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Cellular Signalling Jun 2024Cholangiocarcinoma (CCA) is a malignancy with an extremely poor prognosis, and much remains unknown about its pathogenesis and treatment modalities. Circular RNA...
Cholangiocarcinoma (CCA) is a malignancy with an extremely poor prognosis, and much remains unknown about its pathogenesis and treatment modalities. Circular RNA (circRNA) has been proven to play regulatory roles in various tumorigenesis, yet its potential function and mechanism in cholangiocarcinoma require further investigation. This study is the first to identify the aberrant expression and functional role of a novel circRNA, circ_0007534, derived from the DDX42 gene, in cholangiocarcinoma. Compared to the normal control group, the expression of circ_0007534 was significantly elevated in the tissues and cells with CCA and that high expression correlated with lymph node invasion and poor prognosis. Functional experiments indicated that downregulating circ_0007534 markedly inhibited the proliferation, migration, invasion, stemness, and anti-anoikis ability of CCA cells, as well as the tumor growth and liver and lung metastasis in nude mice. Mechanistic studies revealed that DDX42, as the parent gene of circ_0007534, can mutually regulate each other's expression. Predominantly located in the cytoplasm, circ_0007534 can form a complex with the RNA-binding protein DDX3X, which enhances the stability of DDX42 mRNA, thereby upregulating the expression of DDX42. This creates a positive feedback loop among the three, collectively promoting the progression of cholangiocarcinoma. In conclusion, this study sheds light on the pivotal role and molecular mechanism of circ_0007534 in the development of CCA, offering potential new targets for early diagnosis and treatment.
Topics: Animals; Mice; MicroRNAs; RNA, Circular; Anoikis; Mice, Nude; Feedback; Cell Line, Tumor; Cholangiocarcinoma; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Cell Proliferation; Gene Expression Regulation, Neoplastic; Cell Movement
PubMed: 38492624
DOI: 10.1016/j.cellsig.2024.111141 -
Translational Cancer Research Feb 2024The recurrence and mortality rates of bladder cancer are extremely high, and its diagnosis and treatment are global concerns. The mechanism of anoikis is closely related...
Identification and verification of anoikis-related gene markers to predict the prognosis of patients with bladder cancer and assist in the diagnosis and treatment of bladder cancer.
BACKGROUND
The recurrence and mortality rates of bladder cancer are extremely high, and its diagnosis and treatment are global concerns. The mechanism of anoikis is closely related to tumor metastasis.
METHODS
First, we obtained all the data needed for this study from a public database through a formal operational process. The data were then analyzed by bioinformatics technology. Through the limma package, we screened and obtained 313 anoikis-related genes [false discovery rate (FDR) <0.05, |log fold change (FC) | >0.585]. Then, through univariate independent prognostic analysis, we further screened 146 genes (P<0.05) related to the prognosis of bladder cancer from 313 differential genes. These 146 prognostically relevant differential genes were used for least absolute shrinkage and selection operator (LASSO) regression for further screening to obtain model-related genes and output model formulas. Through the nomogram, we can calculate the survival rate of patients more accurately. The accuracy of the nomogram was also confirmed by calibration curves, independent prognostic analysis, receiver operating characteristic (ROC) curves, decision curve analysis (DCA) curves. We then analysed the sensitivity of immunotherapy in bladder cancer patients with different risk scores via Tumor Immune Dysfunction and Exclusion (TIDE).
RESULTS
Through bioinformatics technology and public databases, a prognostic model including 9 anoikis-related genes (, , , , , , , , ) was obtained. Integrating risk scores with clinical information, we obtained a nomogram that can accurately predict patient survival. By querying the immunohistochemical results of the Human Protein Atlas database, two of the nine model-related genes (, ) have the value of further research and are expected to become new biomarkers to assist the diagnosis and treatment of bladder cancer. Through immune-related analysis, we found that patients in the low-risk group appeared to be more suitable for immunotherapy, while drug sensitivity analysis showed that bladder cancer patients in the high-risk group were more sensitive to common chemotherapy drugs.
CONCLUSIONS
In this study, a prognostic model that can accurately predict the prognosis of patients with bladder cancer was constructed. and are expected to become a new biomarker for the diagnosis and treatment of bladder cancer.
PubMed: 38482431
DOI: 10.21037/tcr-23-1770 -
International Wound Journal Mar 2024This study aims to investigate the role of anoikis-related genes in diabetic foot (DF) by utilizing bioinformatics analysis to identify key genes associated with anoikis...
This study aims to investigate the role of anoikis-related genes in diabetic foot (DF) by utilizing bioinformatics analysis to identify key genes associated with anoikis in DF. We selected the GEO datasets GSE7014, GSE80178 and GSE68183 for the extraction and analysis of differentially expressed anoikis-related genes (DE-ARGs). GO analysis and KEGG analysis indicated that DE-ARGs in DF were primarily enriched in apoptosis, positive regulation of MAPK cascade, anoikis, focal adhesion and the PI3K-Akt signalling pathway. Based on the LASSO and SVM-RFE algorithms, we identified six characteristic genes. ROC curve analysis revealed that these six characteristic genes had an area under the curve (AUC) greater than 0.7, indicating good diagnostic efficacy. Expression analysis in the validation set revealed downregulation of CALR in DF, consistent with the training set results. GSEA results demonstrated that CALR was mainly enriched in blood vessel morphogenesis, endothelial cell migration, ECM-receptor interaction and focal adhesion. The HPA database revealed that CALR was moderately enriched in endothelial cells, and CALR was found to interact with 63 protein-coding genes. Functional analysis with DAVID suggested that CALR and associated genes were enriched in the phagosome component. CALR shows promise as a potential marker for the development and treatment of DF.
Topics: Humans; Diabetic Foot; Anoikis; Endothelial Cells; Phosphatidylinositol 3-Kinases; Algorithms; Diabetes Mellitus
PubMed: 38468369
DOI: 10.1111/iwj.14771 -
Discover Oncology Mar 2024Skin cutaneous melanoma (SKCM) is a highly lethal cancer, ranking among the top four deadliest cancers. This underscores the urgent need for novel biomarkers for SKCM...
BACKGROUND
Skin cutaneous melanoma (SKCM) is a highly lethal cancer, ranking among the top four deadliest cancers. This underscores the urgent need for novel biomarkers for SKCM diagnosis and prognosis. Anoikis plays a vital role in cancer growth and metastasis, and this study aims to investigate its prognostic value and mechanism of action in SKCM.
METHODS
Utilizing consensus clustering, the SKCM samples were categorized into two distinct clusters A and B based on anoikis-related genes (ANRGs), with the B group exhibiting lower disease-specific survival (DSS). Gene set enrichment between distinct clusters was examined using Gene Set Variation Analysis (GSVA) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis.
RESULTS
We created a predictive model based on three anoikis-related differently expressed genes (DEGs), specifically, FASLG, IGF1, and PIK3R2. Moreover, the mechanism of these prognostic genes within the model was investigated at the cellular level using the single-cell sequencing dataset GSE115978. This analysis revealed that the FASLG gene was highly expressed on cluster 1 of Exhausted CD8( +) T (Tex) cells.
CONCLUSIONS
In conclusion, we have established a novel classification system for SKCM based on anoikis, which carries substantial clinical implications for SKCM patients. Notably, the elevated expression of the FASLG gene on cluster 1 of Tex cells could significantly impact SKCM prognosis through anoikis, thus offering a promising target for the development of immunotherapy for SKCM.
PubMed: 38460046
DOI: 10.1007/s12672-024-00926-0 -
Cancer Research Communications Mar 2024Epithelial-mesenchymal transition (EMT) in cancer promotes metastasis and chemotherapy resistance. A subset of triple-negative breast cancer (TNBC) exhibits a...
UNLABELLED
Epithelial-mesenchymal transition (EMT) in cancer promotes metastasis and chemotherapy resistance. A subset of triple-negative breast cancer (TNBC) exhibits a mesenchymal gene signature that is associated with poor patient outcomes. We previously identified PTK6 tyrosine kinase as an oncogenic driver of EMT in a subset of TNBC. PTK6 induces EMT by stabilizing SNAIL, a key EMT-initiating transcriptional factor. Inhibition of PTK6 activity reverses mesenchymal features of TNBC cells and suppresses their metastases by promoting SNAIL degradation via a novel mechanism. In the current study, we identify membrane-associated RING-CH2 (MARCH2) as a novel PTK6-regulated E3 ligase that promotes the ubiquitination and degradation of SNAIL protein. The MARCH2 RING domain is critical for SNAIL ubiquitination and subsequent degradation. PTK6 inhibition promotes the interaction of MARCH2 with SNAIL. Overexpression of MARCH2 exhibits tumor suppressive properties and phenocopies the effects of SNAIL downregulation and PTK6 inhibition in TNBC cells, such as inhibition of migration, anoikis resistance, and metastasis. Consistent with this, higher levels of MARCH2 expression in breast and other cancers are associated with better prognosis. We have identified MARCH2 as a novel SNAIL E3 ligase that regulates EMT and metastases of mesenchymal TNBC.
SIGNIFICANCE
EMT is a process directly linked to drug resistance and metastasis of cancer cells. We identified MARCH2 as a novel regulator of SNAIL, a key EMT driver, that promotes SNAIL ubiquitination and degradation in TNBC cells. MARCH2 is oncogene regulated and inhibits growth and metastasis of TNBC. These insights could contribute to novel strategies to therapeutically target TNBC.
Topics: Humans; Gene Expression Regulation; Oncogenes; Triple Negative Breast Neoplasms; Ubiquitin-Protein Ligases; Ubiquitination; Membrane Proteins
PubMed: 38457262
DOI: 10.1158/2767-9764.CRC-23-0090 -
Gland Surgery Feb 2024Anoikis presents a significant barrier in the metastasis of cancer. As the most aggressive type of thyroid cancer, anaplastic thyroid cancer (ATC) exhibits a high risk...
BACKGROUND
Anoikis presents a significant barrier in the metastasis of cancer. As the most aggressive type of thyroid cancer, anaplastic thyroid cancer (ATC) exhibits a high risk of metastasis and is characterized by high mortality. Therefore, investigating the molecular mechanisms of anoikis resistance in ATC is important for devising therapeutic targets in clinical research.
METHODS
Differentially Expressed Genes were screened in ATC cells under attached and detached culture conditions with RNA-seq. Investigate the impact of enolase 2 (ENO2) on apoptosis and spheroid formation by gain and loss of function. Changes of reactive oxygen species (ROS), glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) were detected to assess redox balance. The transcriptional regulatory role of signal transducer and activator of transcription 1 (STAT1) on ENO2 was validated through Dual-Luciferase Reporter Gene Assay. Explore the impact of ENO2 expression on the formation of lung metastases in nude mice.
RESULTS
We found that the glycolysis process was activated in detached ATC cells. Several genes in the glycolysis process, particularly , a member of the enolase superfamily was upregulated in ATC cells cultured in suspension. The upregulation of ENO2 enabled the maintenance of redox balance by supplying GSH and NADPH, thereby preventing cells from undergoing anoikis. In terms of mechanism, the expression of STAT1 was enhanced in anoikis resistance cells, which in turn positively regulated the expression of ENO2. , ENO2-suppressed ATC cells resulted in a significantly lower rate of lung colonization compared to control ATC cells.
CONCLUSIONS
Stable expression of ENO2 and the maintenance of redox balance played a pivotal role in facilitating anoikis resistance of ATC.
PubMed: 38455357
DOI: 10.21037/gs-24-44 -
Cellular Signalling Jun 2024Cancer stem-like cells (CSLCs) and anoikis resistance play crucial roles in the metastasis of cancers. However, it remains unclear whether CSLCs are related to anoikis...
Cancer stem-like cells (CSLCs) and anoikis resistance play crucial roles in the metastasis of cancers. However, it remains unclear whether CSLCs are related to anoikis resistance in intrahepatic cholangiocarcinoma (ICC). Here we identified a group of stemness-related anoikis genes (SRAGs) via bioinformatic analysis of public data. Accordingly, a novel anoikis-related classification was established and it divided ICC into C1 and C2 type. Different type ICC displayed distinct prognosis, molecular as well immune characteristics. Furthermore, we found one key SRAGs via several machine learning algorithms. HK2 was up-regulated in tumor-repopulating cells (TRCs) of ICC, a kind of CSLCs with a potent resistance to anoikis. Its up-regulation may be caused by the activation of MTORC1 signaling in ICC-TRCs. And inhibition of HK2 significantly increased anoikis and decreased migration as well invasion in ICC-TRCs. Our studies provide an insight into the molecular mechanism underlying the resistance of ICC-TRCs to anoikis and enhance the evidences for targeting HK2 in ICC.
Topics: Humans; Anoikis; Cell Line, Tumor; Cholangiocarcinoma; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Cell Proliferation
PubMed: 38453126
DOI: 10.1016/j.cellsig.2024.111126 -
Cell Death Discovery Mar 2024Serine protease inhibitor clade E member 1 (SERPINE1) inhibits extracellular matrix proteolysis and cell detachment. However, SERPINE1 expression also promotes tumor...
Serine protease inhibitor clade E member 1 (SERPINE1) inhibits extracellular matrix proteolysis and cell detachment. However, SERPINE1 expression also promotes tumor progression and plays a crucial role in metastasis. Here, we solve this apparent paradox and report that Serpine1 mRNA per se, independent of its protein-coding function, confers mesenchymal properties to the cell, promoting migration, invasiveness, and resistance to anoikis and increasing glycolytic activity by sequestering miRNAs. Expression of Serpine1 mRNA upregulates the expression of the TRA2B splicing factor without affecting its mRNA levels. Through transcriptional profiling, we found that Serpine1 mRNA expression downregulates through TRA2B the expression of genes involved in the immune response. Analysis of human colon tumor samples showed an inverse correlation between SERPINE1 mRNA expression and CD8+ T cell infiltration, unveiling the potential value of SERPINE1 mRNA as a promising therapeutic target for colon tumors.
PubMed: 38448406
DOI: 10.1038/s41420-024-01886-8 -
Methods in Molecular Biology (Clifton,... Mar 2024Non-small cell lung cancer (NSCLC) is among the most malignant tumors with high propensity for metastasis and is the leading cause of cancer-related death globally. Most...
Non-small cell lung cancer (NSCLC) is among the most malignant tumors with high propensity for metastasis and is the leading cause of cancer-related death globally. Most patients present with regional and distant metastasis, associated with poor prognosis. Lipids may play an essential role in either activating or inhibiting detachment-induced apoptosis (anoikis), where the latter is a crucial mechanism to prevent metastasis, and it may have a cross-talk with autophagy. Autophagy has been shown to be induced in various human cancer metastasis, modulating tumor cell motility and invasion, cancer cell differentiation, resistance to anoikis, and epithelial to mesenchymal transition. Hence, it may play a crucial role in the transition of benign to malignant phenotypes, the core of metastasis initiation. Here, we provide a method we have established in our laboratory for detecting lipids in attached and detached non-small lung cancer cells and show how to analyze lipidomics data to find its correlation with autophagy-related pathways.
PubMed: 38441721
DOI: 10.1007/7651_2024_524 -
Cancer Metastasis Reviews Mar 2024Metastasis remains the principal trigger for relapse and mortality across diverse cancer types. Circulating tumor cells (CTCs), which originate from the primary tumor or... (Review)
Review
Metastasis remains the principal trigger for relapse and mortality across diverse cancer types. Circulating tumor cells (CTCs), which originate from the primary tumor or its metastatic sites, traverse the vascular system, serving as precursors in cancer recurrence and metastasis. Nevertheless, before CTCs can establish themselves in the distant parenchyma, they must overcome significant challenges present within the circulatory system, including hydrodynamic shear stress (HSS), oxidative damage, anoikis, and immune surveillance. Recently, there has been a growing body of compelling evidence suggesting that a specific subset of CTCs can persist within the bloodstream, but the precise mechanisms of their survival remain largely elusive. This review aims to present an outline of the survival challenges encountered by CTCs and to summarize the recent advancements in understanding the underlying survival mechanisms, suggesting their implications for cancer treatment.
PubMed: 38436892
DOI: 10.1007/s10555-024-10178-7