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Cancer Medicine May 2024Tumors that resist anoikis, a programmed cell death triggered by detachment from the extracellular matrix, promote metastasis; however, the role of anoikis-related genes...
Identification of the molecular subtypes and signatures to predict the prognosis, biological functions, and therapeutic response based on the anoikis-related genes in colorectal cancer.
BACKGROUND
Tumors that resist anoikis, a programmed cell death triggered by detachment from the extracellular matrix, promote metastasis; however, the role of anoikis-related genes (ARGs) in colorectal cancer (CRC) stratification, prognosis, and biological functions remains unclear.
METHODS
We obtained transcriptomic profiles of CRC and 27 ARGs from The Cancer Genome Atlas, the Gene Expression Omnibus, and MSigDB databases, respectively. CRC tissue samples were classified into two clusters based on the expression pattern of ARGs, and their functional differences were explored. Hub genes were screened using weighted gene co-expression network analysis, univariate analysis, and least absolute selection and shrinkage operator analysis, and validated in cell lines, tissues, or the Human Protein Atlas database. We constructed an ARG-risk model and nomogram to predict prognosis in patients with CRC, which was validated using an external cohort. Multifaceted landscapes, including stemness, tumor microenvironment (TME), immune landscape, and drug sensitivity, between high- and low-risk groups were examined.
RESULTS
Patients with CRC were divided into C1 and C2 clusters. Cluster C1 exhibited higher TME scores, whereas cluster C2 had favorable outcomes and a higher stemness index. Eight upregulated hub ARGs (TIMP1, P3H1, SPP1, HAMP, IFI30, ADAM8, ITGAX, and APOC1) were utilized to construct the risk model. The qRT-PCR, Western blotting, and immunohistochemistry results were consistent with those of the bioinformatics analysis. Patients with high risk exhibited worse overall survival (p < 0.01), increased stemness, TME, immune checkpoint expression, immune infiltration, tumor mutation burden, and drug susceptibility compared with the patients with low risk.
CONCLUSION
Our results offer a novel CRC stratification based on ARGs and a risk-scoring system that could predict the prognosis, stemness, TME, immunophenotypes, and drug susceptibility of patients with CRC, thereby improving their prognosis. This stratification may facilitate personalized therapies.
Topics: Humans; Colorectal Neoplasms; Anoikis; Prognosis; Tumor Microenvironment; Gene Expression Regulation, Neoplastic; Male; Biomarkers, Tumor; Nomograms; Female; Transcriptome; Gene Expression Profiling
PubMed: 38785271
DOI: 10.1002/cam4.7315 -
International Journal of Oncology Mar 2024Carcinoembryonic antigen (CEA)‑related cell adhesion molecule 6 (CEACAM6) is a cell adhesion protein of the CEA family of glycosyl phosphatidyl inositol anchored cell... (Review)
Review
Carcinoembryonic antigen (CEA)‑related cell adhesion molecule 6 (CEACAM6) is a cell adhesion protein of the CEA family of glycosyl phosphatidyl inositol anchored cell surface glycoproteins. A wealth of research has demonstrated that CEACAM6 is generally upregulated in pancreatic adenocarcinoma, breast cancer, non‑small cell lung cancer, gastric cancer, colon cancer and other cancers and promotes tumor progression, invasion and metastasis. The transcriptional expression of CEACAM6 is regulated by various factors, including the CD151/TGF‑β1/Smad3 axis, microRNA (miR)‑146, miR‑26a, miR‑29a/b/c, miR‑128, miR‑1256 and DNA methylation. In addition, the N‑glycosylation of CEACAM6 protein at Asn256 is mediated by α‑1,6‑mannosylglycoptotein 6‑β‑N‑acetylglucosaminyltransferase. In terms of downstream signaling pathways, CEACAM6 promotes tumor proliferation by increasing levels of cyclin D1 and cyclin‑dependent kinase 4 proteins. CEACAM6 can activate the ERK1/2/MAPK or SRC/focal adhesion kinase/PI3K/AKT pathways directly or through EGFR, leading to stimulation of tumor proliferation, invasion, migration, resistance to anoikis and chemotherapy, as well as angiogenesis. This article provides a review of the expression pattern, biological function and relationship with prognosis of CEACAM6 in cancer. In summary, CEACAM6 may be a valuable diagnostic biomarker and potential therapeutic target for human cancers exhibiting overexpression of CEACAM6.
Topics: Humans; Cell Adhesion; Carcinoembryonic Antigen; Adenocarcinoma; Carcinoma, Non-Small-Cell Lung; Phosphatidylinositol 3-Kinases; Pancreatic Neoplasms; Lung Neoplasms; Cell Adhesion Molecules; GPI-Linked Proteins; MicroRNAs; Cell Line, Tumor; Antigens, CD
PubMed: 38240103
DOI: 10.3892/ijo.2024.5615 -
Journal of Korean Medical Science May 2024The process of cancer metastasis is dependent on the cancer cells' capacity to detach from the primary tumor, endure in a suspended state, and establish colonies in... (Review)
Review
The process of cancer metastasis is dependent on the cancer cells' capacity to detach from the primary tumor, endure in a suspended state, and establish colonies in other locations. Anchorage dependence, which refers to the cells' reliance on attachment to the extracellular matrix (ECM), is a critical determinant of cellular shape, dynamics, behavior, and, ultimately, cell fate in nonmalignant and cancer cells. Anchorage-independent growth is a characteristic feature of cells resistant to anoikis, a programmed cell death process triggered by detachment from the ECM. This ability to grow and survive without attachment to a substrate is a crucial stage in the progression of metastasis. The recently discovered phenomenon named "adherent-to-suspension transition (AST)" alters the requirement for anchoring and enhances survival in a suspended state. AST is controlled by four transcription factors (IKAROS family zinc finger 1, nuclear factor erythroid 2, BTG anti-proliferation factor 2, and interferon regulatory factor 8) and can detach cells without undergoing the typical epithelial-mesenchymal transition. Notably, AST factors are highly expressed in circulating tumor cells compared to their attached counterparts, indicating their crucial role in the spread of cancer. Crucially, the suppression of AST substantially reduces metastasis while sparing primary tumors. These findings open up possibilities for developing targeted therapies that inhibit metastasis and emphasize the importance of AST, leading to a fundamental change in our comprehension of how cancer spreads.
Topics: Humans; Neoplasm Metastasis; Neoplasms; Cell Adhesion; Extracellular Matrix; Epithelial-Mesenchymal Transition; Anoikis; Transcription Factors
PubMed: 38769921
DOI: 10.3346/jkms.2024.39.e156 -
Scientific Reports May 2024Colorectal cancer (CRC) is a malignant tumor originating from epithelial cells of the colon or rectum, and its invasion and metastasis could be regulated by anoikis....
Colorectal cancer (CRC) is a malignant tumor originating from epithelial cells of the colon or rectum, and its invasion and metastasis could be regulated by anoikis. However, the key genes and pathways regulating anoikis in CRC are still unclear and require further research. The single cell transcriptome dataset GSE221575 of GEO database was downloaded and applied to cell subpopulation type identification, intercellular communication, pseudo time cell trajectory analysis, and receptor ligand expression analysis of CRC. Meanwhile, the RNA transcriptome dataset of TCGA, the GSE39582, GSE17536, and GSE17537 datasets of GEO were downloaded and merged into one bulk transcriptome dataset. The differentially expressed genes (DEGs) related to anoikis were extracted from these data sets, and key marker genes were obtained after feature selection. A clinical prognosis prediction model was constructed based on the marker genes and the predictive effect was analyzed. Subsequently, gene pathway analysis, immune infiltration analysis, immunosuppressive point analysis, drug sensitivity analysis, and immunotherapy efficacy based on the key marker genes were conducted for the model. In this study, we used single cell datasets to determine the anoikis activity of cells and analyzed the DEGs of cells based on the score to identify the genes involved in anoikis and extracted DEGs related to the disease from the transcriptome dataset. After dimensionality reduction selection, 7 marker genes were obtained, including TIMP1, VEGFA, MYC, MSLN, EPHA2, ABHD2, and CD24. The prognostic risk model scoring system built by these 7 genes, along with patient clinical data (age, tumor stage, grade), were incorporated to create a nomogram, which predicted the 1-, 3-, and 5-years survival of CRC with accuracy of 0.818, 0.821, and 0.824. By using the scoring system, the CRC samples were divided into high/low anoikis-related prognosis risk groups, there are significant differences in immune infiltration, distribution of immune checkpoints, sensitivity to chemotherapy drugs, and efficacy of immunotherapy between these two risk groups. Anoikis genes participate in the differentiation of colorectal cancer tumor cells, promote tumor development, and could predict the prognosis of colorectal cancer.
Topics: Humans; Colorectal Neoplasms; Anoikis; Prognosis; Gene Expression Regulation, Neoplastic; Cell Differentiation; Transcriptome; Biomarkers, Tumor; Gene Expression Profiling; Female
PubMed: 38773226
DOI: 10.1038/s41598-024-62370-y -
International Journal of Molecular... Jul 2023Triple-Negative Breast Cancer (TNBC) is a particularly aggressive subtype among breast cancers (BCs), characterized by anoikis resistance, high invasiveness, and...
Triple-Negative Breast Cancer (TNBC) is a particularly aggressive subtype among breast cancers (BCs), characterized by anoikis resistance, high invasiveness, and metastatic potential as well as Epithelial-Mesenchymal Transition (EMT) and stemness features. In the last few years, our research focused on the function of MCL1, an antiapoptotic protein frequently deregulated in TNBC. Here, we demonstrate that MCL1 inhibition by A-1210477, a specific BH3-mimetic, promotes anoikis/apoptosis in the MDA-MB-231 cell line, as shown via an increase in proapoptotic markers and caspase activation. Our evidence also shows A-1210477 effects on Focal Adhesions (FAs) impairing the integrin trim and survival signaling pathways, such as FAK, AKT, ERK, NF-κB, and GSK3β-inducing anoikis, thus suggesting a putative role of MCL1 in regulation of FA dynamics. Interestingly, in accordance with these results, we observed a reduction in migratory and invasiveness capabilities as confirmed by a decrease in metalloproteinases (MMPs) levels following A-1210477 treatment. Moreover, MCL1 inhibition promotes a reduction in EMT characteristics as demonstrated by the downregulation of Vimentin, MUC1, DNMT1, and a surprising re-expression of E-Cadherin, suggesting a possible mesenchymal-like phenotype reversion. In addition, we also observed the downregulation of stemness makers such as , , , as well as CD133, EpCAM, and CD49f. Our findings support the idea that MCL1 inhibition in MDA-MB-231 could be crucial to reduce anoikis resistance, aggressiveness, and metastatic potential and to minimize EMT and stemness features that distinguish TNBC.
Topics: Humans; MDA-MB-231 Cells; Triple Negative Breast Neoplasms; Cell Line, Tumor; Myeloid Cell Leukemia Sequence 1 Protein; Anoikis; Cell Proliferation; Epithelial-Mesenchymal Transition; Cell Movement
PubMed: 37446326
DOI: 10.3390/ijms241311149 -
Scientific Reports Aug 2023Colon adenocarcinoma (COAD) is a serious public health problem, the third most common cancer and the second most deadly cancer in the world. About 9.4% of cancer-related...
Colon adenocarcinoma (COAD) is a serious public health problem, the third most common cancer and the second most deadly cancer in the world. About 9.4% of cancer-related deaths in 2020 were due to COAD. Anoikis is a specialized form of programmed cell death that plays an important role in tumor invasion and metastasis. The presence of anti-anoikis factors is associated with tumor aggressiveness and drug resistance. Various bioinformatic methods, such as differential expression analysis, and functional annotation analysis, machine learning, were used in this study. RNA-sequencing and clinical data from COAD patients were obtained from the Gene expression omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Construction of a prognostic nomogram for predicting overall survival (OS) using multivariate analysis and Lasso-Cox regression. Immunohistochemistry (IHC) was our method of validating the expression of seven genes that are linked to anoikis in COAD. We identified seven anoikis-related genes as predictors of COAD survival and prognosis, and confirmed their accuracy in predicting colon adenocarcinoma prognosis by KM survival curves and ROC curves. A seven-gene risk score consisting of NAT1, CDC25C, ATP2A3, MMP3, EEF1A2, PBK, and TIMP1 showed strong prognostic value. Meanwhile, we made a nomogram to predict the survival rate of COAD patients. The immune infiltration assay showed T cells. CD4 memory. Rest and macrophages. M0 has a higher proportion in COAD, and 11 genes related to tumor immunity are important. GDSC2-based drug susceptibility analysis showed that 6 out of 198 drugs were significant in COAD. Anoikis-related genes have potential value in predicting the prognosis of COAD and provide clues for developing new therapeutic strategies for COAD. Immune infiltration and drug susceptibility results provide important clues for finding new personalized treatment options for COAD. These findings also suggest possible mechanisms that may affect prognosis. These results are the starting point for planning individualized treatment and managing patient outcomes.
Topics: Humans; Colonic Neoplasms; Adenocarcinoma; Genes, Regulator; Genes, cdc; Anoikis; Peptide Elongation Factor 1
PubMed: 37626132
DOI: 10.1038/s41598-023-40907-x -
Aging Jan 2024Hepatocellular carcinoma (HCC) exhibits a high degree of invasiveness and is closely associated with rapid disease progression. Multiple lines of evidence indicate a...
BACKGROUND
Hepatocellular carcinoma (HCC) exhibits a high degree of invasiveness and is closely associated with rapid disease progression. Multiple lines of evidence indicate a strong correlation between anoikis resistance and tumor progression, invasion, and metastasis. Nevertheless, the classification of anoikis in HCC and the investigation of novel biological target mechanisms in this context continue to pose challenges, requiring further exploration.
METHODS
Combined with HCC samples from TCGA, GEO and ICGC databases, cluster analysis was conducted on anoikis genes, revealing novel patterns among different subtypes. Significant gene analysis of different gene subtypes was performed using WCGNA. The anoikis prognostic risk model was established by Lasso-Cox. Go, KEGG, and GSEA were applied to investigate pathway enrichment primarily observed in risk groups. We compared the disparities in immune infiltration, TMB, tumor microenvironment (TME), and drug sensitivity between the two risk groups. RT-qPCR and Western blotting were performed to validate the expression levels of SLCO4C1 in HCC. The biological functions of SLCO4C1 in HCC cells were assessed through various experiments, including CCK8 assay, colony formation assay, invasion migration assay, wound healing assay, and flow cytometry analysis.
RESULTS
HCC was divided into 2 anoikis subtypes, and the subtypeB had a better prognosis. An anoikis prognostic model based on 12 (COPZ2, ACTG2, IFI27, SPP1, EPO, SLCO4C1, RAB26, STC2, RAC3, NQO1, MYCN, HSPA1B) risk genes is important for survival and prognosis. Significant differences were observed in immune cell infiltration, TME, and drug sensitivity analysis between the risk groups. SLCO4C1 was downregulated in HCC. SLCO4C1 downregulation promoted the proliferation, invasion, migration, and apoptosis of HCC cells. The tumor-suppressive role of SLCO4C1 in HCC has been confirmed.
CONCLUSIONS
Our study presents a novel anoikis classification method for HCC that reveals the association between anoikis features and HCC. The anoikis feature is a critical biomarker bridging tumor cell death and tumor immunity. In this study, we provided the first evidence of SLCO4C1 functioning as a tumor suppressor in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Anoikis; Liver Neoplasms; Biomarkers; Biological Assay; Tumor Microenvironment; Prognosis; Organic Anion Transporters
PubMed: 38226966
DOI: 10.18632/aging.205438 -
Scientific Reports Nov 2023Anoikis resistance, a notable factor in osteosarcoma, plays a significant role in tumor invasion and metastasis. This study seeks to identify a distinct gene signature...
Anoikis resistance, a notable factor in osteosarcoma, plays a significant role in tumor invasion and metastasis. This study seeks to identify a distinct gene signature that is specifically associated with the anoikis subcluster in osteosarcoma. Clinical, single-cell, and transcriptional data from TARGET and GEO datasets were used to develop a gene signature for osteosarcoma based on the anoikis subcluster. Univariate Cox and LASSO regression analyses were employed. The signature's predictive value was evaluated using time-dependent ROC and Kaplan-Meier analyses. Functional enrichment analyses and drug sensitivity analyses were conducted. Validation of three modular genes was performed using RT-qPCR and Western blotting. Signature (ZNF583, CGNL1, CXCL13) was developed to predict overall survival in osteosarcoma patients, targeting the anoikis subcluster. The signature demonstrated good performance in external validation. Stratification based on the signature revealed significantly different prognoses. The signature was an independent prognostic factor. The low-risk group showed enhanced immune cell infiltration and improved immune function. Drug sensitivity analysis indicated efficacy of chemotherapy agents. Prognostic nomograms incorporating the signature provided greater predictive accuracy and clinical utility. Signatures related to the anoikis subcluster play a significant role in osteosarcoma progression. Incorporating these findings into clinical decision-making can improve osteosarcoma treatment and patient outcomes.
Topics: Humans; Anoikis; Prognosis; Immunotherapy; Osteosarcoma; Bone Neoplasms
PubMed: 37980450
DOI: 10.1038/s41598-023-47367-3 -
Heliyon Aug 2023Ovarian serous cystadenocarcinoma (OSC) is the most prevalent histological subtype of ovarian cancer (OV) and presents a serious threat to women's health. Anoikis is an...
BACKGROUND
Ovarian serous cystadenocarcinoma (OSC) is the most prevalent histological subtype of ovarian cancer (OV) and presents a serious threat to women's health. Anoikis is an essential component of metastasis, and tumor cells can get beyond it to become viable. The impact of anoikis on OSC, however, has only been the topic of a few studies.
METHODS
The mRNA sequencing and clinical information of OSC came from The Cancer Genome Atlas Target Genotype-Tissue Expression (TCGA TARGET GTEx) dataset. Anoikis-related genes (ARGs) were collected by Harmonizome and GeneCards websites. Centered on these ARGs, we used unsupervised consensus clustering to explore potential tumor typing and filtered hub ARGs to create a model of predictive signature for OSC patients. Furthermore, we presented clinical specialists with a novel nomogram based on ARGs, revealing the underlying clinical relevance of this signature. Finally, we explored the immune microenvironment among various risk groups.
RESULTS
We identified 24 ARGs associated with the prognosis of OSC and classified OSC patients into three subtypes, and the subtype with the best prognosis was more enriched in immune-related pathways. Seven ARGs (ARHGEF7, NOTCH4, CASP2, SKP2, PAK4, LCK, CCDC80) were chosen to establish a risk model and a nomogram that can provide practical clinical decision support. Risk scores were found to be an independent and significant prognostic factor in OSC patients. The CIBERSORTx result revealed an inflammatory microenvironment is different for risk groups, and the proportion of immune infiltrates of Macrophages M1 is negatively correlated with risk score ( = -0.21, < 0.05). Ultimately, quantitative reverse transcription polymerase chain reaction (RT-PCR) was utilized to validate the expression of the seven pivotal ARGs.
CONCLUSION
In this study, based on seven ARGs, a risk model and nomogram established can be used for risk stratification and prediction of survival outcomes in patients with OSC, providing a reliable reference for individualized therapy of OSC patients.
PubMed: 37554782
DOI: 10.1016/j.heliyon.2023.e18708 -
Biochemical and Biophysical Research... Jun 2024Low-grade glioma (LGG) has an extremely poor prognosis, and the mechanism leading to malignant development has not been determined. The aim of our study was to clarify...
BACKGROUND
Low-grade glioma (LGG) has an extremely poor prognosis, and the mechanism leading to malignant development has not been determined. The aim of our study was to clarify the function and mechanism of anoikis and TIMP1 in the malignant progression of LGG.
METHODS
We screened 7 anoikis-related genes from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to construct a prognostic-predicting model. The study assessed the clinical prognosis, pathological characteristics, and immune cell infiltration in both high- and low-risk groups. Additionally, the potential modulatory effects of TIMP1 on proliferation, migration, and anoikis in LGG were investigated both in vivo and in vitro.
RESULTS
In this study, we identified seven critical genes, namely, PTGS2, CCND1, TIMP1, PDK4, LGALS3, CDKN1A, and CDKN2A. Kaplan‒Meier (K‒M) curves demonstrated a significant correlation between clinical features and overall survival (OS), and single-cell analysis and mutation examination emphasized the heterogeneity and pivotal role of hub gene expression imbalances in LGG development. Immune cell infiltration and microenvironment analysis further elucidated the relationships between key genes and immune cells. In addition, TIMP1 promoted the malignant progression of LGG in both in vitro and in vivo models.
CONCLUSIONS
This study confirmed that TIMP1 promoted the malignant progression of LGG by inhibiting anoikis, providing insights into LGG pathogenesis and potential therapeutic targets.
Topics: Humans; Anoikis; Glioma; Prognosis; Tissue Inhibitor of Metalloproteinase-1; Animals; Brain Neoplasms; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Mice; Male; Cell Proliferation; Female; Mice, Nude; Tumor Microenvironment; Neoplasm Grading
PubMed: 38603834
DOI: 10.1016/j.bbrc.2024.149894