The pathogenesis of inflammation and tumors is a focal point of scientific inquiry, with oxidative stress often serving as the primary initiator. Within the human genome, the SESN3 gene encodes the SESN3 protein, a crucial antioxidant stress protein. Acting as a regulatory factor, SESN3 intricately modulates cellular oxidative stress, actively participating in cellular protection and repair mechanisms. Its functions span antioxidative, anti-aging, and anti-tumor properties. The expression of SESN3 is closely linked to cellular and oxidative stress, metabolic status, and specific signaling pathways. This review aims to delve into the origins and functions of SESN3, its role within signaling pathways, and its contributions to inflammation and tumorigenesis.

Breast cancer is the most prevalent and lethal malignancy among females, with a critical need for safer and less invasive treatments. Photodynamic therapy (PDT) can effectively eliminate tumor cells with minimal side effects. Furthermore, the combination of PDT and immunotherapy using nanoparticles has shown promise in treating both primary and distant metastatic tumor cells. Therefore, this study proposes applying the PDT-immunotherapy combination to breast cancer treatment. However, the low immunogenicity characteristic of "cold" tumors in part of breast cancer significantly diminishes therapeutic efficacy. To address this challenge, here, a nano-gel system (designated as HCSC-gel) is constructed, which co-delivers a mitochondria-targeted photosensitizer and a STING agonist, capable of robustly activating "cold" tumor immunity. This system is further enhanced by collagenase (CN) to improve therapeutic outcomes. Upon injection into the primary tumor site, HCSC-gel rapidly forms a gel matrix, releasing CN to degrade the tumor extracellular matrix and facilitate the penetration of photosensitizers, STING agonists, and oxygen into the tumor tissue. Under laser irradiation, PDT and STING-mediated immune responses are activated, reversing the low immunogenicity of breast cancer and effectively treating both primary and metastatic lesions. This HCSC-gel nano hydrogel delivery platform is anticipated to provide novel insights for the clinical management of breast cancer and other low immunogenic "cold" tumors, offering significant benefits to patients.

As one of the most prevalent primary brain tumors, glioblastoma (GBM) is characterized by its severe malignancy and extremely poor prognosis. Recent studies have demonstrated that targeting anoikis and malignancy showed impressed efficiency for treatment in a wide range of solid tumors, however, relevant research on GBM still remains unclarified.

In this study, genes related with malignancy and anoikis of GBM were identified by utilizing the Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA) and the Molecular Signatures Database (MSigDB). Subsequently, the role of the key gene was validated via proliferation, invasion and migration experiments both in conditions with and without attachment. Moreover, RNA sequencing analysis was employed to reveal further mechanisms.

Here, Type V collagen alpha 1 (COL5A1) was identified as a critical gene associated with anoikis and poor outcomes. Additionally, COL5A1 knockdown induced significant reduction in malignancy of GBM both in vitro and in vivo. Moreover, cell anoikis was remarkable enhanced by reduced expression of COL5A1 after low-attachment cell culture. Mechanically, RNA sequencing analysis revealed that the activity of the Wnt/β-catenin signaling pathway was diminished following COL5A1 knockdown, which indicated that COL5A1 reduced anoikis via regulating Wnt/β-catenin signaling pathway thus promoted malignancies of GBM cells.

These findings demonstrated the novel evidence that COL5A1 serves as an essential regulatory factor influencing both anoikis and malignancy of GBM cells by regulating Wnt/β-catenin signaling pathway, indicating that COL5A1 could be a novel prognosis-related biomarker and potential therapeutic target for GBM.

Resisting anoikis is a prerequisite for cancer to spread and invade and a major cause of cancer-related deaths. Yet, the intricate mechanisms of how cancer cells evade anoikis remain largely unknown. There is a significant need to explore how these mechanisms play out in breast cancer (BC).

Bioinformatics analysis revealed the expression levels of SQLE and FOXM1 in BC tissue, along with their correlation. The enrichment pathways of SQLE were also explored. qPCR detected the expression of SQLE and FOXM1 in BC cells. CCK-8 assessed cell viability, while flow cytometry measured anoikis. Western blot was employed to examine the protein expression of key genes in glycolytic metabolism and apoptosis-related proteins. Extracellular acidification rate was quantified, and corresponding kits evaluated glucose consumption, lactate production, and adenosine triphosphate levels in cells. Dual-luciferase reporter assays and chromatin immunoprecipitation tests unveiled the binding relationship between FOXM1 and SQLE.

SQLE was found to be highly expressed in BC and enriched in pathways associated with anoikis and glycolysis. SQLE curbed anoikis in BC via the aerobic glycolysis pathway. There was also a direct binding between FOXM1 and SQLE and a positive correlation between their expression. Recovery experiments substantiated that FOXM1 targeted SQLE to suppress anoikis in BC cells.

FOXM1 upregulates SQLE, which in turn mediates glycolysis to suppress anoikis in BC. The FOXM1/SQLE axis is a promising therapeutic target for BC treatment.

Anoikis and immune cell infiltration are pivotal factors in the pathophysiological mechanism of diabetic nephropathy (DN), yet a comprehensive understanding of the mechanism is lacking. This work aimed to pinpoint distinctive anoikis-related genes (ARGs) in DN and delve into their impact on the immune landscape. Three datasets (GSE30528, GSE47184, and GSE96804) were downloaded from the gene expression omnibus (GEO) dataset. Differentially expressed genes (DEGs) were identified using the "limma" package, while ARGs were obtained from GSEA, GeneCard, and Harmonizome datasets. The intersection of DEGs and ARGs was analyzed for Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. The CIBERSORT algorithm was employed to estimate the infiltration percentage of 22 immune cell types in DN renal tissue. Subsequently, the least absolute shrinkage and selection operator (LASSO), support vector machine recursive feature elimination (SVM-RFE), and random forest (RF) algorithms were adopted to screen key ARGs related to DN. After that, receiver operating characteristic (ROC) analysis was employed to assess the diagnostic accuracy of each gene and the real-time quantitative polymerase chain reaction (RT-qPCR) was adopted to quantitatively detect the expression of biomarkers in DN cell models. Finally, correlations between key genes and immune cell infiltration were analyzed, and a competitive endogenous ribonucleic acid (RNA) (ceRNA) network based on key genes was constructed. A total of 59 DEARGs were identified. GO functional annotation enrichment analysis revealed their involvement in kidney development, extracellular matrix (ECM), cytoplasmic vesicle cavity, immunoinflammatory response, and cytokine effect. KEGG pathway analysis indicated that MAPK, PI3K -Akt, IL -17, TNF, and HIF- 1 signaling pathways are critical for DN. In addition, seven key genes, including PDK4, S100A8, HTRA1, CHI3L1, WT1, CDKN1B, and EGF, were screened by machine learning algorithm. Most of these genes exhibited low expression in renal tissue of DN patients and positive correlation with neutrophils, and their expressions were verified in an external dataset cell model. The ceRNA analysis suggested potential regulatory pathways (H19/miR-15b-5p/PDK4 and KCNQ1T1/miR-1207-3p/WT1) influencing early DN progression. This work provided a comprehensive analysis of the role of DEARGs in DN for the first time, offering valuable insights for further understanding the disease mechanism and guiding clinical diagnosis, treatment, and research of DN.

Breast cancer (BC) is the most common malignant tumor and the leading cause of cancer-related deaths among women worldwide. Great progress has been recently achieved in controlling breast cancer; however, mortality from breast cancer remains a substantial challenge, and new treatment mechanisms are being actively sought. Programmed cell death (PCD) is associated with the progression and treatment of many types of human cancers. PCD can be divided into multiple pathways including autophagy, apoptosis, mitotic catastrophe, necroptosis, ferroptosis, pyroptosis, and anoikis. Ubiquitination is a post-translational modification process in which ubiquitin, a 76-amino acid protein, is coupled to the lysine residues of other proteins. Ubiquitination is involved in many physiological events and promotes cancer development and progression. This review elaborates the role of ubiquitin-specific protease (USP) in programmed cell death, which is common in breast cancer cells, and lays the foundation for tumor diagnosis and targeted therapy.

Intratumoral heterogeneity of breast cancer cells causes undesired drug resistance and predispose to disease recurrence. We investigate the molecular heterogeneity of breast cancer cells derived from malignant pleural effusions (MPE) to understand variations in drug resistance and cellular evolution. MPE provides a unique environment, with cells experiencing significant microenvironmental changes that promote intratumoral heterogeneity and therapeutic resistance. By establishing 24 cell lines and 3 organoids from MPE samples of breast cancer patients, we performed extensive genomic, transcriptomic, and drug sensitivity analyses. Our findings reveal substantial genetic and transcriptomic diversity among MPE-derived cell lines, highlighting dynamic alterations in driver mutations and signaling pathways that correlate with variable drug responses. Notably, temporal and spatial heterogeneity within patient-derived samples emphasized the adaptability of breast cancer cells in MPE, as different subclones displayed distinct drug sensitivities. This work underscores the critical role of molecular profiling in understanding treatment resistance in breast cancer, presenting MPE-derived cell lines as valuable preclinical models for exploring personalized therapies in aggressive cancer phenotypes.

Exosomes are indispensable extracellular vesicles that facilitate intercellular communication and are crucial for both healthy and pathological conditions, including cancer. The capacity of exosomes to echo the molecular characteristics of their cells of origin, including malignant cells, makes them indispensable tools for diagnosing and tracking disease progression in the field of oncology. Oral squamous cell carcinoma (OSCC), which has been identified as the sixth most prevalent cancer worldwide, has been linked to numerous risk factors, including tobacco use, alcohol consumption, human papillomavirus (HPV) infection, and inadequate oral hygiene. Exosomes pointedly influence the advancement of oral cancer via promoting tumor cell growth, invasion, angiogenesis, and immune evasion through the alteration of the tumor microenvironment. A critical apparatus in cancer metastasis is the epithelial-to-mesenchymal transition (EMT), during which cancer cells acquire improved migratory and invasive properties. EMT plays a role in metastasis, resistance to treatment, and evasion of the immune response. Exosomes facilitate EMT in oral cancer by delivering bioactive molecules that influence EMT signaling pathways. These exosomes inspire EMT in recipient cells, by this means enhancing tumor invasion and metastasis. This study aims to identify the specific exosomal components and signaling pathways that are tangled in EMT, in that way providing new avenues for targeted therapies designed to hinder the metastasis of oral cancer.

Despite advances, Glioblastoma (GBM) treatment remains challenging due to its rapid progression and resistance to therapies.

This study aimed to investigate the role of anoikis-a mechanism by which cells evade programmed cell death upon detachment from the extracellular matrix-in GBM progression and prognosis.

Utilizing single-cell sequencing and bulk-transcriptome sequencing data from TCGA, GEO, and CGGA databases, we performed comprehensive bioinformatics analyses. We identified anoikis-related genes, constructed a prognostic model using 101 machine learning algorithms, and validated its clinical utility across multiple cohorts.Finally, we also verified the expression of model genes and the function of key gene in clinical samples and cell lines.

Single-cell sequencing revealed heterogeneous expression of anoikis-related genes across distinct cell populations within GBM. MES-like Malignant cells and Myeloids exhibited higher enrichment of these genes, implicating their role in anoikis resistance and tumor aggressiveness. The prognostic model, based on identified genes, effectively stratified patients into high-risk and low-risk groups, demonstrating significant differences in survival outcomes. Mutation and tumor microenvironment analyses highlighted distinct genetic landscapes and immune cell infiltration patterns associated with different risk groups. SLC43A3 emerged as a key gene, showing significant upregulation in tumor tissues and correlating with poor prognosis in GBM.

This study provides insights into the molecular mechanisms of anoikis resistance in GBM, underscoring its critical role in tumor progression and patient prognosis. The developed prognostic model offers a promising tool for personalized treatment strategies and warrants further exploration of targeted therapies to improve outcomes for GBM patients.

Liver cancer poses a global health challenge with limited therapeutic options. Notably, the limited success of current therapies in patients with primary liver cancers (PLCs) may be attributed to the high heterogeneity of both hepatocellular carcinoma (HCCs) and intrahepatic cholangiocarcinoma (iCCAs). This heterogeneity evolves over time as tumor-initiating stem cells, or cancer stem cells (CSCs), undergo (epi)genetic alterations or encounter microenvironmental changes within the tumor microenvironment. These modifications enable CSCs to exhibit plasticity, differentiating into various resistant tumor cell types. Addressing this challenge requires urgent efforts to develop personalized treatments guided by biomarkers, with a specific focus on targeting CSCs. The lack of effective precision treatments for PLCs is partly due to the scarcity of ex vivo preclinical models that accurately capture the complexity of CSC-related tumors and can predict therapeutic responses. Fortunately, recent advancements in the establishment of patient-derived liver cancer cell lines and organoids have opened new avenues for precision medicine research. Notably, patient-derived organoid (PDO) cultures have demonstrated self-assembly and self-renewal capabilities, retaining essential characteristics of their respective in vivo tissues, including both inter- and intratumoral heterogeneities. The emergence of PDOs derived from PLCs serves as patient avatars, enabling preclinical investigations for patient stratification, screening of anticancer drugs, efficacy testing, and thereby advancing the field of precision medicine. This review offers a comprehensive summary of the advancements in constructing PLC-derived PDO models. Emphasis is placed on the role of CSCs, which not only contribute significantly to the establishment of PDO cultures but also faithfully capture tumor heterogeneity and the ensuing development of therapy resistance. The exploration of PDOs' benefits in personalized medicine research is undertaken, including a discussion of their limitations, particularly in terms of culture conditions, reproducibility, and scalability.

The cytoskeleton is an important structural component that regulates various aspects of cell morphology, movement, and intracellular signaling. It plays a pivotal role in the cellular response to biomechanical stimuli, particularly in endothelial cells, which are critical for vascular homeostasis and the pathogenesis of cardiovascular diseases. Mechanical forces, such as shear and tension, activate intracellular signaling cascades that regulate transcription, translation, and cellular behaviors. Despite extensive research into cytoskeletal functions, the precise mechanisms by which the cytoskeleton transduces mechanical signals remain incompletely understood. This review focuses on the role of cytoskeletal components in membrane, cytoplasm, and nucleus in mechanotransduction, with an emphasis on their structure, mechanical and biological behaviors, dynamic interactions, and response to mechanical forces. The collaboration between membrane cytoskeleton, cytoplasmic cytoskeleton, and nucleoskeleton is indispensable for endothelial cells to respond to mechanical stimuli. Understanding their mechanoresponsive mechanisms is essential for advancing therapeutic strategies for cardiovascular diseases.

Lappaol F (LAF), a lignan extracted from Fructus Arctii, has a wide spectrum of anti-tumor effects, including inhibition of TNBC cell growth. However, the pharmacological mechanism of LAF targeting epithelial-mesenchymal transition (EMT) to inhibit Triple-negative breast cancer (TNBC) growth remains poorly understood. The present study aimed to reveal the potential mechanism of LAF against TNBC by in vivo and in vitro experiments.

In situ, transplantation-induced MDA-MB-231 solid tumor model in NCG mice and cultured MDA-MB-231 and Hs-578T cells were used to evaluate the anti-TNBC effect of LAF. Flow cytometry, wound healing, transwell assay, western blot, RT-PCR, and immunofluorescence analysis were carried out to investigate the pharmacological mechanism of LAF against TNBC.

LAF significantly inhibited the growth of MDA-MB-231 tumors, with downregulated tumor level of vimentin and upregulated level of ZO-1. In MDA-MB-231 and Hs-578T cells, LAF markedly suppressed cell proliferation, migration and invasion, and promoted apoptosis. Similarly, LAF increased the expression of ZO-1 and occludin proteins in MDA-MB-231 cells, and inhibited the expression of vimentin, snail and slug proteins in MDA-MB-231 and Hs-578T cells, as well as the expression of N-caderin in Hs-578T cells. Moreover, LAF also inhibited the phosphorylation of GSK-3β, thereby inhibited the downstream nuclear translocation of β-catenin and the expression of YAP. Furthermore, LAF significantly inhibited the expression of PI3K and AKT, and the phosphorylation of downstream mTOR.

LAF showed anti-TNBC effect both in vitro and in vivo. Reversal of EMT by inhibiting GSK-3β/YAP/β-catenin signaling and PI3K/AKT/mTOR signaling contributes to the effect.

To explore the relationship between an innovative anoikis-related gene signature and inflammatory infiltrates in patients with osteoarthritis.

Gene expression profiles (GSM1248759 and GSE200843) were curated from the Gene Expression Omnibus database, followed by the construction of a protein-protein interaction network. Functional and genomic enrichment analyses were conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The CIBERSORT method was employed to investigate immune cell infiltration differences between osteoarthritic and control tissues. Additionally, the ConsensusClusterPlus package in R software was utilized to identify distinct anoikis patterns (Cluster C1 and Cluster C2) and conduct molecular biological investigations.

Analysis revealed two distinct anoikis patterns (Cluster C1 and Cluster C2), with Cluster C2 patients exhibiting varying immune cell levels compared to Cluster C1 patients. Molecular investigations identified 84 DEGs enriched in specific pathways such as adipocytokine signaling, cytokine-cytokine receptor interaction, ECM-receptor interaction, and the PPAR signaling pathway. qPCR experiments confirmed the elevated expression levels of specific genes, including SOD2, MAPK14, CEACM3, LAMB3, COL13A1, TLR3, NOTCH3, and KLF12, in the IL-1β-induced group compared with the osteoarthritis group.

This study highlights the role of anoikis-related genes and immune infiltration differences in osteoarthritis, enhancing our understanding of its development.

Categorizing breast neoplasia as ductal or lobular is a daily exercise that relies on a combination of histologic and immunohistochemical tools. The historically robust link between loss of the E-cadherin molecule and lobular neoplasia has rendered staining for E-cadherin by immunohistochemistry a staple of this diagnostic process. Unfortunately, discordances between E-cadherin expression and histomorphology, and variations in E-cadherin staining patterns and intensities abound in clinical practice, but are often neglected in favour of a binary interpretation of the E-cadherin result. In this article, we highlight the complexities of E-cadherin expression through a review of the E-cadherin protein and its associated gene (CDH1), the mechanisms leading to aberrant/absent E-cadherin expression, and the implications of these factors on the reliability of the E-cadherin immunohistochemical stain in the classification of ductal versus lobular mammary neoplasia.

Cell death mechanisms are broadly classified into accidental cell death (ACD) and regulated cell death (RCD). ACD such as necrosis, is an uncontrolled, accidental process, while RCD is tightly regulated by specific signaling pathways and molecular mechanisms. Tumor cells are characterized by their ability to evade cell death and sustain uncontrolled proliferation. The failure of programmed cell death is a key contributor to tumor initiation, progression, and resistance to cancer therapies. Traditionally, research has focused primarily on apoptosis as the dominant form of RCD in cancer. However, emerging evidence highlights the importance of other non-apoptotic forms of RCD, such as pyroptosis, ferroptosis, necroptosis, and parthanatos, in tumorigenesis and treatment response. These pathways are gaining attention for their potential roles in overcoming therapy resistance. In this review, we will discuss the recent advances in the study of non-apoptotic cell death pathways in malignant tumors and explore their therapeutic implications, offering insights into new targets for cancer treatment strategies.

Chronic kidney disease (CKD) is a progressive condition that arises from diverse etiological factors, resulting in structural alterations and functional impairment of the kidneys. We aimed to establish the Anoikis-related gene signature in CKD by bioinformatics analysis.

We retrieved 3 datasets from the Gene Expression Omnibus (GEO) database to obtain differentially expressed genes (DEGs), followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) of them, which were intersected with Anoikis-related genes (ARGs) to derive Anoikis-related differentially expressed genes (ARDEGs). Besides, we conducted weighted gene co-expression network analysis (WGCNA) to identify hub genes. And then, we adopted the quantitative real-time PCR (RT-qPCR) assay to validate the hub genes among several CKD animal models. Furthermore, we constructed a competitive endogenous RNA (ceRNA) network for the hub genes utilizing the ENCORI and miRDB databases, while also calculating Spearman correlation coefficients. Ultimately, we applied the CIBERSORTx algorithm to conduct immune infiltration analysis, classifying immune characteristics based on the abundance of 22 immune cell types.

To summarize, we identified 13 ARDEGs. WGCNA yielded 6 hub genes, all of which demonstrated significant diagnostic potential in univariate logistic regression analysis (P<0.05). The principal pathways enriched were involved in cell cycle progression Toxoplasmosis, Cell adhesion molecules, Influenza A, Pathogenic Escherichia coli infection, Small cell lung cancer, Amoebiasis, TNF signaling pathway, and Leukocyte transendothelial migration. Notably, 6 immune cell types exhibited significant differences (P<0.05) across subgroups with distinct immune characteristics. Moreover, 2 hub genes showed significant variations (P<0.05) across these immune characteristic subtypes. Among the 4 types of CKD mouse models, the mRNA expression levels of LAMB3 and CDH3 were significantly (P<0.05) up-regulated in the model group.

We identified 6 hub genes that may serve as potential key biomarkers of Anoikis-related progression in CKD.

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy that often develops unnoticed. Typically, these tumors are identified at advanced stages, resulting in a relatively low chance of successful treatment. Anoikis serves as a natural defense against the spread of tumor cells, meaning circumventing anoikis can effectively inhibit tumor metastasis. Nonetheless, studies focusing on anoikis in the context of HNSCC remain scarce.

Anoikis-related genes (ARGs) were identified by using the GeneCards and Harmonizome databases. Expression data of these genes and relevant clinical features were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A LASSO regression and a prognostic risk score model were developed to determine their prognostic significance. The analysis included the use of the CIBERSORT algorithm to quantify immune and stromal cell presence. Furthermore, in vitro and in vivo, we confirmed the expression and functional roles of proteins and mRNA of genes independently predictive of prognosis.

The study identified eight genes linked to prognosis (ANXA5, BAK1, CDKN2A, PPARG, CCR7, MAPK11, CRYAB, CRYBA1) and developed a prognostic model that effectively forecasts the survival outcomes for patients with HNSCC. A higher survival likelihood is associated with lower risk scores. In addition, a significant relationship was found between immune and risk score, and ANXA5 deletion promoted the killing of HNSCC cells by activated CD8+ T cells. During the screening process, 65 different chemotherapeutic drugs were found to have significant differences in IC50 values when comparing high- and low-risk categories. ANXA5 emerged as a gene with independent prognostic significance, exhibiting notably elevated protein and mRNA levels in HNSCC tissue compared to non-tumorous tissue. The suppression of ANXA5 gene activity resulted in a substantial decrease in both the growth and mobility of HNSCC cells. Animal model experiments demonstrated that inhibiting ANXA5 suppressed HNSCC growth and migration in vivo.

Through bioinformatics, a prognostic risk model of high precision was developed, offering valuable insights into the survival rates and immune responses in patients with HNSCC. ANXA5 is highlighted as a significant prognostic factor among the identified genes, indicating its promise as a potential therapeutic target for those with HNSCC.

Anoikis, a form of programmed cell death induced by loss of cell contact, is closely associated with tumor invasion and metastasis, making it highly significant in lung cancer research. We examined the expression patterns and prognostic relevance of Anoikis-related genes (ARGs) in lung adenocarcinoma (LUAD) using the TCGA-LUAD database. This study identified molecular subtypes associated with Anoikis in LUAD and conducted functional enrichment analyses. We constructed an ARG risk score using univariate least absolute shrinkage and selection operator (LASSO) Cox regression, validated externally with GEO datasets and clinical samples. The clinical applicability of the prognostic model was evaluated using nomograms, calibration curves, decision curve analysis (DCA), and time-dependent AUC assessments. We identified four prognostically significant genes (PLK1, SLC2A1, CDKN3, PHLDA2) and two ARG-related molecular subtypes. ARGs were generally upregulated in LUAD and correlated with multiple pathways including the cell cycle and DNA replication. The prognostic model indicated that the low-risk group had better outcomes and significant correlations with clinicopathological features, tumor microenvironment, immune therapy responses, drug sensitivity, and pan-RNA epigenetic modification-related genes. Patients with low-risk LUAD were potential beneficiaries of immune checkpoint inhibitor (ICI) therapy. Prognostic ARGs' distribution and expression across various immune cell types were further analyzed using single-cell RNA sequencing. The pivotal role of CDKN3 in LUAD was confirmed through qRT-PCR and gene knockout experiments, demonstrating that CDKN3 knockdown inhibits tumor cell proliferation, migration, and invasion. Additionally, we constructed a ceRNA network involving CDKN3/hsa-miR-26a-5p/SNHG6, LINC00665, DUXAP8, and SLC2A1/hsa-miR-218-5p/RNASEH1-AS1, providing new insights for personalized and immune therapy decisions in LUAD patients.

Collagen is a crucial protein in the extracellular matrix (ECM) essential for preserving tissue architecture and supporting crucial cellular functions like proliferation and differentiation. There are twenty-eight identified types of collagen, which are further divided into different subgroups. This protein plays a critical role in regulating tissue homeostasis. However, in solid tumors, the balance can be disrupted, due to an abundance of collagen in the tumor microenvironment, which significantly affects tumor growth, cell invasion, and metastasis. It is important to investigate the specific types of collagens in cancer ECM and their distinct roles in tumor progression to comprehend their unique contribution to tumor behavior. The diverse pathophysiological functions of different collagen types in cancers illustrate collagen's dual roles, offering potential therapeutic options and serving as prognostic markers.

In homeostatic conditions, the basal progenitor cells of the esophagus differentiate into a stratified squamous epithelium. However, in the setting of acid exposure or inflammation, there is a marked failure of basal cell differentiation, leading to basal cell hyperplasia. We have previously shown that lysyl oxidase (LOX), a collagen crosslinking enzyme, is upregulated in the setting of allergic inflammation of the esophagus; however, its role beyond collagen crosslinking is unknown. Herein, we propose a non-canonical epithelial-specific role of LOX in the maintenance of epithelial homeostasis using 3D organoid and murine models. We performed quantitative reverse transcriptase PCR, Western blot, histologic analysis, and RNA sequencing on immortalized non-transformed human esophageal epithelial cells (EPC2-hTERT) with short-hairpin RNA (shRNA) targeting LOX mRNA in both monolayer and 3D organoid culture. A novel murine model with a tamoxifen-induced Lox knockout specific to the stratified epithelium (K5CreER; Loxfl/fl) was utilized to further define the role of epithelial LOX in vivo. We found that LOX knockdown decreased the proliferative capacity of the esophageal epithelial cells in monolayer culture, and dramatically reduced the organoid formation rate (OFR) in the shLOX organoids. LOX knockdown was associated with decreased expression of the differentiation markers filaggrin, loricrin, and involucrin, with RNA sequencing analysis revealing 1224 differentially expressed genes demonstrating downregulation of pathways involved in cell differentiation and epithelial development. Mice with Lox knockout in their stratified epithelium demonstrated increased basaloid content of their esophageal epithelium and decreased Ki-67 staining compared to the vehicle-treated mice, suggesting reduced differentiation and proliferation in the Lox-deficient epithelium in vivo. Our results demonstrate, both in vivo and in vitro, that LOX may regulate epithelial homeostasis in the esophagus through the modulation of epithelial proliferation and differentiation. Understanding the mechanisms of perturbation in epithelial proliferation and differentiation in an inflamed esophagus could lead to the development of novel treatments that could promote epithelial healing and restore homeostasis.

Cell death is a critical biological phenomenon that can be categorized into accidental cell death (ACD) and programmed cell death (PCD), each exhibiting distinct signaling, mechanistic and morphological characteristics. This paper provides a comprehensive overview of seven types of ACD, including coagulative, liquefactive, caseous, fat, fibrinoid, gangrenous and secondary necrosis, discussing their pathological implications in conditions such as ischemia and inflammation. Additionally, we review eighteen forms of PCD, encompassing autophagy, apoptosis, necroptosis, pyroptosis, paraptosis, ferroptosis, anoikis, entosis, NETosis, eryptosis, parthanatos, mitoptosis, and newly recognized types such as methuosis, autosis, alkaliptosis, oxeiptosis, cuprotosis and erebosis. The implications of these cell death modalities for cellular processes, development, and disease-particularly in the context of neoplastic and neurodegenerative disorders-are also covered. Furthermore, we explore the crosstalk between various forms of PCD, emphasizing how apoptotic mechanisms can influence pathways like necroptosis and pyroptosis. Understanding this interplay is crucial for elucidating cellular responses to stress, as well as for its potential relevance in clinical applications and therapeutic strategies. Future research should focus on clarifying the molecular mechanisms that govern different forms of PCD and their interactions.

According to study, anoikis-related genes (ARGs) have been demonstrated to play a significant impact in cirrhosis, a major disease threatening human health worldwide.

To investigate the relationship between ARGs and cirrhosis development to provide insights into the clinical treatment of cirrhosis.

RNA-sequencing data related to cirrhosis were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between cirrhotic and normal tissues were intersected with ARGs to derive differentially expressed ARGs (DEARGs). The DEARGs were filtered using the least absolute shrinkage and selection operator, support vector machine recursive feature elimination, and random forest algorithms to identify biomarkers for cirrhosis. These biomarkers were used to create a nomogram for predicting the prognosis of cirrhosis. The proportions of diverse immune cell subsets in cirrhotic vs normal tissues were compared using the CIBERSORT computational method. In addition, the linkage between immune cells and biomarkers was assessed, and a regulatory network of mRNA, miRNA, and transcription factors was constructed relying on the biomarkers.

The comparison of cirrhotic and normal tissue samples led to the identification of 635 DEGs. Subsequent intersection of the DEGs with ARGs produced a set of 26 DEARGs. Subsequently, three DEARGs, namely, ACTG1, STAT1, and CCR7, were identified as biomarkers using three machine-learning algorithms. The proportions of M1 and M2 macrophages, resting CD4 memory T cells, resting mast cells, and plasma cells significantly differed between cirrhotic and normal tissue samples. The proportions of M1 and M2 macrophages, resting CD4 memory T cells, and resting mast cells were significantly correlated with the expression of the three biomarkers. The mRNA-miRNA-TF network showed that ACTG1, CCR7, and STAT1 were regulated by 28, 42, and 35 miRNAs, respectively. Moreover, AR, MAX, EP300, and FOXA1 were found to regulate four miRNAs related to the biomarkers.

This study revealed ACTG1, STAT1, and CCR7 as biomarkers of cirrhosis, providing a reference for developing novel diagnostic and therapeutic strategies for cirrhosis.

Triple-negative breast cancer is a heterogeneous disease with high recurrence and mortality, linked to cancer stem cells (CSCs). Our study characterized distinct cell subpopulations and signaling pathways to explore chemoresistance. We observed cellular heterogeneity among and within the cells regarding phenotyping and drug response. In untreated BT-549 cells, we noted plasticity properties in both CD44+/CD24+/CD146+ hybrid cells and CD44-/CD24+/CD146+ epithelial cells, enabling phenotypic conversion into CD44+/CD24-/CD146- epithelial-mesenchymal transition (EMT)-like like breast CSCs (BCSCs). Additionally, non-BCSCs may give rise to ALDH+ epithelial-like BCSCs. Enriched BCSCs demonstrated the potential to differentiation into CD44-/CD24-/CD146- cells and exhibited self-renewal capabilities. Similar phenotypic plasticity was not observed in untreated Hs 578T and HMT-3522 S1 cells. BT-549 cells were more resistant to paclitaxel/PTX than to doxorubicin/DOX, a phenomenon potentially linked to the presence of CD24+ cells prior to treatment. Under the CSCs-enriched spheroids model, BT-549 demonstrated extreme resistance to DOX, likely due to the enrichment of BCSCs CD44+/CD24-/CD146- and the tumor cells CD44-/CD24-/CD146-. Additionally, DOX treatment induced the enrichment of plastic and chemoresistant cells, further exacerbating resistance mechanisms. BT-549 exhibited high heterogeneity, leading to significant alterations in cell subpopulations under BCSCs enrichment, demonstrating increased phenotypic plasticity during EMT. This phenomenon appears to play a major role in DOX resistance, as indicated by the presence of the refractory cells CD44+/CD24-/CD146- BCSCs EMT-like, CD44-/CD24-/CD146- tumor cells, and elevated STAT3 expression. Gene expression data from BT-549 CSCs-enriched spheroids suggests that ferroptosis may be occurring via autophagic regulation triggered by RAB7A, highlighting this gene as a potential therapeutic target.

Background/Objectives: Anoikis-related genes (ANRGs) are crucial in the invasion and metastasis of breast cancer (BC). The underlying role of ANRGs in the prognosis of breast cancer patients warrants further study. Methods: The anoikis-related prognostic signature (ANRS) was generated using a variety of machine learning methods, and the correlation between the ANRS and the tumor microenvironment (TME), drug sensitivity, and immunotherapy was investigated. Moreover, single-cell analysis and spatial transcriptome studies were conducted to investigate the expression of prognostic ANRGs across various cell types. Finally, the expression of ANRGs was verified by RT-PCR and Western blot analysis (WB), and the expression level of PLK1 in the blood was measured by the enzyme-linked immunosorbent assay (ELISA). Results: The ANRS, consisting of five ANRGs, was established. BC patients within the high-ANRS group exhibited poorer prognoses, characterized by elevated levels of immune suppression and stromal scores. The low-ANRS group had a better response to chemotherapy and immunotherapy. Single-cell analysis and spatial transcriptomics revealed variations in ANRGs across cells. The results of RT-PCR and WB were consistent with the differential expression analyses from databases. NU.1025 and imatinib were identified as potential inhibitors for SPIB and PLK1, respectively. Additionally, findings from ELISA demonstrated increased expression levels of PLK1 in the blood of BC patients. Conclusions: The ANRS can act as an independent prognostic indicator for BC patients, providing significant guidance for the implementation of chemotherapy and immunotherapy in these patients. Additionally, PLK1 has emerged as a potential blood-based diagnostic marker for breast cancer patients.

Metastasis is the leading cause of cancer‑related death in osteosarcoma (OS). OS stem cells (OSCs) and anoikis resistance are considered to be essential for tumor metastasis formation. However, the underlying mechanisms involved in the maintenance of a stem‑cell phenotype and anoikis resistance in OS are mostly unknown. Fos‑like antigen 1 (FOSL1) is important in maintaining a stem‑like phenotype in various cancers; however, its role in OSCs and anoikis resistance remains unclear. In the present study, the dynamic expression patterns of FOSL1 were investigated during the acquisition of cancer stem‑like properties using RNA sequencing, PCR, western blotting and immunofluorescence. Flow cytometry, tumor‑sphere formation, clone formation assays, anoikis assays, western blotting and in vivo xenograft and metastasis models were used to further investigate the responses of the stem‑cell phenotype and anoikis resistance to FOSL1 overexpression or silencing in OS cell lines. The underlying molecular mechanisms were evaluated, focusing on whether SOX2 is crucially involved in FOSL1‑mediated stemness and anoikis in OS. FOSL1 expression was observed to be upregulated in OSCs and promoted tumor‑sphere formation, clone formation and tumorigenesis in OS cells. FOSL1 expression correlated positively with the expression of stemness‑related factors (SOX2, NANOG, CD117 and Stro1). Moreover, FOSL1 facilitated OS cell anoikis resistance and promoted metastases by regulating the expression of apoptosis related proteins BCL2 and BAX. Mechanistically, FOSL1 upregulated SOX2 expression by interacting with the SOX2 promoter and activating its transcription. The results also showed that SOX2 is critical for FOSL1‑mediated stem‑like properties and anoikis resistance. The current findings indicated that FOSL1 is an important regulator that promotes a stem cell‑like phenotype and anoikis resistance to facilitate tumorigenesis and metastasis in OS by regulating the transcription of SOX2. Thus, FOSL1 might represent an attractive target for therapeutic interventions in OS.

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.

Anoikis, as a specific form of programmed cell death, involves in tumor metastasis. However, there is still lacking of anoikis-related long non-coding RNA (lncRNA) risk signature in the diagnosis and prognosis of lung adenocarcinoma (LUAD). This study constructed a prognostic risk model by comprehensively analyzing anoikis-related lncRNAs which could effectively diagnose and predict the outcomes of LUAD patients.

A list of anoikis-related genes (ARGs) was retrieved from literatures. Anoikis-related lncRNAs were selected using co-expression analysis from The Cancer Genome Atlas (TCGA) database. Univariate and multivariate regression analyses were used to construct a prognostic model. The performance of the risk signature in predicting the prognosis and clinical significance were determined by Kaplan-Meier survival analysis, receiver operating characteristic (ROC) curves, univariate and multivariate regression analyses. Moreover, the differences of tumor immune microenvironment between the high- and low-risk groups were explored. Finally, a novel nomogram was developed by combining the signature and clinicopathological factors, and the association between lncRNAs and differential N6-methyladenosine (m6A) genes was analyzed by Spearman's analysis.

A total of 1,694 anoikis-related lncRNAs were identified from 479 cases of LUAD. According to the univariate and multivariate Cox analyses, we established a prognostic risk model consisting of seven lncRNAs (AC026355.2, AL606489.1, AL031667.3, LINC02802, LINC01116, AC018529.1, and AP000844.2). This prognostic risk model could efficiently classify low- and high-risk patients. The area under the curve (AUC) value was 0.717, which indicated more powerful predictive capability than commonly used clinicopathological factors. The high- and low-risk groups demonstrated different immune microenvironment. Moreover, the nomogram also demonstrated good performance in predicting the prognosis. Twelve differential m6A regulators were identified, and RBM15 was found to be correlated positively with the hub lncRNA AL606489.1.

Our study constructed a prognostic risk model based on anoikis-related lncRNAs, which could provide novel perspective on the prognosis of LUAD patients.

Breast cancer (BC) currently ranks second in the global cancer incidence rate. Hypoxia is a common phenomenon in BC. Under hypoxic conditions, cells in the tumor microenvironment (TME) secrete numerous extracellular vesicles (EVs) to achieve intercellular communication and alter the metabolism of primary and metastatic tumors that shape the TME. In addition, emerging studies have indicated that hypoxia can promote resistance to tumor treatment. Engineered EVs are expected to become carriers for cancer treatment due to their high biocompatibility, low immunogenicity, high drug delivery efficiency, and ease of modification. In this review, we summarize the mechanisms of EVs in the primary TME and distant metastasis of BC under hypoxic conditions. Additionally, we highlight the potential applications of engineered EVs in mitigating the malignant phenotypes of BC cells under hypoxia.

Anoikis-Related Genes (ARGs) lead to the organism manifesting resistance to anoikis and are associated with unfavorable prognostic outcomes across various malignancies.Therefore, it is crucial to identify the pivotal target genes related to anoikis in HCC .We found that ARGs were significantly correlated with prognosis and immune responses in HCC. The core gene, SPP1, notably promoted anoikis resistance and metastasis in HCC through both in vivo and in vitro studies. The PI3K-Akt-mTOR pathway played a critical role in anoikis suppression within HCC contexts. Our research unveiled SPP1's role in enhancing PKCα phosphorylation, which in turn activated the PI3K-Akt-mTOR cascade. Additionally, SPP1 was identified as a key regulator of MDSCs and Tregs migration, directly affecting their immunosuppressive capabilities.These findings indicate that in HCC, SPP1 promoted anoikis resistance and facilitated immune evasion by modulating MDSCs and Tregs.

The extracellular matrix (ECM) governs a wide spectrum of cellular fate processes, with a particular emphasis on anoikis, an integrin-dependent form of cell death. Currently, anoikis is defined as an intrinsic apoptosis. In contrast to traditional apoptosis and necroptosis, integrin correlates ECM signaling with intracellular signaling cascades, describing the full process of anoikis. However, anoikis is frequently overlooked in physiological and pathological processes as well as traditional in vitro research models. In this review, we summarized the role of anoikis in physiological and pathological processes, spanning embryonic development, organ development, tissue repair, inflammatory responses, cardiovascular diseases, tumor metastasis, and so on. Similarly, in the realm of stem cell research focused on the functional evolution of cells, anoikis offers a potential solution to various challenges, including in vitro cell culture models, stem cell therapy, cell transplantation, and engineering applications, which are largely based on the regulation of cell fate by anoikis. More importantly, the regulatory mechanisms of anoikis based on molecular processes and ECM signaling will provide new strategies for therapeutic interventions (drug therapy and cell-based therapy) in disease. In summary, this review provides a systematic elaboration of anoikis, thus shedding light on its future research.

Metastasis, the leading cause of renal cell carcinoma (RCC) mortality, involves cancer cells resisting anoikis and invading. Until now, the role of the matrix metalloproteinase (MMP)-related enzyme, A disintegrin and metalloprotease with thrombospondin motifs 1 (ADAMTS1), in RCC anoikis regulation remains unclear.

The clinical significance of ADAMTS1 and its associated molecules in patients with RCC was investigated using data from the Gene Expression Omnibus (GEO) and TCGA datasets. Human phosphoreceptor tyrosine kinase (RTK) array, luciferase reporter assays, immunoprecipitation (IP) assays, western blotting, and real-time reverse-transcription quantitative polymerase chain reaction (RT-qPCR) were used to elucidate the underlying mechanisms of ADAMTS1. Functional assays, including anoikis resistance assays, invasion assays, and a Zebrafish xenotransplantation model, were conducted to assess the roles of ADAMTS1 in conferring resistance to anoikis in RCC.

This study found elevated ADAMTS1 transcripts in RCC tissues that were correlated with a poor prognosis. ADAMTS1 manipulation significantly affected cell anoikis through the mitochondrial pathway in RCC cells. Human receptor tyrosine kinase (RTK) array screening identified that epidermal growth factor receptor (EGFR) activation was responsible for ADAMTS1-induced anoikis resistance and invasion. Further investigations revealed that enzymatically active ADAMTS1-induced versican V1 (VCAN V1) proteolysis led to EGFR transactivation, which in turn, through positive feedback, regulated ADAMTS1. Additionally, ADAMTS1 can form a complex with p53 to influence EGFR signaling. In vivo, VCAN or EGFR knockdown reversed ADAMTS1-induced prometastatic characteristics of RCC. A clinical analysis revealed a positive correlation between ADAMTS1 and VCAN or the EGFR and patients with RCC with high ADAMTS1 and VCAN expression had the worst prognoses.

Our results collectively uncover a novel cyclic axis involving ADAMTS1-VCAN-EGFR, which significantly contributes to RCC invasion and resistance to anoikis, thus presenting a promising therapeutic target for RCC metastasis.

Anoikis and epithelial-mesenchymal transition (EMT) are pivotal in the distant metastasis of lung adenocarcinoma (LUAD). A detailed understanding of their interplay and the identification of key genes is vital for effective therapeutic strategies against LUAD metastasis.

Key prognostic genes related to anoikis and EMT were identified through univariate Cox regression analysis. We utilized ten machine learning algorithms to develop the Anoikis and EMT-Related Optimal Model (AEOM). The TCGA-LUAD dataset served as the training cohort, while six additional international multicenter LUAD datasets were employed as validation cohorts. The average concordance index (c-index) was used to evaluate model performance and identify the most effective model. Subsequent multi-omics analyses were conducted to explore differences in pathway enrichment, immune infiltration, and mutation landscapes between high and low AEOM groups. Experimental validation demonstrated that RHPN2, a key biomarker within the model, acts as an oncogene facilitating LUAD progression.

The AEOM displayed superior prognostic predictive performance for LUAD patients, outperforming numerous previously published LUAD signatures. Biologically, the AEOM was notably associated with immune features; the high AEOM group exhibited decreased immune activity and a tendency towards immune-cold tumors, as well as a higher tumor mutational burden (TMB). Subgroup analysis revealed that the low AEOM + high TMB group had the most favorable prognosis. The high AEOM group was primarily enriched in cell cycle-related pathways, promoting cancer cell proliferation. RHPN2, a crucial gene within the AEOM (correlation = 0.85, P < 0.05), was linked to poorer prognosis in LUAD patients with elevated RHPN2 expression. Further in vitro experiments showed that RHPN2 modulates LUAD cell proliferation and invasion.

The AEOM provides a robust prognostic model for LUAD, uncovering critical immune and biological pathways, with RHPN2 identified as a key oncogenic driver. These findings offer valuable insights for targeted therapies and enhanced patient outcomes.

Anoikis tolerance is an important biological process of tumor colonization and metastasis outside the primary tumor. Recent research has progressively elucidated the function and underlying mechanisms of anoikis in the metastasis of various solid tumors. Nevertheless, the specific mechanisms of anoikis in bladder cancer and its consequent effects on the tumor immune microenvironment remain ambiguous. In this study, we developed an anoikis score based on five genes (ETV7, NGF, SCD, LAMC1, and CASP6) and categorized subjects into high and low-risk groups using the median score from the TCGA database. Our findings indicate that SCD enhances the proliferation of bladder cancer cells in vitro. Furthermore, integrating the anoikis score with clinicopathological features to construct a prognostic nomogram demonstrated precision in assessing patient outcomes. Immune cell analysis revealed elevated infiltration levels of Treg cells and M2 macrophages in the high anoikis score group, whereas CD8+ T cell levels were reduced. This study highlights the importance of anoikis score in predicting patient prognosis, immune cell infiltration, and drug response, which may provide a treatment modality worth exploring in depth for the study of bladder cancer.

Tumor cells can survive when detached from the extracellular matrix (ECM) or lose cell-cell connections, a phenomenon known as anoikis-resistance (AR). AR is closely associated with tumor cell metastasis and recurrence, enabling tumor cells to disseminate, migrate, and invade after detachment. To address this issue, a novel intervention method combining intraoperative hemostasis with multifunctional nanozyme driven-enhanced chemodynamic therapy (ECDT) has been proposed, which holds the potential to weaken the AR capability of tumor cells and suppress tumor recurrence. Here, a nanocomposite containing a dendritic mesoporous nanoframework with Cu2+ was developed using an anion-assisted approach after surface PEG grafting and glucose oxidase (GOx) anchoring (DMSN-Cu@GOx/PEG). DMSN-Cu@GOx/PEG was further encapsulated in a thermal-sensitive hydrogel (H@DMSN-Cu@GOx/PEG). DMSN-Cu@GOx/PEG utilizes its high peroxidase (POD) activity to elevate intracellular ROS levels, thereby weakening the AR capability of bladder cancer cells. Additionally, through its excellent catalase (CAT) activity, DMSN-Cu@GOx/PEG converts the high level of hydrogen peroxide (H2O2) catalyzed by intracellular GOx into oxygen (O2), effectively alleviating tumor hypoxia, downregulating hypoxia-inducible factor-1α (HIF-1α) expression, inhibiting epithelial-mesenchymal transition (EMT) processes, and ultimately suppressing the migration and invasion of bladder cancer cells. Interestingly, in vivo results showed that the thermosensitive hydrogel H@DMSN-Cu@GOx/PEG could rapidly gel at body temperature, forming a gel film on wounds to eliminate residual tumor tissue after tumor resection surgery. Importantly, H@DMSN-Cu@GOx/PEG exhibited excellent hemostatic capabilities, effectively enhancing tissue coagulation during post-tumor resection surgery and mitigating the risk of cancer cell dissemination and recurrence due to surgical bleeding. Such hydrogels undoubtedly possess strong surgical application. Our developed novel nanosystem and hydrogel can inhibit the AR capability of tumor cells and prevent recurrence post-surgery. This study represents the first report of using dendritic mesoporous silica-based nanoreactors for inhibiting the AR capability of bladder cancer cells and suppressing tumor recurrence post-surgery, providing a new avenue for developing strategies to impede tumor recurrence after surgery.

This study intended to determine the molecular subtypes of liver hepatocellular carcinoma (LIHC) on the strength of anoikis-related genes (ARGs) and to assess their prognostic value and prospective relationship with immune cell infiltration and cancer-associated fibroblasts (CAFs). Univariate Cox regression analysis yielded 66 prognosis-related ARGs and classified LIHC into two distinct subtypes, with subtype A demonstrating overexpression of most prognosis-related ARGs and a significant survival disadvantage. Furthermore, a reliable prediction model was developed using ARGs to evaluate the risk of LIHC patients. This model served as an independent prognostic indicator and a quantitative tool for clinical prognostic prediction. Additionally, subtype-specific differences in immune cell infiltration were observed, and the risk score was potentially linked to immune-related characteristics. Moreover, the study identified a significant association between CAF score and LIHC prognosis, with a low CAF score indicating a favorable patient prognosis. In conclusion, this study reveals the molecular mechanisms underlying the development and progression of LIHC and identifies potential therapeutic targets for the disease.

Triple-negative breast cancer (TNBC) poses a challenging prognosis due to early metastasis driven by anoikis resistance. Identifying crucial regulators to overcome this resistance is vital for improving patient outcomes. In this study, a genome-wide CRISPR/Cas9 knockout screen in TNBC cells has identified tyrosine-protein phosphatase nonreceptor type 14 (PTPN14) as a key regulator of anoikis resistance. PTPN14 expression has shown a progressive decrease from normal breast tissue to metastatic tumors. Overexpressing PTPN14 has induced anoikis and inhibited cell proliferation in TNBC cells, while normal human breast cells are unaffected. Mechanistically, PTPN14 is identified as a key factor in dephosphorylating breast cancer antiestrogen resistance 3, a novel substrate, leading to the subsequent inhibition of PI3K/AKT and ERK signaling pathways. Local delivery of in vitro transcribed PTPN14 mRNA encapsulated by lipid nanoparticles in a TNBC mouse model has effectively inhibited tumor growth and metastasis, prolonging survival. The study underscores PTPN14 as a potential therapeutic target for metastatic TNBC, with the therapeutic strategy based on mRNA expression of PTPN14 demonstrating clinical application prospects in alleviating the burden of both primary tumors and metastatic disease.

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.