunoblotting in combination with TCGA database analysis showed that PTPN2 was highly expressed and associated with a poor prognosis in HCC patients. Kyoto Encyclopedia of Genes and Genomes enrichment analysis showed that PTPN2 was associated with various pathways, including cancer-related pathways, the Notch signaling pathway, and the MAPK signaling pathway. Gene Set Enrichment Analysis showed that PTPN2 was highly expressed in various immune-related pathways, such as the epithelial mesenchymal transition process. A risk model score based on PTPN2 showed that immune escape was significantly enhanced in the high-risk group compared with the low-risk group. This study investigated PTPN2 from multiple biological perspectives, revealing that PTPN2 can function as a biomarker of poor prognosis and mediate immune evasion in HCC.

Lacidipine Inhibits NF-κB and Notch Pathways and Mitigates DSS-Induced Colitis.

Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon, with a global incidence that is rising. Despite the increasing prevalence, effective treatment options for UC remain limited. We utilized an NF-κB promoter dual fluorescence reporter system to screen for compounds that could inhibit p65 and IκBα phosphorylation. The anti-hypertension drug lacidipine was identified as a candidate. Its efficacy was further evaluated in a murine model of dextran sulfate sodium (DSS)-induced colitis. The analysis included the assessment of colon lesions, inflammation markers, and signal pathway activation, with a focus on NF-κB and Notch signaling. Lacidipine effectively inhibited p65 and IκBα phosphorylation in the reporter system. In the DSS-induced colitis murine model, lacidipine treatment led to a reduction in colon lesions and inflammatory markers. Target analysis showed significant enrichment of the Notch signaling pathway. Additionally, lacidipine inhibited both NF-κB and Notch activation in DSS-stimulated colons. Lacidipine demonstrated a protective effect in UC, reducing inflammation and modulating key signaling pathways. These findings suggest that lacidipine could be a promising candidate for the treatment of UC.

A patient-derived cell model for malignant transformation in IDH-mutant glioma

Malignant transformation (MT) is commonly seen in IDH-mutant gliomas. There has been a growing research interest in revealing its underlying mechanisms and intervening prior to MT at the early stages of the transforming process. Here we established a unique pair of matched 3D cell models: 403L, derived from a low-grade glioma (LGG), and 403H, derived from a high-grade glioma (HGG), by utilizing IDH-mutant astrocytoma samples from the same patient when the tumor was diagnosed as WHO grade 2 (tumor mutational burden (TMB) of 3.96/Mb) and later as grade 4 (TMB of 70.07/Mb), respectively. Both cell models were authenticated to a patient’s sample retaining endogenous expression of IDH1 R132H. DNA methylation profiles of the parental tumors referred to LGG and HGG IDH-mutant glioma clusters. The immunopositivity of SOX2, NESTIN, GFAP, OLIG2, and beta 3-Tubulin suggested the multilineage potential of both models. 403H was more prompt to cell invasion and developed infiltrative HGG in vivo. The differentially expressed genes (DEGs) from the RNA sequencing analysis revealed the tumor invasion and aggressiveness related genes exclusively upregulated in the 403H model. Pathway analysis showcased an enrichment of genes associated with epithelial-mesenchymal transition (EMT) and Notch signaling pathways in 403H and 403L, respectively. Mass spectrometry-based targeted metabolomics and hyperpolarized (HP) 1-13C pyruvate in-cell NMR analyses demonstrated significant alterations in the TCA cycle and fatty acid metabolism. Citrate, glutamine, and 2-HG levels were significantly higher in 403H. To our knowledge, this is the first report describing the development of a matched pair of 3D patient-derived cell models representative of MT and temozolomide (TMZ)-induced hypermutator phenotype (HMP) in IDH-mutant glioma, providing insights into genetic and metabolic changes during MT/HMP. This novel in vitro model allows further investigation of the mechanisms of MT at the cellular level.Graphic

Life in the fastlane? A comparative analysis of gene expression profiles across annual, semi-annual, and non-annual killifishes (Cyprinodontiformes: Nothobranchiidae).

The Turquoise Killifish is an important vertebrate for the study of aging and age-related diseases due to its short lifespan. Within Nothobranchiidae, species possess annual, semi-annual, or non-annual life-histories. We took a comparative approach and examined gene expression profiles (QuantSeq) from 62 individuals from eleven nothobranchid species that span three life-histories. Our results show significant differences in differentially expressed genes (DEGs) across life-histories with non-annuals and semi-annuals being most similar, and annuals being the most distinct. At finer scales, we recovered significant differences in DEGs for DNA repair genes and show that non-annual and semi-annuals share similar gene expression profiles, while annuals are distinct. Most of the GO terms enriched in annuals are related to metabolic processes. However, GO terms, including translation, protein transport, and DNA replication initiation also are enriched in annuals. Non-annuals are enriched in Notch signaling pathway genes and downregulated in the canonical Wnt signaling pathway compared to annual species, which suggests that non-annuals have stronger regulation in cellular processes. This study provides support for congruency in DEGs involved in these life-histories and provides strong evidence that a particular set of candidate genes may be worthy of study to investigate their role in the aging process.