-
Medical Science Monitor : International... Jun 2024BACKGROUND Hepatocellular carcinoma (HCC) poses a significant threat to human life and is the most prevalent form of liver cancer. The intricate interplay between...
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.
Topics: Humans; Anoikis; Apoptosis; Biomarkers, Tumor; Carcinoma, Hepatocellular; Databases, Genetic; Gene Expression Regulation, Neoplastic; Liver Neoplasms; Prognosis; RNA, Long Noncoding
PubMed: 38824386
DOI: 10.12659/MSM.943523 -
Anticancer Research Jun 2024Epidermal growth factor receptor (EGFR) over-expression is commonly observed in advanced head and neck squamous cell carcinoma (HNSCC) and is correlated with poor...
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.
Topics: Humans; Dual Specificity Phosphatase 6; ErbB Receptors; Squamous Cell Carcinoma of Head and Neck; Cell Movement; Head and Neck Neoplasms; Disease Progression; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Anoikis; Signal Transduction; Carcinoma, Squamous Cell
PubMed: 38821599
DOI: 10.21873/anticanres.17060 -
Breast Cancer Research : BCR May 2024Despite progress understanding the mechanisms underlying tumor spread, metastasis remains a clinical challenge. We identified the choline-producing...
BACKGROUND
Despite progress understanding the mechanisms underlying tumor spread, metastasis remains a clinical challenge. We identified the choline-producing glycerophosphodiesterase, EDI3 and reported its association with metastasis-free survival in endometrial cancer. We also observed that silencing EDI3 slowed cell migration and other cancer-relevant phenotypes in vitro. Recent work demonstrated high EDI3 expression in ER-HER2+ breast cancer compared to the other molecular subtypes. Silencing EDI3 in ER-HER2+ cells significantly reduced cell survival in vitro and decreased tumor growth in vivo. However, a role for EDI3 in tumor metastasis in this breast cancer subtype was not explored. Therefore, in the present work we investigate whether silencing EDI3 in ER-HER2+ breast cancer cell lines alters phenotypes linked to metastasis in vitro, and metastasis formation in vivo using mouse models of experimental metastasis.
METHODS
To inducibly silence EDI3, luciferase-expressing HCC1954 cells were transduced with lentiviral particles containing shRNA oligos targeting EDI3 under the control of doxycycline. The effect on cell migration, adhesion, colony formation and anoikis was determined in vitro, and significant findings were confirmed in a second ER-HER2+ cell line, SUM190PT. Doxycycline-induced HCC1954-luc shEDI3 cells were injected into the tail vein or peritoneum of immunodeficient mice to generate lung and peritoneal metastases, respectively and monitored using non-invasive bioluminescence imaging. Metabolite levels in cells and tumor tissue were analyzed using targeted mass spectrometry and MALDI mass spectrometry imaging (MALDI-MSI), respectively.
RESULTS
Inducibly silencing EDI3 reduced cell adhesion and colony formation, as well as increased susceptibility to anoikis in HCC1954-luc cells, which was confirmed in SUM190PT cells. No influence on cell migration was observed. Reduced luminescence was seen in lungs and peritoneum of mice injected with cells expressing less EDI3 after tail vein and intraperitoneal injection, respectively, indicative of reduced metastasis. Importantly, mice injected with EDI3-silenced cells survived longer. Closer analysis of the peritoneal organs revealed that silencing EDI3 had no effect on metastatic organotropism but instead reduced metastatic burden. Finally, metabolic analyses revealed significant changes in choline and glycerophospholipid metabolites in cells and in pancreatic metastases in vivo.
CONCLUSIONS
Reduced metastasis upon silencing supports EDI3's potential as a treatment target in metastasizing ER-HER2+ breast cancer.
Topics: Animals; Female; Humans; Mice; Cell Line, Tumor; Receptor, ErbB-2; Breast Neoplasms; Receptors, Estrogen; Disease Models, Animal; Cell Movement; Gene Knockdown Techniques; Tumor Burden; Neoplasm Metastasis; Lung Neoplasms; Cell Proliferation
PubMed: 38816770
DOI: 10.1186/s13058-024-01849-y -
Advanced Healthcare Materials May 2024Bone metastases occur in more than 70% of advanced prostate cancer (PCa) patients, leading to a poor prognosis. Resistance to detachment-induced apoptosis, also known as...
Bone metastases occur in more than 70% of advanced prostate cancer (PCa) patients, leading to a poor prognosis. Resistance to detachment-induced apoptosis, also known as anoikis, plays a crucial role in the onset of tumor metastasis. Targeting anoikis resistance is of immense therapeutic significance in repression of metastatic spread. In this study, based on an anoikis-related prognostic risk model of PCa, this study identifies TUBB3 as a key anoikis-related prognostic gene that is highly expressed in bone metastatic PCa. TUBB3 expression is increased in anoikis-resistant PCa cells, and TUBB3 depletion significantly reverses anoikis resistance during extracellular matrix (ECM) detachment and inhibits anoikis-resistance-induced PCa cell invasion and migration as well as epithelial-mesenchymal transition (EMT) process. TUBB3 knockdown significantly reduces αvβ3/FAK/Src axis activation, blocking its downstream oncogenic signaling. In addition, this work develops bone-targeting lipid nanoparticles (BT-LNP) based on bisphosphonate-modified ionizable lipid for systemic delivery of siRNA targeting TUBB3 (siTUBB3). BT-LNP-delivered siTUBB3 therapy with localization in the bone microenvironment significantly attenuate PCa bone metastasis progression in vivo upon intravenous administration. These findings pinpoint that TUBB3, as a key regulator of anoikis resistance, is an effective therapeutic target in bone metastatic PCa and that BT-LNP-mediated systemic delivery of siTUBB3 can be developed as a novel therapeutic strategy for this disease.
PubMed: 38809199
DOI: 10.1002/adhm.202400673 -
Lung Cancer (Amsterdam, Netherlands) Jun 2024We aimed to reveal the clinicopathological differences between epidermal growth factor receptor (EGFR)-mutated and wild-type (WT) lung adenocarcinoma (LUAD) focusing on...
OBJECTIVES
We aimed to reveal the clinicopathological differences between epidermal growth factor receptor (EGFR)-mutated and wild-type (WT) lung adenocarcinoma (LUAD) focusing on the predominant subtype.
METHODS
This study included 352 with EGFR mutation and 370 with WT patients in consecutive stage I LUAD classified by the predominant subtype, and their clinicopathological characteristics and prognosis were analyzed. Using the Cancer Genome Atlas Program (TCGA) cohort, we analyzed differences in gene expression between EGFR mutation and WT groups. Furthermore, we performed immunohistochemical evaluations for 46 with EGFR mutation and 47 with WT patients in consecutive stage I papillary predominant adenocarcinoma (PPA).
RESULTS
Compared to the PPA with WT [n = 115], those with EGFR mutation [n = 99] exhibited smaller invasive size (p = 0.03) and less frequent vessel invasion (p < 0.01). However, PPA with EGFR mutation showed significantly worse 5-ys recurrence-free survival (RFS) rates compared to those with WT (70.6 % versus 83.3 %, p = 0.03). Contrarily, no significant differences were observed in other predominant subtypes. In the TCGA cohort, PPA with EGFR mutation tended to show higher expression of galectin-3, which is associated with tumor metastasis and resistance to anoikis, compared to those with WT (p = 0.06). Immunohistochemical evaluation revealed that galectin-3 expression was significantly higher in PPA with EGFR mutation than in those with WT (p < 0.01).
CONCLUSIONS
The prognosis of PPA with EGFR mutation proved to be less favorable compared to that with WT, and galectin-3 is highly expressed in EGFR-mutated PPA.
Topics: Humans; ErbB Receptors; Male; Female; Mutation; Lung Neoplasms; Adenocarcinoma of Lung; Aged; Middle Aged; Prognosis; Neoplasm Staging; Biomarkers, Tumor; Galectin 3; Aged, 80 and over; Adult; Adenocarcinoma, Papillary
PubMed: 38805901
DOI: 10.1016/j.lungcan.2024.107830 -
Heliyon May 2024Esophageal cancer (EC) is a prevalent malignancy with heterogeneous outcomes. This study explores the significance of anoikis-related long non-coding RNAs (lncRNAs) in...
BACKGROUND
Esophageal cancer (EC) is a prevalent malignancy with heterogeneous outcomes. This study explores the significance of anoikis-related long non-coding RNAs (lncRNAs) in EC, aiming to unravel their molecular roles and clinical implications.
METHODS
Transcriptome and clinical data were obtained from TCGA database for EC samples. We identified anoikis-related genes and lncRNAs by Pearson correlation analysis. The risk score model hinged on prognostic lncRNAs filtered from multiple steps. Risk scores were calculated using the derived formula, and categorized patients into low- and high-risk groups. Model robustness was assessed through Kaplan-Meier (KM) survival analysis and Receiver Operating Characteristic (ROC) curve, with clinical utility achieved via a constructed nomogram. We also explored the interplay between the risk score and immune cell infiltration, and investigated drug sensitivity.
RESULTS
We identified 2365 anoikis-related lncRNAs through co-expression analysis, including 1415 significant lncRNAs differentially expressed between normal and tumor samples. A risk score model was constructed from ten prognostic lncRNAs. The risk score model effectively stratified patients based on the median score, and its predictive capacity was validated through KM survival, ROC curve analyses, and the external GSE53622 dataset. The nomogram provided a practical tool for individualized prognosis evaluation. We unveiled significant correlations between specific immune cell subsets and the risk score. Eosinophils and common lymphoid progenitors exhibited positive associations, while endothelial cells and myeloid dendritic cells showed negative correlations. Drug sensitivity analysis revealed potential sensitive drugs for EC treatment that aligned with the risk subgroups.
CONCLUSION
This study established an anoikis-related lncRNAs risk score model that may predict the prognosis, immune infiltration, and drug sensitivity in EC, in hope of facilitating tailored patient management.
PubMed: 38803953
DOI: 10.1016/j.heliyon.2024.e31202 -
Cell Stress 2024Anoikis is a common programmed death for most of detached cells, but cancer cells can obtain anoikis resistance to facilitate their distant metastasis through the...
Anoikis is a common programmed death for most of detached cells, but cancer cells can obtain anoikis resistance to facilitate their distant metastasis through the circulation system. Researches have indicated that enhanced autophagic flux accounts for the survival of many cancer cells under detached conditions. Targeting ATG4B, the key factor of autophagy progress, can inhibit cancer metastasis , but ATG4B-deficient mice are susceptible to many serious diseases, which indicates the potential uncontrolled side effects of direct targeting of ATG4B. In our recent research, we confirmed that ATG4B is a novel RNA binding protein in the gastric cancer (GC) cell. It interacts with SPECC1 which consequently facilitates the liquid-liquid phase separation and ubiquitination of ATG4B. Additionally, the mA reader ELAVL1 inhibits the expression of SPECC1 to enhance the expression of ATG4B and anoikis resistance of GC cells. Further, we screened out an FDA-approved compound, lopinavir, to restore SPECC1 abundance and suppress GC metastasis. In conclusion, our research identified a novel signal pathway (ELAVL1-SPECC1-ATG4B-autophagy) to facilitate anoikis resistance and metastasis of GC cells and screened out a compound with clinical application potential to block this pathway, providing a novel strategy for the prevention of GC metastasis.
PubMed: 38803355
DOI: 10.15698/cst2024.05.296 -
Scientific Reports May 2024This study tackles the persistent prognostic and management challenges of clear cell renal cell carcinoma (ccRCC), despite advancements in multimodal therapies. Focusing...
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.
Topics: Humans; Carcinoma, Renal Cell; Anoikis; Kidney Neoplasms; Prognosis; Biomarkers, Tumor; Tumor Microenvironment; Gene Expression Regulation, Neoplastic; Epithelial Cells; Male; Female; Gene Expression Profiling; Nomograms
PubMed: 38802480
DOI: 10.1038/s41598-024-62978-0 -
Gene Oct 2024Pancreatic adenocarcinoma (PAAD) is one of the most malignant cancers. After escaping death, cancer cells are made more metastatic, aggressive, and also drug-resistant...
Pancreatic adenocarcinoma (PAAD) is one of the most malignant cancers. After escaping death, cancer cells are made more metastatic, aggressive, and also drug-resistant through anoikis resistance. The aim of this study is to explore the molecular mechanisms of anoikis-related genes in PAAD and to identify potential key biomarkers. We integrated information about PAAD from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx) databases and identified anoikis-related gene BCL2L1 by survival analysis, univariate Cox regression analysis, and multifactorial Cox regression analysis. Various bioinformatics approaches showed that BCL2L1 was a valuable prognostic marker that might be involved in PAAD development and progression through different mechanisms, including cancer intervention, genomic heterogeneity, and RNA modifications. Our analysis showed that BCL2L1 expression also closely correlates with the expression of various immune checkpoint inhibitors. In particular, we found that long non-coding RNA MIR4435-2HG acted as ceRNA sponging miR-513a-5p to promote the expression of BCL2L1, thereby promoting pancreatic cancer cells proliferation. In conclusion, BCL2L1 expression regulated by the MIR4435-2HG-miR-513a-5p-BCL2L1 ceRNA axis might be used as a biomarker for cancer prognosis, treatment selection, and follow-up in PAAD patients.
Topics: Humans; Pancreatic Neoplasms; RNA, Long Noncoding; MicroRNAs; Biomarkers, Tumor; Prognosis; bcl-X Protein; Gene Expression Regulation, Neoplastic; Adenocarcinoma; Cell Line, Tumor; Cell Proliferation; Male; RNA, Competitive Endogenous
PubMed: 38788819
DOI: 10.1016/j.gene.2024.148615 -
Archives of Dermatological Research May 2024Skin cutaneous melanoma (SKCM) is malignant cancer known for its high aggressiveness and unfavorable prognosis, particularly in advanced tumors. Anoikis is a specific...
Skin cutaneous melanoma (SKCM) is malignant cancer known for its high aggressiveness and unfavorable prognosis, particularly in advanced tumors. Anoikis is a specific pattern of programmed cell death associated with tumor regeneration, migration, and metastasis. Nevertheless, limited research has been conducted to investigate the function of anoikis in SKCM. Anoikis-related genes (ARGs) were extracted from Genecards to identify SKCM subtypes and to explore the immune microenvironment between the different subtypes. Prognostic models of SKCM were developed by LASSO COX regression analysis. Subsequently, the predictive value of risk scores in SKCM and the association with immunotherapy were further explored. Finally, the expression of 6 ARGs involved in the model construction was detected by immunohistochemistry and PCR. This study identified 20 ARGs significantly associated with SKCM prognosis and performed disease subtype analysis of samples based on these genes, different subtypes exhibited significantly different clinical features and tumor immune microenvironment (TIME) landscapes. The risk score prognostic model was generated by further screening and identification of the six ARGs. The model exhibited a high degree of sensitivity and specificity to predict the prognosis of individuals with SKCM. These high- and low-risk populations showed different immune statuses and drug sensitivity. Further immunohistochemical and PCR experiments identified significant differential expression of the six ARGs in tumor and normal samples. Anoikis-based features may serve as novel prognostic biomarkers for SKCM and may provide important new insights for survival prediction and individualized treatment development.
Topics: Humans; Melanoma; Anoikis; Skin Neoplasms; Biomarkers, Tumor; Tumor Microenvironment; Prognosis; Immunotherapy; Female; Male; Melanoma, Cutaneous Malignant; Middle Aged; Gene Expression Regulation, Neoplastic
PubMed: 38787413
DOI: 10.1007/s00403-024-03085-y