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BMC Biology Jun 2024The intermediate filament protein vimentin is widely recognized as a molecular marker of epithelial-to-mesenchymal transition. Although vimentin expression is strongly...
BACKGROUND
The intermediate filament protein vimentin is widely recognized as a molecular marker of epithelial-to-mesenchymal transition. Although vimentin expression is strongly associated with cancer metastatic potential, the exact role of vimentin in cancer metastasis and the underlying mechanism of its pro-metastatic functions remain unclear.
RESULTS
This study revealed that vimentin can enhance integrin β1 surface expression and induce integrin-dependent clustering of cells, shielding them against anoikis cell death. The increased integrin β1 surface expression in suspended cells was caused by vimentin-mediated protection of the internal integrin β1 pool against lysosomal degradation. Additionally, cell detachment was found to induce vimentin Ser38 phosphorylation, allowing the translocation of internal integrin β1 to the plasma membrane. Furthermore, the use of an inhibitor of p21-activated kinase PAK1, one of the kinases responsible for vimentin Ser38 phosphorylation, significantly reduced cancer metastasis in animal models.
CONCLUSIONS
These findings suggest that vimentin can act as an integrin buffer, storing internalized integrin β1 and releasing it when needed. Overall, this study provides insights regarding the strong correlation between vimentin expression and cancer metastasis and a basis for blocking metastasis using this novel therapeutic mechanism.
Topics: Vimentin; Integrin beta1; Anoikis; Humans; Animals; Cell Survival; Mice; Cell Line, Tumor; Phosphorylation; p21-Activated Kinases
PubMed: 38915055
DOI: 10.1186/s12915-024-01942-w -
International Journal of Molecular... May 2024Anoikis, a form of apoptosis resulting from the loss of cell-extracellular matrix interaction, is a significant barrier to cancer cell metastasis. However, the...
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 (), 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.
Topics: Humans; Anoikis; Colorectal Neoplasms; Sirtuins; Gene Expression Regulation, Neoplastic; Cell Cycle Proteins; Cell Line, Tumor; Intracellular Signaling Peptides and Proteins; Down-Regulation; Signal Transduction; Epigenesis, Genetic
PubMed: 38891773
DOI: 10.3390/ijms25115585 -
Aging Jun 2024Lung 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...
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 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.
Topics: Humans; RNA, Long Noncoding; Anoikis; Adenocarcinoma of Lung; Lung Neoplasms; Prognosis; Gene Expression Regulation, Neoplastic; Biomarkers, Tumor; Female; Male; Cell Line, Tumor; Nomograms; Middle Aged; Cell Movement
PubMed: 38850527
DOI: 10.18632/aging.205905 -
Biomedicine & Pharmacotherapy =... Jul 2024Tumor metastasis occurs in hepatocellular carcinoma (HCC), leading to tumor progression and therapeutic failure. Anoikis is a matrix detachment-induced apoptosis, also... (Review)
Review
Tumor metastasis occurs in hepatocellular carcinoma (HCC), leading to tumor progression and therapeutic failure. Anoikis is a matrix detachment-induced apoptosis, also known as detachment-induced cell death, and mechanistically prevents tumor cells from escaping their native extracellular matrix to metastasize to new organs. Deciphering the regulators and mechanisms of anoikis in cancer metastasis is urgently needed to treat HCC. Several natural and synthetic products induce anoikis in HCC cells and in vivo models. Here, we first briefly summarize the current understanding of the molecular mechanisms of anoikis regulation and relevant regulators involved in HCC metastasis. Then we discuss the therapeutic potential of pharmacological induction of anoikis as a potential treatment against HCC. Finally, we discuss the key limitations of this therapeutic paradigm and propose possible strategies to overcome them. Cumulatively this review suggests that the pharmacological induction of anoikis can be used a promising therapeutic modality against HCC.
Topics: Anoikis; Carcinoma, Hepatocellular; Liver Neoplasms; Humans; Animals; Antineoplastic Agents; Neoplasm Metastasis
PubMed: 38843588
DOI: 10.1016/j.biopha.2024.116878 -
BMC Medical Genomics Jun 2024Zinc 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...
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.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; Zinc Finger E-box-Binding Homeobox 1; Prognosis; Anoikis; Biomarkers, Tumor; MicroRNAs; Zinc Finger E-box Binding Homeobox 2; Gene Expression Regulation, Neoplastic; Male; Female; Kaplan-Meier Estimate
PubMed: 38840097
DOI: 10.1186/s12920-024-01895-7 -
BMC Musculoskeletal Disorders Jun 2024Osteosarcoma (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...
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.
Topics: Osteosarcoma; Humans; Anoikis; Bone Neoplasms; Neoadjuvant Therapy; Mitogen-Activated Protein Kinase 1; Tumor Microenvironment; Prognosis; Male; Female; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Child; Adolescent
PubMed: 38835052
DOI: 10.1186/s12891-024-07547-2 -
Briefings in Bioinformatics May 2024Recent advances in tumor molecular subtyping have revolutionized precision oncology, offering novel avenues for patient-specific treatment strategies. However, a...
Recent advances in tumor molecular subtyping have revolutionized precision oncology, offering novel avenues for patient-specific treatment strategies. However, a comprehensive and independent comparison of these subtyping methodologies remains unexplored. This study introduces 'Themis' (Tumor HEterogeneity analysis on Molecular subtypIng System), an evaluation platform that encapsulates a few representative tumor molecular subtyping methods, including Stemness, Anoikis, Metabolism, and pathway-based classifications, utilizing 38 test datasets curated from The Cancer Genome Atlas (TCGA) and significant studies. Our self-designed quantitative analysis uncovers the relative strengths, limitations, and applicability of each method in different clinical contexts. Crucially, Themis serves as a vital tool in identifying the most appropriate subtyping methods for specific clinical scenarios. It also guides fine-tuning existing subtyping methods to achieve more accurate phenotype-associated results. To demonstrate the practical utility, we apply Themis to a breast cancer dataset, showcasing its efficacy in selecting the most suitable subtyping methods for personalized medicine in various clinical scenarios. This study bridges a crucial gap in cancer research and lays a foundation for future advancements in individualized cancer therapy and patient management.
Topics: Humans; Precision Medicine; Neoplasms; Biomarkers, Tumor; Computational Biology; Medical Oncology; Breast Neoplasms; Female
PubMed: 38833322
DOI: 10.1093/bib/bbae261 -
BioRxiv : the Preprint Server For... May 2024Drug discovery starts with known function, either of a compound or a protein, in-turn prompting investigations to probe 3D structure of the compound-protein interface....
Drug discovery starts with known function, either of a compound or a protein, in-turn prompting investigations to probe 3D structure of the compound-protein interface. As protein structure determines function, we hypothesized that unique 3D structural motifs represent primary information denoting unique function that can drive discovery of novel agents. Using a physics-based protein structure analysis platform developed by us, designed to conduct computationally intensive analysis at supercomputing speeds, we probed a high-resolution protein x-ray crystallographic library developed by us. We selected 3D structural motifs whose function was not otherwise established, that offered environments supporting binding of drug-like chemicals and were present on proteins that were not established therapeutic targets. For each of eight potential binding pockets on six different proteins we accessed a 60 million compound library and used our analysis platform to evaluate binding. Using eight-day colony formation assays acquired compounds were screened for efficacy against human breast, prostate, colon and lung cancer cells and toxicity against human bone marrow stem cells. Compounds selectively inhibiting cancer growth segregated to two pockets on separate proteins. The compound, Dxr2-017, exhibited selective activity against human melanoma cells in the NCI-60 cell line screen, had an IC50 of 19 nM against human melanoma M14 cells in our eight-day assay, while over 2100-fold higher concentrations inhibited stem cells by less than 30%. We show that Dxr2-017 induces anoikis, a unique form of programmed cell death in need of targeted therapeutics. The predicted target protein for Dxr2-017 is expressed in bacteria, not in humans. This supports our strategy of focusing on unique 3D structural motifs. It is known that functionally important 3D structures are evolutionarily conserved. Here we demonstrate proof-of-concept that protein structure represents high value primary data to support discovery of novel therapeutics. This approach is widely applicable.
PubMed: 38826221
DOI: 10.1101/2024.05.17.594634 -
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 -
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