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Aging Nov 2023Overcoming anoikis is a necessity during the metastasis and invasion of tumors. Recently, anoikis has been reported to be involved in tumor immunity and has been used to...
TJP3 promotes T cell immunity escape and chemoresistance in breast cancer: a comprehensive analysis of anoikis-based prognosis prediction and drug sensitivity stratification.
BACKGROUND
Overcoming anoikis is a necessity during the metastasis and invasion of tumors. Recently, anoikis has been reported to be involved in tumor immunity and has been used to construct prognosis prediction models. However, the roles of anoikis in regulating tumor immunity and drug sensitivity in breast cancer are still not clear and therefore worth uncovering.
METHODS
TCGA and GEO data are the source of gene expression profiles, which are used to identify anoikis-related-gene (ARG)-based subtypes. R4.2 is used for data analysis.
RESULTS
Breast cancer is divided into three subgroups, amongst which shows prognosis differences in pan-cancer cohort, ACC, BLCA, BRCA, LUAD, MESO, PAAD, and SKCM. In breast cancer, it shows significant differences in clinical features, immune cell infiltration and drug sensitivity. Machine learning constructs prognosis prediction model, which is useful to perform chemotherapy sensitivity stratification. Following, TJP3 is identified and verified as the key ARG, up-regulation of which increases tolerance of paclitaxel-induced cell toxicity, accompanied with increased expression of caspas3 and cleaved-caspase3. In addition, Down-regulation of TJP3 weakens the cell migration, which accompanied with increased expression of E-cad and decreased expression of vimentin, twist1, zeb1, and MMP7. Furthermore, the expression level of PD-L1 is negative correlated with TJP3.
CONCLUSION
ARGs-based subgroup stratification is useful to recognize chemotherapy sensitive cohort, and also is useful to predict clinical outcome. TJP3 promotes chemoresistance, tumor metastasis and potential immunotherapy escape in breast cancer.
Topics: Humans; Female; Breast Neoplasms; Anoikis; Drug Resistance, Neoplasm; T-Lymphocytes; Prognosis; Zonula Occludens Proteins
PubMed: 37950731
DOI: 10.18632/aging.205208 -
European Journal of Pharmacology Jul 2023As a key component of the COP9 signalosome complex, which participates in a variety of physiological processes, COPS3 is intimately related to multiple cancers. It...
As a key component of the COP9 signalosome complex, which participates in a variety of physiological processes, COPS3 is intimately related to multiple cancers. It promotes cell proliferation, progression and metastasis in several cancer cells. However, whether COPS3 participates in regulating anoikis, a specific kind of apoptosis and functions as an essential modulator of cell metastasis, has not yet been studied. Here, we found COPS3 is highly expressed in several cancers especially in osteosarcoma (OS). Overexpression of COPS3 promoted cell proliferation, cell viability and migration/invasion in both control cells and oxaliplatin (Oxa) treated cells. On the contrary, knockdown of COPS3 further enhanced the cytotoxicity of Oxa. Utilizing bioinformatics analysis, we found that COPS3 was higher expressed in the metastatic group, and associated with the extra-cellular matrix (ECM) receptor interaction pathway, which involve in regulating anoikis. In an anoikis model, COPS3 expression varied and genetic modification of COPS3 influenced the cell death enhanced by Oxa. PFKFB3, an essential modulator of glycolysis, was found to interact with COPS3. Inhibition of PFKFB3 promoted apoptosis and anoikis enhanced by Oxa, and COPS3 overexpression failed to rescue this cell death. On the contrary, in the COPS3 knockdown cells, overexpression of PFKFB3 recovered the anoikis resistance, indicating COPS3 function upstream of PFKFB3. In summary, our results elucidated that COPS3 modulated anoikis via affecting PFKFB3 in OS cancer cells.
Topics: Humans; Anoikis; Cell Proliferation; Oxaliplatin; Phosphoric Monoester Hydrolases; Osteosarcoma; Bone Neoplasms; Cell Line, Tumor; COP9 Signalosome Complex; Proto-Oncogene Proteins; Phosphofructokinase-2
PubMed: 37201626
DOI: 10.1016/j.ejphar.2023.175799 -
International Immunopharmacology Feb 2023Osteosarcoma is highly aggressive and prone to metastasis, with a poor prognosis. Increasing evidence identified anoikis has a critical effect in tumor metastasis and...
OBJECTIVES
Osteosarcoma is highly aggressive and prone to metastasis, with a poor prognosis. Increasing evidence identified anoikis has a critical effect in tumor metastasis and invasion. However, the prognostic value of anoikis-related genes (ANRGs) in osteosarcoma and their role in the immune landscape of osteosarcoma remain unclear.
METHODS
The RNA sequencing and clinical data of patients with osteosarcoma were extracted from the TARGET and GEO databases, and ANRGs were identified from the GeneCards database. Unsupervised clustering analysis was employed to identify anoikis-related patterns. The ESTIMATE, TIMER and ssGSEA algorithms were used to assess the immune microenvironment of different subtypes. A prognostic signature based on the identified ANRGs was constructed via univariate, LASSO and multivariate Cox regression analyses. KEGG, GO and GSEA were used for functional enrichment of genes associated with different risk subtypes. qPCR, WB and IHC were used to validate the expression of candidate genes.
RESULTS
Two anoikis-related patterns with distinct clinical features and immune statuses were identified based on prognosis-related ANRGs. Cluster 2 had more active immunogenicity and a better prognosis than Cluster 1. Subsequently, we developed and validated an anoikis prognostic signature demonstrating excellent predictive ability for the prognosis of osteosarcoma. Anoikis risk score was positively associated with osteosarcoma metastasis and was identified as an independent prognostic marker. Additionally, a nomogram was established to predict the 3- and 5-year survival probability of patients with osteosarcoma. Functional enrichment analysis revealed that immune dysregulation was correlated with poor prognosis. Besides, patients in the low-risk group had higher infiltration levels of immune cells and more active immune function than patients in the high-risk group. Drug sensitivity analysis revealed several chemotherapeutic agents for the treatment of different subtypes of osteosarcoma.
CONCLUSION
Our study demonstrated the role of ANRGs in osteosarcoma progression, providing insights into clinical decision making in osteosarcoma.
Topics: Humans; Prognosis; Anoikis; Nomograms; Osteosarcoma; Bone Neoplasms; Tumor Microenvironment
PubMed: 36630752
DOI: 10.1016/j.intimp.2023.109684 -
Pathology, Research and Practice Jan 2023Colorectal cancer (CRC) is a deadly malignancy and therapeutic approaches for CRC are evolving every day. Anoikis is a key mechanism for programmed cell death of cancer... (Review)
Review
Colorectal cancer (CRC) is a deadly malignancy and therapeutic approaches for CRC are evolving every day. Anoikis is a key mechanism for programmed cell death of cancer cells that undergo anchorage-independent growth at a different matrix than the one which is expected. Yet, anoikis is a less studied mechanism of cell death in comparison to other mechanisms such as apoptosis. Relating to this, resistance to anoikis among cancer cells remains critical for improved metastasis and survival in a new environment evading anoikis. Since CRC cells have the ability to metastasize from proximal sites to secondary organs such as liver and promote cancer in those distant sites, a clear knowledge of the mechanisms essential for anchorage-independent growth and subsequent metastasis is necessary to counteract CRC progression and spread. Therefore, the identification of novel drug candidates and studying the roles of anoikis in assisting CRC therapy using such drugs can prevent anchorage-independent cancer cell growth. Additionally, the identification of novel biomarkers or therapeutic targets seems essential for implementing superior therapy, impeding relapse among malignant cells and improving the survival rate of clinical patients. As there are no reviews published on this topic till date, anoikis as a mechanism of cell death and its therapeutic roles in CRC are discussed in this review. In addition, several molecules were identified as therapeutic targets for CRC.
Topics: Humans; Anoikis; Colorectal Neoplasms; Cell Line, Tumor
PubMed: 36455367
DOI: 10.1016/j.prp.2022.154256 -
Journal of Cell Science Sep 2022Epithelial morphogenesis and oncogenic transformation can cause loss of cell adhesion, and detached cells are eliminated by anoikis. Here, we reveal that transforming...
Epithelial morphogenesis and oncogenic transformation can cause loss of cell adhesion, and detached cells are eliminated by anoikis. Here, we reveal that transforming growth factor β receptor 3 (TGFBR3) acts as an anoikis mediator through the coordination of activating transcription factor 4 (ATF4). In breast cancer tissues, TGFBR3 is progressively lost, but elevated TGFBR3 is associated with a histologic subtype characterized by cellular adhesion defects. Dissecting the impact of extracellular matrix (ECM) deprivation, we demonstrate that ECM loss promotes TGFBR3 expression, which in turn causes differentiation of cell aggregates, conferring a low-adhesion phenotype, and drives the intrinsic apoptotic pathway. We demonstrate that inhibition of TGFBR3 impairs epithelial anoikis by activating ATF4 signaling. These preclinical findings provide a rationale for therapeutic inhibition of ATF4 in the subgroup of breast cancer patients with low TGFBR3 expression.
Topics: Activating Transcription Factor 4; Anoikis; Cell Transformation, Neoplastic; Humans; Proteoglycans; Receptors, Transforming Growth Factor beta
PubMed: 35912788
DOI: 10.1242/jcs.258396 -
Aging Apr 2023Anoikis plays a critical role in variable cancer types. However, studies that focus on the prognostic values of anoikis-related genes (ANRGs) in OV are scarce. Cohorts...
Anoikis plays a critical role in variable cancer types. However, studies that focus on the prognostic values of anoikis-related genes (ANRGs) in OV are scarce. Cohorts with transcriptome data and corresponding clinicopathologic data of OV patients were collected and consolidated from public databases. Multiple bioinformatics approaches were used to screen key genes from 446 anoikis-related genes, including Cox regression analysis, random survival forest analysis, and Kaplan-Meier analysis of best combinations. A five-gene signature was constructed in the discovery cohort (TCGA) and validated in four validation cohorts (GEO). Risk score of the signature stratified patients into high-risk (HRisk) and low-risk (LRisk) subgroups. Patients in the HRisk group were associated with worse OS than those in the LRisk group in both the TCGA cohort (p<0.0001, HR=2.718, 95%CI:1.872-3.947) and the four GEO cohorts (p<0.05). Multivariate Cox regression analyses confirmed that the risk score served as an independent prognostic factor in both cohorts. The signature's predictive capacity was further demonstrated by the nomogram analysis. Pathway enrichment analysis revealed that immunosuppressive and malignant progression-related pathways were enriched in the HRisk group, including TGF-β, WNT and ECM pathways. The LRisk group was characterized by immune-active signaling pathways (interferon-gamma, T cell activation, etc.) and higher proportions of anti-tumor immune cells (NK, M1, etc.) while HRisk patients were associated with higher stromal scores and less TCR richness. In conclusion, the signature reveals a close relationship between the anoikis and prognosis and may provide a potential therapeutic target for OV patients.
Topics: Humans; Female; Anoikis; Ovarian Neoplasms; Prognosis; Nomograms; Risk Factors
PubMed: 37179119
DOI: 10.18632/aging.204634 -
Frontiers in Immunology 2023Despite progression in its treatment, the clinical outcome of patients with clear cell renal cell carcinoma (ccRCC) remains not ideal. Anoikis is a unique form of...
BACKGROUND
Despite progression in its treatment, the clinical outcome of patients with clear cell renal cell carcinoma (ccRCC) remains not ideal. Anoikis is a unique form of programmed apoptosis, owing to insufficient cell-matrix interactions. Anoikis plays a crucial role in tumor migration and invasion, and tumor cells could protect themselves through the capacity of anoikis resistance.
METHODS
Anoikis-related genes (ARGs) were obtained from Genecards and Harmonizome portals. The ARGs related to ccRCC prognosis were identified through univariate Cox regression analysis, then we utilized these ARGs to construct a novel prognostic model for ccRCC patients. Moreover, we explored the expression profile of ARGs in ccRCC using the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. We also conducted Real-Time Polymerase Chain Reaction (RT-PCR) to probe ARGs expression of the risk score. Finally, we performed correlation analysis between ARGs and tumor immune microenvironment.
RESULTS
We identified 17 ARGs associated with ccRCC survival, from which 7 genes were chosen to construct a prognostic model. The prognostic model was verified as an independent prognostic indicator. The expression of most ARGs was higher in ccRCC samples. These ARGs were closely correlated with immune cell infiltration and immune checkpoint members, and had independent prognostic value respectively. Functional enrichment analysis demonstrated that these ARGs were significantly associated with multiple types of malignances.
CONCLUSION
The prognostic signature was identified to be highly efficient in predicting ccRCC prognosis, and these ARGs were closely related to tumor microenvironment.
Topics: Humans; Carcinoma, Renal Cell; Anoikis; Prognosis; Carcinoma; Kidney Neoplasms; Tumor Microenvironment
PubMed: 37056778
DOI: 10.3389/fimmu.2023.1171883 -
Apoptosis : An International Journal on... Apr 2024This analysis covers 4494 anoikis-related publications (2003-2022). It explores annual trends, top countries, core journals, leading institutions, keywords, references,...
This analysis covers 4494 anoikis-related publications (2003-2022). It explores annual trends, top countries, core journals, leading institutions, keywords, references, authors, and collaborations. Key findings include the United States leading in publications, Chulalongkorn University as the top institution, and Oncogene as the most prolific journal. The Journal of Biological Chemistry holds the highest influence. Burst keywords like "signal transduction," "apoptosis resistance," "metabolism," and "tumor microenvironment" highlight emerging research areas. This study offers a comprehensive overview, aiding researchers in grasping anoikis research trends, contributors, and prospects.
Topics: Humans; Anoikis; Oncogenes; Bibliometrics; Signal Transduction; Tumor Microenvironment
PubMed: 38001344
DOI: 10.1007/s10495-023-01910-9 -
The Libyan Journal of Medicine Dec 2023As a dominant type of gastric cancer, stomach adenocarcinoma (STAD) is characterized by high morbidity and mortality rates. Anoikis factors participate in tumor...
As a dominant type of gastric cancer, stomach adenocarcinoma (STAD) is characterized by high morbidity and mortality rates. Anoikis factors participate in tumor metastasis and invasion. This study was designed to identify prognostic risk factors in anoikis-related long non-coding RNAs (lncRNAs) for STAD. First, with STAD expression datasets and anoikis-related gene sets downloaded from public databases, anoikis-related prognostic lncRNA signatures (AC091057.1, ADAMTS9.AS1, AC090825.1, AC084880.3, EMX2OS, HHIP.AS1, AC016583.2, EDIL3.DT, DIRC1, LINC01614, and AC103702.2) were screened by Cox regression to establish a prognostic risk model. Kaplan-Meier and receiver operating characteristic curves were used to evaluate the survival status of patients and verify predictive accuracy of the model. Besides, risk score could be an independent prognostic factor to assess the prognosis of STAD patients. Nomograms of the prognostic model that combined clinical information and risk score could effectively predict survival of STAD patients, as validated by calibration curve. Gene ontology and Kyoto encyclopedia of genes and genomes enrichment analyses were performed for differentially expressed genes (DEGs) in high- and low-risk groups. These DEGs were related to neurotransmitter transmission, signal transmission, and endocytosis. Moreover, we analyzed immune status of different risk groups and found that STAD patients in low-risk group were more sensitive to immunotherapy. A prognostic risk assessment model for STAD using anoikis-related lncRNA genes was constructed here, which was proven to have high predictive accuracy and thus could offer a reference for prognostic evaluation and clinical treatment of STAD patients.
Topics: Humans; Prognosis; RNA, Long Noncoding; Stomach Neoplasms; Clinical Relevance; Anoikis; Adenocarcinoma; Calcium-Binding Proteins; Cell Adhesion Molecules
PubMed: 37300839
DOI: 10.1080/19932820.2023.2220153 -
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