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Scientific Reports Aug 2023Colon adenocarcinoma (COAD) is a serious public health problem, the third most common cancer and the second most deadly cancer in the world. About 9.4% of cancer-related...
Colon adenocarcinoma (COAD) is a serious public health problem, the third most common cancer and the second most deadly cancer in the world. About 9.4% of cancer-related deaths in 2020 were due to COAD. Anoikis is a specialized form of programmed cell death that plays an important role in tumor invasion and metastasis. The presence of anti-anoikis factors is associated with tumor aggressiveness and drug resistance. Various bioinformatic methods, such as differential expression analysis, and functional annotation analysis, machine learning, were used in this study. RNA-sequencing and clinical data from COAD patients were obtained from the Gene expression omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Construction of a prognostic nomogram for predicting overall survival (OS) using multivariate analysis and Lasso-Cox regression. Immunohistochemistry (IHC) was our method of validating the expression of seven genes that are linked to anoikis in COAD. We identified seven anoikis-related genes as predictors of COAD survival and prognosis, and confirmed their accuracy in predicting colon adenocarcinoma prognosis by KM survival curves and ROC curves. A seven-gene risk score consisting of NAT1, CDC25C, ATP2A3, MMP3, EEF1A2, PBK, and TIMP1 showed strong prognostic value. Meanwhile, we made a nomogram to predict the survival rate of COAD patients. The immune infiltration assay showed T cells. CD4 memory. Rest and macrophages. M0 has a higher proportion in COAD, and 11 genes related to tumor immunity are important. GDSC2-based drug susceptibility analysis showed that 6 out of 198 drugs were significant in COAD. Anoikis-related genes have potential value in predicting the prognosis of COAD and provide clues for developing new therapeutic strategies for COAD. Immune infiltration and drug susceptibility results provide important clues for finding new personalized treatment options for COAD. These findings also suggest possible mechanisms that may affect prognosis. These results are the starting point for planning individualized treatment and managing patient outcomes.
Topics: Humans; Colonic Neoplasms; Adenocarcinoma; Genes, Regulator; Genes, cdc; Anoikis; Peptide Elongation Factor 1
PubMed: 37626132
DOI: 10.1038/s41598-023-40907-x -
Scientific Reports Nov 2023Anoikis resistance, a notable factor in osteosarcoma, plays a significant role in tumor invasion and metastasis. This study seeks to identify a distinct gene signature...
Anoikis resistance, a notable factor in osteosarcoma, plays a significant role in tumor invasion and metastasis. This study seeks to identify a distinct gene signature that is specifically associated with the anoikis subcluster in osteosarcoma. Clinical, single-cell, and transcriptional data from TARGET and GEO datasets were used to develop a gene signature for osteosarcoma based on the anoikis subcluster. Univariate Cox and LASSO regression analyses were employed. The signature's predictive value was evaluated using time-dependent ROC and Kaplan-Meier analyses. Functional enrichment analyses and drug sensitivity analyses were conducted. Validation of three modular genes was performed using RT-qPCR and Western blotting. Signature (ZNF583, CGNL1, CXCL13) was developed to predict overall survival in osteosarcoma patients, targeting the anoikis subcluster. The signature demonstrated good performance in external validation. Stratification based on the signature revealed significantly different prognoses. The signature was an independent prognostic factor. The low-risk group showed enhanced immune cell infiltration and improved immune function. Drug sensitivity analysis indicated efficacy of chemotherapy agents. Prognostic nomograms incorporating the signature provided greater predictive accuracy and clinical utility. Signatures related to the anoikis subcluster play a significant role in osteosarcoma progression. Incorporating these findings into clinical decision-making can improve osteosarcoma treatment and patient outcomes.
Topics: Humans; Anoikis; Prognosis; Immunotherapy; Osteosarcoma; Bone Neoplasms
PubMed: 37980450
DOI: 10.1038/s41598-023-47367-3 -
Current Medical Science Aug 2023Histone modification has a significant effect on gene expression. Enhancer of zeste homolog 2 (EZH2) contributes to the epigenetic silencing of target chromatin through...
OBJECTIVE
Histone modification has a significant effect on gene expression. Enhancer of zeste homolog 2 (EZH2) contributes to the epigenetic silencing of target chromatin through its roles as a histone-lysine N-methyltransferase enzyme. The development of anoikis resistance in tumor cells is considered to be a critical step in the metastatic process of primary malignant tumors. The purpose of this study was to investigate the effect and mechanism of anoikis resistance in ovarian adenocarcinoma peritoneal metastasis.
METHODS
In addition to examining EZH2 protein expression in ovarian cancer omental metastatic tissues, we established a model of ovarian cancer cell anoikis and a xenograft tumor model in nude mice. Anoikis resistance and ovarian cancer progression were tested after EZH2 and N6-methyladenosine (m6A) levels were modified.
RESULTS
EZH2 expression was significantly higher in ovarian cancer omental metastatic tissues than in normal ovarian tissues. Reducing the level of EZH2 decreased the level of m6A and ovarian cancer cell anoikis resistance in vitro and inhibited ovarian cancer progression in vivo. M6a regulation altered the effect of EZH2 on anoikis resistance.
CONCLUSION
Our results indicate that EZH2 contributes to anoikis resistance and promotes ovarian adenocarcinoma abdominal metastasis by m6A modification. Our findings imply the potential of the clinical application of m6A and EZH2 for patients with ovarian cancer.
Topics: Animals; Female; Humans; Mice; Adenocarcinoma; Anoikis; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Enhancer of Zeste Homolog 2 Protein; Mice, Nude; Ovarian Neoplasms; Peritoneal Neoplasms
PubMed: 37498408
DOI: 10.1007/s11596-023-2719-4 -
Phytomedicine : International Journal... Jul 2024Temozolomide (TMZ) resistance is the main obstacle faced by glioblastoma multiforme (GBM) treatment. Muscone, one of the primary active pharmacological ingredients of...
BACKGROUND
Temozolomide (TMZ) resistance is the main obstacle faced by glioblastoma multiforme (GBM) treatment. Muscone, one of the primary active pharmacological ingredients of Shexiang (Moschus), can cross the blood-brain barrier (BBB) and is being investigated as an antineoplastic medication. However, muscone treatment for GBM has received little research, and its possible mechanisms are still unclear.
PURPOSE
This study aims to evaluate the effect and the potential molecular mechanism of muscone on TMZ-resistant GBM cells.
METHODS
The differentially expressed genes (DEGs) between TMZ-resistant GBM cells and TMZ-sensitive GBM cells were screened using GEO2R. By progressively raising the TMZ concentration, a relatively stable TMZ-resistant human GBM cell line was established. The drug-resistance traits of U251-TR cells were assessed via the CCK-8 assay and Western Blot analysis of MGMT and TOP2A expression. Cell viability, cell proliferation, cell migration ability, and drug synergism were detected by the CCK-8 assay, colony formation assay, wound healing assay, and drug interaction relationship test, respectively. Anoikis was quantified by Calcein-AM/EthD-1 staining, MTT assay, and flow cytometry. Measurements of cell cycle arrest, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) were performed using cell cycle staining, Annexin V-FITC/PI labeling, JC-1 assay, and ROS assay, respectively. DNA damage was measured by TUNEL assay, alkaline comet assay, and γ-H2AX foci assay. GEPIA was used to investigate the link between the anoikis marker (FAK)/drug resistance gene and critical proteins in the EGFR/Integrin β1 signaling pathway. Molecular docking was used to anticipate the probable targets of muscone. The intracellular co-localization and expression of EGFR and FAK were shown using immunofluorescence. The U251-TR cell line stably overexpressing EGFR was constructed using lentiviral transduction to assess the involvement of EGFR-related signaling in anoikis resistance. Western Blot was employed to detect the expression of migration-related proteins, cyclins, anoikis-related proteins, DNA damage/repair-related proteins, and associated pathway proteins.
RESULTS
DEGs analysis identified 97 deregulated chemotherapy-resistant genes and 3779 upregulated genes in TMZ-resistant GBM cells. Subsequent experiments verified TMZ resistance and the hyper-expression of DNA repair-related genes (TOP2A and MGMT) in continuously low-dose TMZ-induced U251-TR cells. Muscone exhibited dose-dependent inhibition of U251-TR cell migration and proliferation, and its co-administration with TMZ showed the potential for enhanced therapeutic efficacy. By downregulating FAK, muscone reduced anoikis resistance in anchorage-independent U251-TR cells. It also caused cell cycle arrest in the G2/M phase by upregulating p21 and downregulating CDK1, CDK2, and Cyclin E1. Muscone-induced anoikis was accompanied by mitochondrial membrane potential collapse, ROS production, an increase in the BAX/Bcl-2 ratio, as well as elevated levels of Cytochrome c (Cyt c), cleaved caspase-9, and cleaved caspase-3. These findings indicated that muscone might trigger mitochondrial-dependent anoikis via ROS generation. Moreover, significant DNA damage, DNA double-strand breaks (DSBs), the formation of γ-H2AX foci, and a reduction in TOP2A expression are also associated with muscone-induced anoikis. Overexpression of EGFR in U251-TR cells boosted the expression of Integrin β1, FAK, β-Catenin, and TOP2A, whereas muscone suppressed the expression levels of EGFR, Integrin β1, β-Catenin, FAK, and TOP2A. Muscone may influence the expression of the key DNA repair enzyme, TOP2A, by suppressing the EGFR/Integrin β1/FAK pathway.
CONCLUSION
We first demonstrated that muscone suppressed TOP2A expression through the EGFR/Integrin β1/FAK pathway, hence restoring anoikis sensitivity in TMZ-resistant GBM cells. These data suggest that muscone may be a promising co-therapeutic agent for enhancing GBM treatment, particularly in cases of TMZ-resistant GBM with elevated TOP2A expression.
Topics: Humans; Glioblastoma; Temozolomide; Drug Resistance, Neoplasm; Signal Transduction; Cell Line, Tumor; Focal Adhesion Kinase 1; Anoikis; Integrin beta1; ErbB Receptors; DNA Topoisomerases, Type II; Cell Movement; Cell Proliferation; Poly-ADP-Ribose Binding Proteins; Cell Survival; Apoptosis; Reactive Oxygen Species
PubMed: 38723526
DOI: 10.1016/j.phymed.2024.155714 -
Critical Reviews in Oncology/hematology Aug 2019Metastasis leads to poor prognosis and reduced disease-free survival in breast cancer patients, particularly in those with triple-negative breast cancer (TNBC) which is... (Review)
Review
Metastasis leads to poor prognosis and reduced disease-free survival in breast cancer patients, particularly in those with triple-negative breast cancer (TNBC) which is resistant to common treatments. Anoikis is a type of apoptosis commenced by the detachment of cells from the native extracellular matrix and prohibits the attachment of detached cells to other body organs. Resistance to anoikis is a critical culprit in the development and progression of tumours. It is therefore important to understand the anoikis-related molecular pathways in order to design effective therapies for TNBC. Several compounds have been shown to possess the potential to regulate anoikis in breast cancer cells such as DSF, AEB071, nanoencapsulated doxorubicin, berberine, salinomycin, PEM POL5551, AL10, 5-azacytidine, synthesized flavonoid derivative GL-V9, Tubeimoside V (TBMS-V) and HPW-RX40. We reviewed the molecular basis of anoikis regulation, its potential role as an important target to inhibit metastasis in TNBC, and potential anoikis modulators that could serve as drug candidates.
Topics: Anoikis; Berberine; Chlorobenzoates; Female; Gene Expression Regulation, Neoplastic; Humans; Pyrans; Pyrroles; Quinazolines; Saponins; Signal Transduction; Styrenes; Triple Negative Breast Neoplasms
PubMed: 31154235
DOI: 10.1016/j.critrevonc.2019.05.009 -
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 -
Aging Jan 2024Hepatocellular carcinoma (HCC) exhibits a high degree of invasiveness and is closely associated with rapid disease progression. Multiple lines of evidence indicate a...
BACKGROUND
Hepatocellular carcinoma (HCC) exhibits a high degree of invasiveness and is closely associated with rapid disease progression. Multiple lines of evidence indicate a strong correlation between anoikis resistance and tumor progression, invasion, and metastasis. Nevertheless, the classification of anoikis in HCC and the investigation of novel biological target mechanisms in this context continue to pose challenges, requiring further exploration.
METHODS
Combined with HCC samples from TCGA, GEO and ICGC databases, cluster analysis was conducted on anoikis genes, revealing novel patterns among different subtypes. Significant gene analysis of different gene subtypes was performed using WCGNA. The anoikis prognostic risk model was established by Lasso-Cox. Go, KEGG, and GSEA were applied to investigate pathway enrichment primarily observed in risk groups. We compared the disparities in immune infiltration, TMB, tumor microenvironment (TME), and drug sensitivity between the two risk groups. RT-qPCR and Western blotting were performed to validate the expression levels of SLCO4C1 in HCC. The biological functions of SLCO4C1 in HCC cells were assessed through various experiments, including CCK8 assay, colony formation assay, invasion migration assay, wound healing assay, and flow cytometry analysis.
RESULTS
HCC was divided into 2 anoikis subtypes, and the subtypeB had a better prognosis. An anoikis prognostic model based on 12 (COPZ2, ACTG2, IFI27, SPP1, EPO, SLCO4C1, RAB26, STC2, RAC3, NQO1, MYCN, HSPA1B) risk genes is important for survival and prognosis. Significant differences were observed in immune cell infiltration, TME, and drug sensitivity analysis between the risk groups. SLCO4C1 was downregulated in HCC. SLCO4C1 downregulation promoted the proliferation, invasion, migration, and apoptosis of HCC cells. The tumor-suppressive role of SLCO4C1 in HCC has been confirmed.
CONCLUSIONS
Our study presents a novel anoikis classification method for HCC that reveals the association between anoikis features and HCC. The anoikis feature is a critical biomarker bridging tumor cell death and tumor immunity. In this study, we provided the first evidence of SLCO4C1 functioning as a tumor suppressor in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Anoikis; Liver Neoplasms; Biomarkers; Biological Assay; Tumor Microenvironment; Prognosis; Organic Anion Transporters
PubMed: 38226966
DOI: 10.18632/aging.205438 -
Clinical & Experimental Metastasis Oct 2022Anchorage-independent survival of cancer cells is associated with metastasis as it enables cells to travel to secondary target sites. Tissue integrity is generally... (Review)
Review
Anchorage-independent survival of cancer cells is associated with metastasis as it enables cells to travel to secondary target sites. Tissue integrity is generally maintained by detachment-induced cell death called 'anoikis', but cancer cells undergoing the multistep metastatic process show resistance to anoikis. Anoikis resistance enables these cells to survive through the extracellular matrix (ECM) deprived phase, which starts when cancer cells detach and move into the circulation till cells reach to the secondary target site. Comprehensive analysis of the molecular and functional biology of anoikis resistance in cancer cells will provide crucial details about cancer metastasis, enabling us to identify novel therapeutic targets against cancer cell dissemination and ultimately secondary tumor formation. This review broadly summarizes recent advances in the understanding of cellular and molecular events leading to anoikis and anoikis resistance. It further elaborates more about the signaling cross-talk in anoikis resistance and its regulation during metastasis.
Topics: Anoikis; Cell Line, Tumor; Cell Survival; Extracellular Matrix; Humans; Neoplasm Metastasis; Signal Transduction
PubMed: 35829806
DOI: 10.1007/s10585-022-10172-9 -
Epigenomics Oct 2023Anoikis is a type of programmed cell death that occurs in normal epithelial and endothelial cells. However, the specific role of anoikis regulators (ANRs) in bladder...
Anoikis is a type of programmed cell death that occurs in normal epithelial and endothelial cells. However, the specific role of anoikis regulators (ANRs) in bladder cancer (BLCA) remains unknown. Therefore, the objective of this study was to find subgroups that could identify different levels of anoikis resistance in BLCA and construct an anoikis scoring system to assess prognosis. By obtaining ANRs from public datasets, subgroups of BLCA with varying degrees of anoikis resistance were identified, and risk was determined. ANRs affects the occurrence and prognosis of BLCA and can be predicted by establishing risk models. The anoikis scoring system and anoikis-associated risk profiles may help develop more effective and personalized treatment strategies for BLCA patients.
Topics: Humans; Anoikis; Endothelial Cells; Prognosis; Urinary Bladder Neoplasms; Immunity; Tumor Microenvironment
PubMed: 37942553
DOI: 10.2217/epi-2023-0240 -
Aging Jan 2024Anoikis, a form of apoptotic cell death resulting from inadequate cell-matrix interactions, has been implicated in tumor progression by regulating tumor angiogenesis and...
Anoikis, a form of apoptotic cell death resulting from inadequate cell-matrix interactions, has been implicated in tumor progression by regulating tumor angiogenesis and metastasis. However, the potential roles of anoikis-related long non-coding RNAs (arlncRNAs) in the tumor microenvironment are not well understood. In this study, five candidate lncRNAs were screened through least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis based on differentially expressed lncRNAs associated with anoikis-related genes (ARGs) from TCGA and GSE40595 datasets. The prognostic accuracy of the risk model was evaluated using Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) analyses revealed significant differences in immune-related hallmarks and signal transduction pathways between the high-risk and low-risk groups. Additionally, immune infiltrate analysis showed significant differences in the distribution of macrophages M2, follicular T helper cells, plasma cells, and neutrophils between the two risk groups. Lastly, silencing the expression of PRR34_AS1 and SPAG5_AS1 significantly increased anoikis-induced cell death in ovarian cancer cells. In conclusion, our study constructed a risk model that can predict clinicopathological features, tumor microenvironment characteristics, and prognosis of ovarian cancer patients. The immune-related pathways identified in this study may offer new treatment strategies for ovarian cancer.
Topics: Humans; Female; Anoikis; Prognosis; RNA, Long Noncoding; Ovarian Neoplasms; Tumor Microenvironment; Cell Cycle Proteins
PubMed: 38226979
DOI: 10.18632/aging.205439