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Translational Cancer Research Apr 2024Lung adenocarcinoma (LUAD), a type of lung cancer, is one of the most aggressive and deadly malignancies worldwide. Malignant tumor cells exhibit strong anti-anoikis...
BACKGROUND
Lung adenocarcinoma (LUAD), a type of lung cancer, is one of the most aggressive and deadly malignancies worldwide. Malignant tumor cells exhibit strong anti-anoikis properties to achieve distant metastasis through the circulatory system. However, more research is needed to understand how anoikis is involved in the progression, metastasis and especially the prognosis of LUAD.
METHODS
We obtained anoikis-related genes (ARGs) from two websites, Harmonizome and Genecards, and integrated them to select and model the genes associated with LUAD prognosis. In addition, we investigated differences in the immune cell microenvironment and pathways of enrichment analysis between subtypes. We finally constructed a nomogram based on ARGs and used decision curve analysis (DCA) to demonstrate that this model could help clinicians make clinical decisions.
RESULTS
Sixty-four differentially expressed genes (DEGs) were found to be associated with survival, and of these, six were chosen to build a prognostic model. The time-dependent receiver operating characteristic (ROC) curves showed that the model had a satisfactory predictive ability. Enrichment analysis and immune microenvironment analysis revealed that the immune status and drug sensitivity of populations at high and low risk were different. We integrated the clinicopathological features of LUAD with the risk score to build the nomogram. The nomogram was shown to be a good predictor of short- and long-term survival in LUAD patients through DCA analysis.
CONCLUSIONS
This new model based on six ARGs and nomograms in our study could help patients with LUAD develop personalized treatment plans.
PubMed: 38737691
DOI: 10.21037/tcr-23-2185 -
Translational Cancer Research Apr 2024Hepatocellular carcinoma (HCC) is a major health problem with more than 850,000 cases per year worldwide. This cancer is now the third leading cause of cancer-related...
BACKGROUND
Hepatocellular carcinoma (HCC) is a major health problem with more than 850,000 cases per year worldwide. This cancer is now the third leading cause of cancer-related deaths worldwide, and the number is rising. Cancer cells develop anoikis resistance which is a vital step during cancer progression and metastatic colonization. However, there is not much research that specifically addresses the role of anoikis in HCC, especially in terms of prognosis.
METHODS
This study obtained gene expression data and clinical information from 371 HCC patients through The Cancer Genome Atlas (TCGA) Program and The Gene Expression Omnibus (GEO) databases. A total of 516 anoikis-related genes (ANRGs) were retrieved from GeneCard database and Harmonizome portal. Differential expression analysis identified 219 differentially expressed genes (DEGs), and univariate Cox regression analysis was utilized to select 99 ANRGs associated with the prognosis of HCC patients. A risk scoring model with seven genes was established using the least absolute shrinkage and selection operator (LASSO) regression model, and internal validation of the model was performed.
RESULTS
The identified 99 ANRGs are closely associated with the prognosis of HCC patients. The risk scoring model based on seven characteristic genes demonstrates excellent predictive performance, further validated by receiver operating characteristic (ROC) curves and Kaplan-Meier survival curves. The study reveals significant differences in immune cell infiltration, gene expression, and survival status among different risk groups.
CONCLUSIONS
The prognosis of HCC patients can be predicted using a unique prognostic model built on ANRGs in HCC.
PubMed: 38737687
DOI: 10.21037/tcr-23-2096 -
Medicine May 2024Papillary thyroid carcinoma (PTC) prognosis may be deteriorated due to the metastases, and anoikis palys an essential role in the tumor metastasis. However, the...
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.
Topics: Humans; Thyroid Cancer, Papillary; Anoikis; Thyroid Neoplasms; Prognosis; Single-Cell Analysis; Sequence Analysis, RNA; Protein Interaction Maps; Female; Male; Kaplan-Meier Estimate; Gene Expression Regulation, Neoplastic; Gene Expression Profiling
PubMed: 38728457
DOI: 10.1097/MD.0000000000038144 -
Gut Apr 2024The dysregulation of the axon guidance pathway is common in pancreatic ductal adenocarcinoma (PDAC), yet our understanding of its biological relevance is limited. Here,...
OBJECTIVE
The dysregulation of the axon guidance pathway is common in pancreatic ductal adenocarcinoma (PDAC), yet our understanding of its biological relevance is limited. Here, we investigated the functional role of the axon guidance cue SEMA3A in supporting PDAC progression.
DESIGN
We integrated bulk and single-cell transcriptomic datasets of human PDAC with in situ hybridisation analyses of patients' tissues to evaluate SEMA3A expression in molecular subtypes of PDAC. Gain and loss of function experiments in PDAC cell lines and organoids were performed to dissect how SEMA3A contributes to define a biologically aggressive phenotype.
RESULTS
In PDAC tissues, SEMA3A is expressed by stromal elements and selectively enriched in basal-like/squamous epithelial cells. Accordingly, expression of SEMA3A in PDAC cells is induced by both cell-intrinsic and cell-extrinsic determinants of the basal-like phenotype. , SEMA3A promotes cell migration as well as anoikis resistance. At the molecular level, these phenotypes are associated with increased focal adhesion kinase signalling through canonical SEMA3A-NRP1 axis. SEMA3A provides mouse PDAC cells with greater metastatic competence and favours intratumoural infiltration of tumour-associated macrophages and reduced density of T cells. Mechanistically, SEMA3A functions as chemoattractant for macrophages and skews their polarisation towards an M2-like phenotype. In SEMA3A tumours, depletion of macrophages results in greater intratumour infiltration by CD8+T cells and better control of the disease from antitumour treatment.
CONCLUSIONS
Here, we show that SEMA3A is a stress-sensitive locus that promotes the malignant phenotype of basal-like PDAC through both cell-intrinsic and cell-extrinsic mechanisms.
PubMed: 38670629
DOI: 10.1136/gutjnl-2023-329807 -
Medicine Apr 2024Anoikis is considered strongly associated with a biological procession of tumors. Herein, we utilized anoikis-related genes (ARGs) to predict the prognosis and...
Anoikis is considered strongly associated with a biological procession of tumors. Herein, we utilized anoikis-related genes (ARGs) to predict the prognosis and immunotherapeutic efficacy for skin cutaneous melanoma (SKCM). RNA-seq data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases. After dividing patients into novel subtypes based on the expression of prognostic ARGs, K-M survival was conducted to compare the survival status. Subsequently, differentially expressed ARGs were identified and the predictive model was established. The predictive effects were validated using the areas under the curve about the receiver operating characteristic. Moreover, tumor mutation burden, the enriched functional pathway, immune cells and functions, and the immunotherapeutic response were also analyzed and compared. The distribution of model genes at cell level was visualized by the single-cell seq with tumor immune single-cell hub database. Patients of The Cancer Genome Atlas-SKCM cohort were divided into 2 clusters, the cluster 1 performed a better prognosis. Cluster 2 was more enriched in metabolism-related pathways whereas cluster 1 was more associated with immune pathways. A predictive risk model was established with 6 ARGs, showing the areas under the curves of 1-year, 3-year, and 5-year ROC were 0.715, 0,720, and 0.731, respectively. Moreover, risk score was negatively associated with tumor mutation burden and immune-related pathways enrichment. In addition, patients with high-risk scores performed immunosuppressive status but the decreasing scores enhanced immune cell infiltration, immune function activation, and immunotherapeutic response. In this study, we established a novel signature in predicting prognosis and immunotherapy. It can be considered reliable to formulate the complex treatment for SKCM patients.
Topics: Humans; Melanoma; Skin Neoplasms; Anoikis; Prognosis; Melanoma, Cutaneous Malignant; Male; Female; Immunotherapy; Middle Aged; ROC Curve; Gene Expression Regulation, Neoplastic
PubMed: 38669429
DOI: 10.1097/MD.0000000000037900 -
Aging Apr 2024Thyroid cancer, notably papillary thyroid cancer (PTC), is a global health concern with increasing incidence. Anoikis, a regulator of programmed cell death, is pivotal...
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.
Topics: Humans; Anoikis; Thyroid Cancer, Papillary; Prognosis; Thyroid Neoplasms; Male; Female; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor; Middle Aged; Nomograms; Gene Expression Profiling
PubMed: 38663918
DOI: 10.18632/aging.205766 -
Cellular and Molecular Life Sciences :... Apr 2024Peritoneal metastasis, the third most common metastasis in colorectal cancer (CRC), has a poor prognosis for the rapid progression and limited therapeutic strategy....
Peritoneal metastasis, the third most common metastasis in colorectal cancer (CRC), has a poor prognosis for the rapid progression and limited therapeutic strategy. However, the molecular characteristics and pathogenesis of CRC peritoneal metastasis are poorly understood. Here, we aimed to elucidate the action and mechanism of adipose-derived stem cells (ADSCs), a prominent component of the peritoneal microenvironment, in CRC peritoneal metastasis formation. Database analysis indicated that ADSCs infiltration was increased in CRC peritoneal metastases, and high expression levels of ADSCs marker genes predicted a poor prognosis. Then we investigated the effect of ADSCs on CRC cells in vitro and in vivo. The results revealed that CRC cells co-cultured with ADSCs exhibited stronger metastatic property and anoikis resistance, and ADSCs boosted the intraperitoneal seeding of CRC cells. Furthermore, RNA sequencing was carried out to identify the key target gene, angiopoietin like 4 (ANGPTL4), which was upregulated in CRC specimens, especially in peritoneal metastases. Mechanistically, TGF-β1 secreted by ADSCs activated SMAD3 in CRC cells, and chromatin immunoprecipitation assay showed that SMAD3 facilitated ANGPTL4 transcription by directly binding to ANGPTL4 promoter. The ANGPTL4 upregulation was essential for ADSCs to promote glycolysis and anoikis resistance in CRC. Importantly, simultaneously targeting TGF-β signaling and ANGPTL4 efficiently reduced intraperitoneal seeding in vivo. In conclusion, this study indicates that tumor-infiltrating ADSCs promote glycolysis and anoikis resistance in CRC cells and ultimately facilitate peritoneal metastasis via the TGF-β1/SMAD3/ANGPTL4 axis. The dual-targeting of TGF-β signaling and ANGPTL4 may be a feasible therapeutic strategy for CRC peritoneal metastasis.
Topics: Humans; Peritoneal Neoplasms; Transforming Growth Factor beta1; Glycolysis; Colorectal Neoplasms; Stem Cells; Tumor Microenvironment; Smad3 Protein; Angiopoietin-Like Protein 4
PubMed: 38643448
DOI: 10.1007/s00018-024-05215-1 -
Experimental Cell Research May 2024Anoikis plays a crucial role in the progression, prognosis, and immune response of lung adenocarcinoma (LUAD). However, its specific impact on LUAD remains unclear. In...
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.
Topics: Humans; Anoikis; Adenocarcinoma of Lung; Lung Neoplasms; Prognosis; Tumor Microenvironment; Gene Expression Regulation, Neoplastic; Female; Male; Middle Aged; Cell Line, Tumor; Apoptosis
PubMed: 38631545
DOI: 10.1016/j.yexcr.2024.114037 -
Biochemical and Biophysical Research... Jun 2024Low-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...
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. Kaplan‒Meier (K‒M) 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.
Topics: Humans; Anoikis; Glioma; Prognosis; Tissue Inhibitor of Metalloproteinase-1; Animals; Brain Neoplasms; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Mice; Male; Cell Proliferation; Female; Mice, Nude; Tumor Microenvironment; Neoplasm Grading
PubMed: 38603834
DOI: 10.1016/j.bbrc.2024.149894 -
Molecular Genetics & Genomic Medicine Apr 2024Anoikis resistance is a hallmark characteristic of oncogenic transformation, which is crucial for tumor progression and metastasis. The aim of this study was to identify...
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.
Topics: Male; Humans; Prognosis; Anoikis; DNA Copy Number Variations; Prostatic Neoplasms; Aneuploidy
PubMed: 38572916
DOI: 10.1002/mgg3.2419