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PURPOSE: This study aims to determine whether Pokemon regulates Bim activity in colorectal carcinoma (CRC) carcinogenesis. METHODS: Clinical tissue samples were analyzed to detect the expression and clinicopathological significance of Pokemon and Bim in CRC. Proliferation, apoptosis, and invasion assays were conducted to identify the regulatory effect of Pokemon on Bim. The combined treatment effects of Pokemon knockdown and diamminedichloroplatinum (DDP) were also examined. RESULTS: Immunohistochemical analysis of 80 samples of colorectal epithelia (CRE), 80 cases of colorectal adenoma (CRA), and 160 of CRC samples revealed protein expression rates of 23.8%, 38.8%, and 70.6% for Pokemon, and 88.8%, 73.8%, and 31.9% for Bim, respectively. A significant negative correlation was observed between Pokemon and Bim expression across the CRE, CRA, and CRC lesion stages. In CRC, higher Pokemon and lower Bim expression correlated with higher histological grades, advanced Dukes stages, and increased cancer invasion. In both LoVo and HCT116 cells, overexpression of Pokemon significantly reduced Bim expression, leading to increased proliferation, resistance to anoikis, and cell invasion. Additionally, Pokemon overexpression significantly decreased DDP-induced Bim expression, reduction of anti-apoptosis and invasion, whereas Pokemon knockdown resulted in the opposite effects. CONCLUSION: These findings suggest that Pokemon inhibits Bim transcription, thereby promoting CRC proliferation, resistance to apoptosis, invasion, and advancing histological grade and Dukes staging. Pokemon knockdown enhances the therapeutic efficacy of DDP in the treatment of CRC.
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Proteína 11 Similar a Bcl2 , Proliferación Celular , Neoplasias Colorrectales , Invasividad Neoplásica , Factores de Transcripción , Humanos , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Proteína 11 Similar a Bcl2/genética , Proteína 11 Similar a Bcl2/metabolismo , Femenino , Masculino , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Persona de Mediana Edad , Anoicis/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Estadificación de Neoplasias , Anciano , Clasificación del Tumor , Regulación Neoplásica de la Expresión Génica , Transcripción Genética , Apoptosis , Línea Celular TumoralRESUMEN
Anoikis, a distinct form of programmed cell death, is crucial for both organismal development and maintaining tissue equilibrium. Its role extends to the proliferation and progression of cancer cells. This study aimed to establish an anoikis-related prognostic model to predict the prognosis of pancreatic cancer (PC) patients. Gene expression data and patient clinical profiles were sourced from The Cancer Genome Atlas (TCGA-PAAD: Pancreatic Adenocarcinoma) and the International Cancer Genome Consortium (ICGC-PACA: Pancreatic Ductal Adenocarcinoma). Non-cancerous pancreatic tissue gene expression data were obtained from the Genotype-Tissue Expression (GTEx) project. The R package was used to construct anoikis-related PC prognostic models, which were later validated with the ICGC-PACA database. Survival analyses demonstrated a poorer prognosis for patients in the high-risk group, consistent across both TCGA-PAAD and ICGC-PACA datasets. A nomogram was designed as a predictive tool to estimate patient mortality. The study also analyzed tumor mutations and immune infiltration across various risk groups, uncovering notable differences in tumor mutation patterns and immune landscapes between high- and low-risk groups. In conclusion, this research successfully developed a prognostic model centered on anoikis-related genes, offering a novel tool for predicting the clinical trajectory of PC patients.
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Anoicis , Neoplasias Pancreáticas , Anoicis/genética , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Regulación Neoplásica de la Expresión Génica , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Nomogramas , Biomarcadores de Tumor/genética , Mutación , Femenino , Masculino , Análisis de Supervivencia , Perfilación de la Expresión GénicaRESUMEN
Anoikis is proved to play a crucial role in the development of cancers. However, the impact of anoikis on the prognosis of bladder cancer (BLCA) is currently unknown. Thus, this study aimed to find potential effect of anoikis in BLCA. The Cancer Genome Atlas (TCGA)-BLCA and GSE13507 cohorts were downloaded from TCGA and the Gene Expression Omnibus (GEO) databases, respectively. Differentially expressed genes (DEGs) were screened between BLCA and normal groups, which intersected with anoikis-related genes to yield anoikis-related DEGs (AR DEGs). Univariate COX, rbsurv, and multivariate COX analyses were adopted in order to build a prognostic risk model. The differences of risk score in the different clinical subgroups and the relevance between survival rate and clinical characteristics were explored as well. Finally, chemotherapy drug sensitivity in different risk groups was analyzed. In total, 78 AR DEGs were acquired and a prognostic signature was build based on the 6 characteristic genes (CALR, FASN, CSPG4, HGF, INHBB, SATB1), where the patients of low-risk group had longer survival time. The survival rate of BLCA patients was significantly differential in different groups of age, stage, smoking history, pathologic-T, and pathologic-N. The IC50 of 56 drugs showed significant differences between 2 risk groups, such as imatinib, docetaxel, and dasatinib. At last, the results of real time quantitative-polymerase chain reaction (RT-qPCR) demonstrated that the expression trend of CALR, HGF, and INHBB was consistent with the result obtained previously based on public databases. Taken together, this study identified 6 anoikis-related characteristic genes (CALR, FASN, CSPG4, HGF, INHBB, SATB1) for the prognosis of BLCA patients, providing a scientific reference for further research on BLCA.
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Anoicis , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/mortalidad , Anoicis/genética , Pronóstico , Masculino , Femenino , Persona de Mediana Edad , Regulación Neoplásica de la Expresión Génica , Anciano , Tasa de Supervivencia , Perfilación de la Expresión Génica/métodos , Biomarcadores de Tumor/genéticaRESUMEN
Anoikis, a form of apoptosis resulting from the loss of cell-extracellular matrix interaction, is a significant barrier to cancer cell metastasis. However, the epigenetic regulation of this process remains to be explored. Here, we demonstrate that the histone deacetylase sirtuin 6 (SIRT6) plays a pivotal role in conferring anoikis resistance to colorectal cancer (CRC) cells. The protein level of SIRT6 is negatively correlated with anoikis in CRC cells. The overexpression of SIRT6 decreases while the knockdown of SIRT6 increases detachment-induced anoikis. Mechanistically, SIRT6 inhibits the transcription of N-myc downstream-regulated gene 1 (NDRG1), a negative regulator of the AKT signaling pathway. We observed the up-regulation of SIRT6 in advanced-stage CRC samples. Together, our findings unveil a novel epigenetic program regulating the anoikis of CRC cells.
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Anoicis , Proteínas de Ciclo Celular , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Péptidos y Proteínas de Señalización Intracelular , Sirtuinas , Humanos , Anoicis/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Sirtuinas/metabolismo , Sirtuinas/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Regulación hacia Abajo , Transducción de Señal , Epigénesis GenéticaRESUMEN
BACKGROUND Hepatocellular carcinoma (HCC) poses a significant threat to human life and is the most prevalent form of liver cancer. The intricate interplay between apoptosis, a common form of programmed cell death, and its role in immune regulation stands as a crucial mechanism influencing tumor metastasis. MATERIAL AND METHODS Utilizing HCC samples from the TCGA database and 61 anoikis-related genes (ARGs) sourced from GeneCards, we analyzed the relationship between ARGs and immune cell infiltration in HCC. Subsequently, we identified long non-coding RNAs (lncRNAs) associated with ARGs, using the least absolute shrinkage and selection operator (LASSO) regression analysis to construct a robust prognostic model. The predictive capabilities of the model were then validated through examination in a single-cell dataset. RESULTS Our constructed prognostic model, derived from lncRNAs linked to ARGs, comprised 11 significant lncRNAs: NRAV, MCM3AP-AS1, OTUD6B-AS1, AC026356.1, AC009133.1, DDX11-AS1, AC108463.2, MIR4435-2HG, WARS2-AS1, LINC01094, and HCG18. The risk score assigned to HCC samples demonstrated associations with immune indicators and the infiltration of immune cells. Further, we identified Annexin A5 (ANXA5) as the pivotal gene among ARGs, with it exerting a prominent role in regulating the lncRNA gene signature. Our validation in a single-cell database elucidated the involvement of ANXA5 in immune cell infiltration, specifically in the regulation of mononuclear cells. CONCLUSIONS This study delves into the intricate correlation between ARGs and immune cell infiltration in HCC, culminating in the development of a novel prognostic model reliant on 11 ARGs-associated lncRNAs. Furthermore, our findings highlight ANXA5 as a promising target for immune regulation in HCC, offering new perspectives for immune therapy in the context of HCC.
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Carcinoma Hepatocelular , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , ARN Largo no Codificante , Humanos , Anoicis/genética , Apoptosis/genética , Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Bases de Datos Genéticas , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Pronóstico , ARN Largo no Codificante/genéticaRESUMEN
BACKGROUND: Osteosarcoma (OS) is the most common bone malignant tumor in children, and its prognosis is often poor. Anoikis is a unique mode of cell death.However, the effects of Anoikis in OS remain unexplored. METHOD: Differential analysis of Anoikis-related genes was performed based on the metastatic and non-metastatic groups. Then LASSO logistic regression and SVM-RFE algorithms were applied to screen out the characteristic genes. Later, Univariate and multivariate Cox regression was conducted to identify prognostic genes and further develop the Anoikis-based risk score. In addition, correlation analysis was performed to analyze the relationship between tumor microenvironment, drug sensitivity, and prognostic models. RESULTS: We established novel Anoikis-related subgroups and developed a prognostic model based on three Anoikis-related genes (MAPK1, MYC, and EDIL3). The survival and ROC analysis results showed that the prognostic model was reliable. Besides, the results of single-cell sequencing analysis suggested that the three prognostic genes were closely related to immune cell infiltration. Subsequently, aberrant expression of two prognostic genes was identified in osteosarcoma cells. Nilotinib can promote the apoptosis of osteosarcoma cells and down-regulate the expression of MAPK1. CONCLUSIONS: We developed a novel Anoikis-related risk score model, which can assist clinicians in evaluating the prognosis of osteosarcoma patients in clinical practice. Analysis of the tumor immune microenvironment and chemotherapeutic drug sensitivity can provide necessary insights into subsequent mechanisms. MAPK1 may be a valuable therapeutic target for neoadjuvant chemotherapy in osteosarcoma.
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Anoicis , Neoplasias Óseas , Proteína Quinasa 1 Activada por Mitógenos , Terapia Neoadyuvante , Osteosarcoma , Microambiente Tumoral , Osteosarcoma/tratamiento farmacológico , Osteosarcoma/genética , Humanos , Anoicis/efectos de los fármacos , Anoicis/genética , Neoplasias Óseas/genética , Neoplasias Óseas/tratamiento farmacológico , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 1 Activada por Mitógenos/genética , Microambiente Tumoral/efectos de los fármacos , Pronóstico , Masculino , Femenino , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Niño , AdolescenteRESUMEN
BACKGROUND: Zinc finger E-box binding homEeobox 1 (ZEB1) and ZEB2 are two anoikis-related transcription factors. The mRNA expressions of these two genes are significantly increased in kidney renal clear cell carcinoma (KIRC), which are associated with poor survival. Meanwhile, the mechanisms and clinical significance of ZEB1 and ZEB2 upregulation in KIRC remain unknown. METHODS: Through the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, expression profiles, prognostic value and receiver operating characteristic curves (ROCs) of ZEB1 and ZEB2 were evaluated. The correlations of ZEB1 and ZEB2 with anoikis were further assessed in TCGA-KIRC database. Next, miRTarBase, miRDB, and TargetScan were used to predict microRNAs targeting ZEB1 and ZEB2, and TCGA-KIRC database was utilized to discern differences in microRNAs and establish the association between microRNAs and ZEBs. TCGA, TIMER, TISIDB, and TISCH were used to analyze tumor immune infiltration. RESULTS: It was found that ZEB1 and ZEB2 expression were related with histologic grade in KIRC patient. Kaplan-Meier survival analyses showed that KIRC patients with low ZEB1 or ZEB2 levels had a significantly lower survival rate. Meanwhile, ZEB1 and ZEB2 are closely related to anoikis and are regulated by microRNAs. We constructed a risk model using univariate Cox and LASSO regression analyses to identify two microRNAs (hsa-miR-130b-3p and hsa-miR-138-5p). Furthermore, ZEB1 and ZEB2 regulate immune cell invasion in KIRC tumor microenvironments. CONCLUSIONS: Anoikis, cytotoxic immune cell infiltration, and patient survival outcomes were correlated with ZEB1 and ZEB2 mRNA upregulation in KIRC. ZEB1 and ZEB2 are regulated by microRNAs.
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Anoicis , Biomarcadores de Tumor , Carcinoma de Células Renales , Neoplasias Renales , MicroARNs , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Homeobox 1 de Unión a la E-Box con Dedos de Zinc , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/inmunología , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/inmunología , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genética , Pronóstico , Anoicis/genética , Biomarcadores de Tumor/genética , MicroARNs/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/metabolismo , Regulación Neoplásica de la Expresión Génica , Masculino , Femenino , Estimación de Kaplan-MeierRESUMEN
Lung adenocarcinoma (LUAD) is the most common type of lung cancer and is characterized by a high death rate and a poor prospect for survival. Anoikis, which is a kind of programmed cell apoptosis, is an important factor in the advancement of tumors. Nonetheless, the function of anoikis-related lncRNAs (ARLRs) in LUAD is still not well understood. The TCGA database was queried for genomic and clinical information. A prognostic signature for ARLRs was established via the use of coexpression analysis and Cox regression. Validation of the model's accuracy was conducted utilizing K-M curves and receiver operating characteristic (ROC) curves, and the signature was utilized to develop a nomogram. LncRNAs were implicated in the progression of tumors, as determined by functional enrichment analysis. There was an improvement in prognosis, increased immune cell infiltration, and higher immune scores among the low-risk patients. Additionally, we found that the two groups had varied anticancer drug sensitivities, which could help guide treatment. The impact of one ARLR, AC026355.2, on migration and invasion was validated by in vitro experiments in LUAD cells. Herein, a new lncRNA signature associated with anoikis was identified and estimated, potentially serving as a prognostic indicator for LUAD patients.
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Adenocarcinoma del Pulmón , Anoicis , Neoplasias Pulmonares , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Anoicis/genética , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/mortalidad , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Pronóstico , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genética , Femenino , Masculino , Línea Celular Tumoral , Nomogramas , Persona de Mediana Edad , Movimiento Celular/genéticaRESUMEN
BACKGROUND/AIM: Epidermal growth factor receptor (EGFR) over-expression is commonly observed in advanced head and neck squamous cell carcinoma (HNSCC) and is correlated with poor patient outcomes. However, the role of dual-specificity phosphatase 6 (DUSP6) in EGFR-associated HNSCC progression remains poorly understood. This study aimed to investigate the correlation between DUSP6 expression and EGFR signaling in malignant HNSCC tissues. MATERIALS AND METHODS: Data mining and in vitro assays were employed to assess DUSP6 expression levels in HNSCC tissues compared to normal tissues. Additionally, the correlation between DUSP6 and EGFR expression was examined. Functional assays were conducted to investigate the modulation of DUSP6 expression by EGFR signaling and its involvement in EGF-induced cell migration and anoikis resistance. RESULTS: Our analysis revealed a significant elevation in DUSP6 expression in HNSCC tissues compared to normal tissues and a strong correlation between DUSP6 and EGFR expression. EGFR signaling modulated DUSP6 expression in a dose- and time-dependent manner, primarily through the extracellular signal-regulated kinase (ERK) pathway. Knockdown experiments demonstrated the functional role of DUSP6 in EGF-induced cell migration and anoikis resistance. CONCLUSION: The findings of this study elucidate the intricate signaling networks governing DUSP6 expression and its interplay with EGFR signaling in HNSCC. Moreover, the results provide insights into the potential role of DUSP6 as a therapeutic target and highlight the importance of personalized treatment strategies in HNSCC management.
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Movimiento Celular , Fosfatasa 6 de Especificidad Dual , Neoplasias de Cabeza y Cuello , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Anoicis/genética , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Línea Celular Tumoral , Progresión de la Enfermedad , Fosfatasa 6 de Especificidad Dual/genética , Fosfatasa 6 de Especificidad Dual/metabolismo , Receptores ErbB/metabolismo , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/metabolismo , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismoRESUMEN
In addition to presenting significant diagnostic and treatment challenges, lung adenocarcinoma (LUAD) is the most common form of lung cancer. Using scRNA-Seq and bulk RNA-Seq data, we identify three genes referred to as HMR, FAM83A, and KRT6A these genes are related to necroptotic anoikis-related gene expression. Initial validation, conducted on the GSE50081 dataset, demonstrated the model's ability to categorize LUAD patients into high-risk and low-risk groups with significant survival differences. This model was further applied to predict responses to PD-1/PD-L1 blockade therapies, utilizing the IMvigor210 and GSE78220 cohorts, and showed strong correlation with patient outcomes, highlighting its potential in personalized immunotherapy. Further, LUAD cell lines were analyzed using quantitative PCR (qPCR) and Western blot analysis to confirm their expression levels, further corroborating the model's relevance in LUAD pathophysiology. The mutation landscape of these genes was also explored, revealing their broad implication in various cancer types through a pan-cancer analysis. The study also delved into molecular subclustering, revealing distinct expression profiles and associations with different survival outcomes, emphasizing the model's utility in precision oncology. Moreover, the diversity of immune cell infiltration, analyzed in relation to the necroptotic anoikis signature, suggested significant implications for immune evasion mechanisms in LUAD. While the findings present a promising stride towards personalized LUAD treatment, especially in immunotherapy, limitations such as the retrospective nature of the datasets and the need for larger sample sizes are acknowledged. Prospective clinical trials and further experimental research are essential to validate these findings and enhance the clinical applicability of our prognostic model.
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Adenocarcinoma del Pulmón , Anoicis , Antígeno B7-H1 , Inmunoterapia , Neoplasias Pulmonares , Receptor de Muerte Celular Programada 1 , RNA-Seq , Humanos , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/mortalidad , Anoicis/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Pronóstico , Inmunoterapia/métodos , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Análisis de la Célula Individual , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Biomarcadores de Tumor/genéticaRESUMEN
Papillary thyroid carcinoma (PTC) prognosis may be deteriorated due to the metastases, and anoikis palys an essential role in the tumor metastasis. However, the potential effect of anoikis-related genes on the prognosis of PTC was unclear. The mRNA and clinical information were obtained from the cancer genome atlas database. Hub genes were identified and risk model was constructed using Cox regression analysis. Kaplan-Meier (K-M) curve was applied for the survival analysis. Immune infiltration and immune therapy response were calculated using CIBERSORT and TIDE. The identification of cell types and cell interaction was performed by Seurat, SingleR and CellChat packages. GO, KEGG, and GSVA were applied for the enrichment analysis. Protein-protein interaction network was constructed in STRING and Cytoscape. Drug sensitivity was assessed in GSCA. Based on bulk RNA data, we identified 4 anoikis-related risk signatures, which were oncogenes, and constructed a risk model. The enrichment analysis found high risk group was enriched in some immune-related pathways. High risk group had higher infiltration of Tregs, higher TIDE score and lower levels of monocytes and CD8 T cells. Based on scRNA data, we found that 4 hub genes were mainly expressed in monocytes and macrophages, and they interacted with T cells. Hub genes were significantly related to immune escape-related genes. Drug sensitivity analysis suggested that cyclin dependent kinase inhibitor 2A may be a better chemotherapy target. We constructed a risk model which could effectively and steadily predict the prognosis of PTC. We inferred that the immune escape may be involved in the development of PTC.
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Anoicis , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Anoicis/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Pronóstico , Análisis de la Célula Individual/métodos , Análisis de Secuencia de ARN , Mapas de Interacción de Proteínas/genética , Femenino , Masculino , Estimación de Kaplan-Meier , Regulación Neoplásica de la Expresión Génica , Perfilación de la Expresión Génica/métodosRESUMEN
This study tackles the persistent prognostic and management challenges of clear cell renal cell carcinoma (ccRCC), despite advancements in multimodal therapies. Focusing on anoikis, a critical form of programmed cell death in tumor progression and metastasis, we investigated its resistance in cancer evolution. Using single-cell RNA sequencing from seven ccRCC patients, we assessed the impact of anoikis-related genes (ARGs) and identified differentially expressed genes (DEGs) in Anoikis-related epithelial subclusters (ARESs). Additionally, six ccRCC RNA microarray datasets from the GEO database were analyzed for robust DEGs. A novel risk prognostic model was developed through LASSO and multivariate Cox regression, validated using BEST, ULCAN, and RT-PCR. The study included functional enrichment, immune infiltration analysis in the tumor microenvironment (TME), and drug sensitivity assessments, leading to a predictive nomogram integrating clinical parameters. Results highlighted dynamic ARG expression patterns and enhanced intercellular interactions in ARESs, with significant KEGG pathway enrichment in MYC + Epithelial subclusters indicating enhanced anoikis resistance. Additionally, all ARESs were identified in the spatial context, and their locational relationships were explored. Three key prognostic genes-TIMP1, PECAM1, and CDKN1A-were identified, with the high-risk group showing greater immune infiltration and anoikis resistance, linked to poorer prognosis. This study offers a novel ccRCC risk signature, providing innovative approaches for patient management, prognosis, and personalized treatment.
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Anoicis , Biomarcadores de Tumor , Carcinoma de Células Renales , Regulación Neoplásica de la Expresión Génica , Neoplasias Renales , Microambiente Tumoral , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Anoicis/genética , Neoplasias Renales/genética , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , Pronóstico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Microambiente Tumoral/genética , Células Epiteliales/metabolismo , Células Epiteliales/patología , Masculino , Femenino , Perfilación de la Expresión Génica , NomogramasRESUMEN
A tumour suppressor miRNA, miR-128-3p, is widely involved in various biological processes and has been found to get downregulated in breast cancer patients. We previously published that ectopically expressed miR-128-3p suppressed migration, invasion, cell cycle arrest, and breast cancer stem cells. In the present study, we explored the role of Empagliflozin (EMPA) as a miR-128-3p functionality-mimicking drug in inducing ferroptosis by inhibiting CD98hc. Given that CD98hc is one of the proteins critical in triggering ferroptosis, we confirmed that miR-128-3p and EMPA inhibited SP1, leading to inhibition of CD98hc expression. Further, transfection with siCD98hc, miR-128-3p mimics, and inhibitors was performed to assess their involvement in the ferroptosis of anoikis-resistant cells. We proved that anoikis-resistant cells possess high ROS and iron levels. Further, miR-128-3p and EMPA treatments induced ferroptosis by inhibiting GSH and enzymatic activity of GPX4 and also induced lipid peroxidation. Moreover, EMPA suppressed bioluminescence of 4T1-Red-FLuc induced thoracic cavity, peritoneal tumour burden and lung nodules in an in-vivo metastatic model of breast cancer. Collectively, we revealed that EMPA sensitized the ECM detached cells to ferroptosis by synergically activating miR-128-3p and lowering the levels of SP1 and CD98hc, making it a potential adjunct drug for breast cancer chemotherapy.
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Anoicis , Compuestos de Bencidrilo , Neoplasias de la Mama , Ferroptosis , Regulación Neoplásica de la Expresión Génica , Glucósidos , MicroARNs , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , MicroARNs/genética , MicroARNs/metabolismo , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Glucósidos/farmacología , Animales , Anoicis/efectos de los fármacos , Anoicis/genética , Ratones , Compuestos de Bencidrilo/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Línea Celular Tumoral , Especies Reactivas de Oxígeno/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto , Peroxidación de Lípido/efectos de los fármacos , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIbRESUMEN
Colorectal cancer (CRC) is a malignant tumor originating from epithelial cells of the colon or rectum, and its invasion and metastasis could be regulated by anoikis. However, the key genes and pathways regulating anoikis in CRC are still unclear and require further research. The single cell transcriptome dataset GSE221575 of GEO database was downloaded and applied to cell subpopulation type identification, intercellular communication, pseudo time cell trajectory analysis, and receptor ligand expression analysis of CRC. Meanwhile, the RNA transcriptome dataset of TCGA, the GSE39582, GSE17536, and GSE17537 datasets of GEO were downloaded and merged into one bulk transcriptome dataset. The differentially expressed genes (DEGs) related to anoikis were extracted from these data sets, and key marker genes were obtained after feature selection. A clinical prognosis prediction model was constructed based on the marker genes and the predictive effect was analyzed. Subsequently, gene pathway analysis, immune infiltration analysis, immunosuppressive point analysis, drug sensitivity analysis, and immunotherapy efficacy based on the key marker genes were conducted for the model. In this study, we used single cell datasets to determine the anoikis activity of cells and analyzed the DEGs of cells based on the score to identify the genes involved in anoikis and extracted DEGs related to the disease from the transcriptome dataset. After dimensionality reduction selection, 7 marker genes were obtained, including TIMP1, VEGFA, MYC, MSLN, EPHA2, ABHD2, and CD24. The prognostic risk model scoring system built by these 7 genes, along with patient clinical data (age, tumor stage, grade), were incorporated to create a nomogram, which predicted the 1-, 3-, and 5-years survival of CRC with accuracy of 0.818, 0.821, and 0.824. By using the scoring system, the CRC samples were divided into high/low anoikis-related prognosis risk groups, there are significant differences in immune infiltration, distribution of immune checkpoints, sensitivity to chemotherapy drugs, and efficacy of immunotherapy between these two risk groups. Anoikis genes participate in the differentiation of colorectal cancer tumor cells, promote tumor development, and could predict the prognosis of colorectal cancer.
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Anoicis , Diferenciación Celular , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/inmunología , Anoicis/genética , Pronóstico , Diferenciación Celular/genética , Transcriptoma/genética , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica , FemeninoRESUMEN
The effect of anoikis-related genes (ARGs) on clinicopathological characteristics and tumor microenvironment remains unclear. We comprehensively analyzed anoikis-associated gene signatures of 1057 colorectal cancer (CRC) samples based on 18 ARGs. Anoikis-related molecular subtypes and gene features were identified through consensus clustering analysis. The biological functions and immune cell infiltration were assessed using the GSVA and ssGSEA algorithms. Prognostic risk score was constructed using multivariate Cox regression analysis. The immunological features of high-risk and low-risk groups were compared. Finally, DAPK2-overexpressing plasmid was transfected to measure its effect on tumor proliferation and metastasis in vitro and in vivo. We identified 18 prognostic ARGs. Three different subtypes of anoikis were identified and demonstrated to be linked to distinct biological processes and prognosis. Then, a risk score model was constructed and identified as an independent prognostic factor. Compared to the high-risk group, patients in the low-risk group exhibited longer survival, higher enrichment of checkpoint function, increased expression of CTLA4 and PD-L1, higher IPS scores, and a higher proportion of MSI-H. The results of RT-PCR indicated that the expression of DAPK2 mRNA was significantly downregulated in CRC tissues compared to normal tissues. Increased DAPK2 expression significantly suppressed cell proliferation, promoted apoptosis, and inhibited migration and invasion. The nude mice xenograft tumor model confirmed that high expression of DAPK2 inhibited tumor growth. Collectively, we discovered an innovative anoikis-related gene signature associated with prognosis and TME. Besides, our study indicated that DAPK2 can serve as a promising therapeutic target for inhibiting the growth and metastasis of CRC.
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Anoicis , Neoplasias Colorrectales , Inmunoterapia , Microambiente Tumoral , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Anoicis/genética , Animales , Pronóstico , Ratones , Inmunoterapia/métodos , Femenino , Masculino , Regulación Neoplásica de la Expresión Génica , Proteínas Quinasas Asociadas a Muerte Celular/genética , Línea Celular Tumoral , Biomarcadores de Tumor/genética , Ratones Desnudos , Transcriptoma , Perfilación de la Expresión Génica , Ensayos Antitumor por Modelo de Xenoinjerto , Persona de Mediana Edad , Proliferación Celular/genética , Ratones Endogámicos BALB CRESUMEN
BACKGROUND: Tumors that resist anoikis, a programmed cell death triggered by detachment from the extracellular matrix, promote metastasis; however, the role of anoikis-related genes (ARGs) in colorectal cancer (CRC) stratification, prognosis, and biological functions remains unclear. METHODS: We obtained transcriptomic profiles of CRC and 27 ARGs from The Cancer Genome Atlas, the Gene Expression Omnibus, and MSigDB databases, respectively. CRC tissue samples were classified into two clusters based on the expression pattern of ARGs, and their functional differences were explored. Hub genes were screened using weighted gene co-expression network analysis, univariate analysis, and least absolute selection and shrinkage operator analysis, and validated in cell lines, tissues, or the Human Protein Atlas database. We constructed an ARG-risk model and nomogram to predict prognosis in patients with CRC, which was validated using an external cohort. Multifaceted landscapes, including stemness, tumor microenvironment (TME), immune landscape, and drug sensitivity, between high- and low-risk groups were examined. RESULTS: Patients with CRC were divided into C1 and C2 clusters. Cluster C1 exhibited higher TME scores, whereas cluster C2 had favorable outcomes and a higher stemness index. Eight upregulated hub ARGs (TIMP1, P3H1, SPP1, HAMP, IFI30, ADAM8, ITGAX, and APOC1) were utilized to construct the risk model. The qRT-PCR, Western blotting, and immunohistochemistry results were consistent with those of the bioinformatics analysis. Patients with high risk exhibited worse overall survival (p < 0.01), increased stemness, TME, immune checkpoint expression, immune infiltration, tumor mutation burden, and drug susceptibility compared with the patients with low risk. CONCLUSION: Our results offer a novel CRC stratification based on ARGs and a risk-scoring system that could predict the prognosis, stemness, TME, immunophenotypes, and drug susceptibility of patients with CRC, thereby improving their prognosis. This stratification may facilitate personalized therapies.
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Anoicis , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , Microambiente Tumoral , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Anoicis/genética , Pronóstico , Microambiente Tumoral/genética , Masculino , Biomarcadores de Tumor/genética , Nomogramas , Femenino , Transcriptoma , Perfilación de la Expresión GénicaRESUMEN
Anoikis plays a crucial role in the progression, prognosis, and immune response of lung adenocarcinoma (LUAD). However, its specific impact on LUAD remains unclear. In this study, we investigated the intricate interplay of nesting apoptotic factors in LUAD. By analyzing nine key nesting apoptotic factors, we categorized LUAD patients into two distinct clusters. Further examination of immune cell profiles revealed that Cluster A exhibited greater infiltration of innate immune cells than did Cluster B. Additionally, we identified two genes closely associated with prognosis and developed a predictive model to differentiate patients based on molecular clusters. Our findings suggest that the loss of specific anoikis-related genes could significantly influence the prognosis, tumor microenvironment, and clinical features of LUAD patients. Furthermore, we validated the expression and functional roles of two pivotal prognostic genes, solute carrier family 2 member 1 (SLC2A1) and sphingosine kinase 1 (SPHK1), in regulating tumor cell viability, migration, apoptosis, and anoikis. These results offer valuable insights for future mechanistic investigations. In conclusion, this study provides new avenues for advancing our understanding of LUAD, improving prognostic assessments, and developing more effective immunotherapy strategies.
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Adenocarcinoma del Pulmón , Anoicis , Neoplasias Pulmonares , Humanos , Anoicis/genética , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Pronóstico , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Regulación Neoplásica de la Expresión Génica , Femenino , Masculino , Persona de Mediana Edad , Línea Celular Tumoral , Apoptosis/genéticaRESUMEN
BACKGROUND: Low-grade glioma (LGG) has an extremely poor prognosis, and the mechanism leading to malignant development has not been determined. The aim of our study was to clarify the function and mechanism of anoikis and TIMP1 in the malignant progression of LGG. METHODS: We screened 7 anoikis-related genes from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to construct a prognostic-predicting model. The study assessed the clinical prognosis, pathological characteristics, and immune cell infiltration in both high- and low-risk groups. Additionally, the potential modulatory effects of TIMP1 on proliferation, migration, and anoikis in LGG were investigated both in vivo and in vitro. RESULTS: In this study, we identified seven critical genes, namely, PTGS2, CCND1, TIMP1, PDK4, LGALS3, CDKN1A, and CDKN2A. KaplanâMeier (KâM) curves demonstrated a significant correlation between clinical features and overall survival (OS), and single-cell analysis and mutation examination emphasized the heterogeneity and pivotal role of hub gene expression imbalances in LGG development. Immune cell infiltration and microenvironment analysis further elucidated the relationships between key genes and immune cells. In addition, TIMP1 promoted the malignant progression of LGG in both in vitro and in vivo models. CONCLUSIONS: This study confirmed that TIMP1 promoted the malignant progression of LGG by inhibiting anoikis, providing insights into LGG pathogenesis and potential therapeutic targets.
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Anoicis , Glioma , Inhibidor Tisular de Metaloproteinasa-1 , Humanos , Anoicis/genética , Glioma/genética , Glioma/inmunología , Glioma/patología , Pronóstico , Inhibidor Tisular de Metaloproteinasa-1/genética , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/mortalidad , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Ratones , Masculino , Proliferación Celular/genética , Femenino , Ratones Desnudos , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Clasificación del TumorRESUMEN
Thyroid cancer, notably papillary thyroid cancer (PTC), is a global health concern with increasing incidence. Anoikis, a regulator of programmed cell death, is pivotal in normal physiology and, when dysregulated, can drive cancer progression and metastasis. This study explored the impact of anoikis on PTC prognosis. Analyzing data from GEO, TCGA, and GeneCards, we identified a prognostic signature consisting of six anoikis-related genes (ARGs): EZH2, PRKCQ, CD36, INHBB, TDGF1, and MMP9. This signature independently predicted patient outcomes, with high-risk scores associated with worse prognoses. A robust predictive ability was confirmed via ROC analysis, and a nomogram achieved a C-index of 0.712. Differences in immune infiltration levels were observed between high- and low-risk groups. Importantly, the high-risk group displayed reduced drug sensitivity and poor responses to immunotherapy. This research provides insights into anoikis in PTC, offering a novel ARG signature for predicting patient prognosis and guiding personalized treatment strategies.
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Anoicis , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Humanos , Anoicis/genética , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Pronóstico , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/mortalidad , Masculino , Femenino , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Nomogramas , Perfilación de la Expresión GénicaRESUMEN
BACKGROUND: Anoikis resistance is a hallmark characteristic of oncogenic transformation, which is crucial for tumor progression and metastasis. The aim of this study was to identify and validate a novel anoikis-related prognostic model for prostate cancer (PCa). METHODS: We collected a gene expression profile, single nucleotide polymorphism mutation and copy number variation (CNV) data of 495 PCa patients from the TCGA database and 140 PCa samples from the MSKCC dataset. We extracted 434 anoikis-related genes and unsupervised consensus cluster analysis was used to identify molecular subtypes. The immune infiltration, molecular function, and genome alteration of subtypes were evaluated. A risk signature was developed using Cox regression analysis and validated with the MSKCC dataset. We also identify potential drugs for high-risk group patients. RESULTS: Two subtypes were identified. C1 exhibited a higher level of CNV amplification, immune score, stromal score, aneuploidy score, homologous recombination deficiency, intratumor heterogeneity, single-nucleotide variant neoantigens, and tumor mutational burden compared to C2. C2 showed a better survival outcome and had a high level of gamma delta T cell and activated B cell infiltration. The risk signature consisting of four genes (HELLS, ZWINT, ABCC5, and TPSB2) was developed (area under the curve = 0.780) and was found to be an independent prognostic factor for overall survival in PCa patients. Four CTRP-derived and four PRISM-derived compounds were identified for high-risk patients. CONCLUSIONS: The anoikis-related prognostic model developed in this study could be a useful tool for clinical decision-making. This study may provide a new perspective for the treatment of anoikis-related PCa.