BACKGROUND:The Mitogen-Activated Protein Kinase (MAPK) signaling pathway is significant in clinical practice for its potential to impede tumor proliferation and migration and to enhance patient prognosis. Yet, the specific contributions of MAPK-related genes to the prognosis of colorectal cancer (CRC) are not clear. METHODS:CRC data was retrieved from TCGA and GEO databases, with the MAPK pathway genes being identified from Kyoto Encyclopedia of Genes and Genomes (KEGG). A risk signature model for CRC associated with the MAPK pathway was formulated using regression analysis. The tumor immune microenvironment of high- and low-risk groups was assessed using single sample gene set enrichment analysis (ssGSEA) and CIBERSORT algorithms. We also looked into the potential differential response to immunotherapy by comparing immune checkpoints, immunophenoscore (IPS) scores, and Tumor Immune Dysfunction and Exclusion (TIDE) scores between the two groups. Moreover, the sensitivity to CRC treatment drugs in high- and low-risk groups was probed by forecasting drug IC50 values with the pRRophetic R package. RESULTS:A risk model was established using eight distinct genes (CDC42, CACNA1D, EREG, TRAF2, MAPKAPK3, DDIT3, NGF, TGFB2) identified from the differential expression of MAPK-related genes. The analysis highlighted that patients in the high-risk group had a higher degree of immune cell infiltration but were less sensitive to immunotherapy (indicated by higher TIDE and lower IPS scores). Drug sensitivity predictions suggested that the high-risk group, despite their poor immunotherapy response, had an increased sensitivity to drugs such as Pazopanib, WH-4-023, and WZ-1-84. CONCLUSION:To encapsulate our findings, we have determined eight MAPK pathway-associated CRC prognostic biomarkers and developed a prognostic model accordingly. This model has proven effective in stratifying the risk levels among CRC patients.
Objective of the present study is to investigate the effect of photodynamic therapy (PDT) mediated by 5-aminolevulinic acid methyl ester hydrochloride (ALA-Me) on inhibiting the primary tumor growth and metastasis of melanoma, in relation with antitumor immunity. Although the effect of ALA-PDT on lymphocyte T cells has been extensively studied, there are limited publications about ALA-PDT effect on B cells and NK cells. In particular, at present there is no study of ALA-Me-PDT on B cells and NK cells. Therefore, in order to only investigate this aspect, we have employed T-lymphocyte deficient Balb/c nude mice. Methods: A non-pigmented melanoma mouse model, which was challenged with human primary melanoma cells WM266-4, was established in 36 nude mice. When the melanoma grew to size of (0.4 & times; 0.4) cm2, the 36 mice were randomly divided into 4 groups, i.e., ALA-Me intravenous (i.v.) injection-PDT, ALA-Me intraperitoneal (i.p.) injection-PDT, ALA-Me topical application-PDT and control group without any treatment. The dose for systemic administration (i.v. and i.p.) of ALA-Me was 250 mg/kg. For topical application of ALA-Me, a cream with 25 mg/cm2 was smeared on the tumor tissue. The tumor site was irradiated by the red light from LEDs lamp with fluence rate 90 mW/cm2 and energy rate 50 J/cm2. Results: The inhibitory effects on both tumor growth and metastasis were observed after all three treatments mentioned above. In terms of inhibiting tumor growth, there was a significant difference in the volume of tumor between the treatment groups and the control group (P < 0.05). Furthermore, a very significant (P < 0.01) inhibitory effect on tumor lung metastasis was found after the three treatments. Moreover, the ALA-Me-PDT-induced immune response was also observed by means of increase of immune cells NK cells in the spleen of the T cell- deficient nude mice. Conclusion: ALA-Me-PDT had significant inhibitory effects both on local tumor growth and distant lung metastasis of melanoma. There was also significant antitumor immunity caused by ALA-Me-PDT. Results of the present study provide a potential possibility for ALA-Me-PDT in the treatment of skin melanoma and its metastasis.
Aluminium is the third common metal of the earth, yet, it is physiologically non-essential and its higher levels on regular exposure can be harmful to the human body, affecting many vital organ systems. Environmental aluminium contamination and toxicity thereof is regarded as a 'silent killer' to the mankind as it is associated with the precipitation of several serious health complications chiefly involving nervous, blood and musculoskeletal systems. Various medicinal plants have been reported to possess aluminium toxicity ameliorative effects. A compilation of research published over the past 21 years on the protective properties of medicinal plants against the toxicity of aluminium is made. Thirty-four such plants reportedly have the ability to mitigate the toxicity of experimental aluminium in animals/cells/tissues leading to marked improvement of aluminium-induced pathophysiological complications, by multiple mechanisms; the prime typical modes inter alia are modulation of oxidative stress-inflammatory pathways and anti-cholinesterase activity. Thus, recent advances in this field of study may help to develop a potential nutraceutical or phytotherapeutic candidate against aluminium toxicity and neurodegenerative diseases for humans.
Recent research highlights the pivotal function of long non-coding RNAs (lncRNAs) in bladder cancer (BCa) progression, emphasizing the need to understand their functions. The clinical significance and molecular mechanisms of lncRNA FENDRR in BCa needed to be elucidated. The Gene Expression Omnibus (GEO) database for BCa-related lncRNAs was screened. Tumor and para cancerous tissues from 118 patients with BCa were collected. Real-time quantitative polymerase chain reaction assessed FENDRR, microRNA (miR)-18a-5p, and estrogen receptor 1 (ESR1) levels. Kaplan-Meier curves assessed FENDRR's prognostic significance. Cell Counting Kit-8, Transwell, and flow cytometry evaluated cell proliferation, migration, invasion, and apoptosis. Dual-Luciferase Reporter and RNA Immunoprecipitation assays revealed miR-18a-5p targeting of FENDRR and ESR1. FENDRR exhibited differential expression in BCa GEO databases. Notably, FENDRR and ESR1 were downregulated, while miR-18a-5p was upregulated in BCa tissues and cell lines. Low FENDRR expression correlated with poor clinical prognosis. Upregulating FENDRR hindered cell proliferation, migration, and invasion while promoting apoptosis; however, miR-18a-5p reversed this suppression. Mechanistically, miR-18a-5p directly targets both FENDRR and ESR1. Our study reveals that low FENDRR expression is a poor prognostic indicator in BCa. FENDRR inhibits miR-18a-5p to upregulate ESR1 and hinder cancer progression, suggesting potential therapeutic targets.
Gastric cancer (GC) remains a significant worldwide health issue, Dapper Antagonist of β-Catenin-1 (DACT1) is a gene implicated in various cancers. Bioinformatics analysis across multiple databases were utilized to investigate DACT1 expression and its correlation with GC prognosis. Subsequent experimental work involved cell culture, Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR), and Western Blot to explore the role of DACT1 in GC cell lines. Bioinformatics analysis revealed that DACT1 was highly expressed and linked to a low overall survival rate in GC. DACT1 expression was linked to epithelial mesenchymal transition (EMT) and Notch signaling pathways, both critical in cancer progression. Experimental validation further demonstrated that the knockdown of DACT1 inhibits GC cell proliferation, migration, the EMT process, and the activity of the Notch signaling pathway. DACT1 may serve as a promising target in GC treatment through its involvement in EMT and Notch signaling. The study provides a foundation for further investigation of DACT1 in GC.
AIM:This research sought to estimate the prognostic performance and cellular behaviors of lncRNA GHET1 (gastric carcinoma highly expressed transcript 1) in sufferers of esophageal cancer. METHOD:GHET1 expression was measured in esophageal cancer through quantitative real-time polymerase chain reaction (qRT-PCR) method. The prognostic performance of GHET1 level was estimated by Kaplan-Meier and Cox regression analyses. The cellular activities of GHET1 on esophageal cancer cells were estimated by transfecting siRNA. RESULTS:The relative abundance of GHET1 was notably elevated in esophageal cancer tissues and cells in respective order (P < 0.001). Abnormal GHET1 expression was notably in relation to differentiation (P = 0.049), LNM (lymph node metastasis, P = 0.002) and TNM (tumor node metastasis, P = 0.015). Moreover, relative to low GHET1 expression group, a poorer overall survival and relapse-free survival time existed in patients expressing high GHET1 expression (log-rank, P < 0.001). Multivariable analysis illustrated that GHET1 levels could be an independent index for the prognosis of patients diagnosed with esophageal cancer (P < 0.001, HR = 3.659, 95%CI: 2.208-6.061). Furthermore, GHET1 was found to bind directly with miR-105-3p, displaying an inverse correlation (r = -0.3790，P < 0.001). Experimental biological studies revealed silencing GHET1 could impede cell growth through the modulation of miR-105-3p (P < 0.001), which was rescued via transfecting miR-105-3p inhibitor in esophageal cancer. CONCLUSION:GHET1 emerges as a promising prognostic biomarker and tumor promoter in esophageal cancer, functioning through the modulation of miR-105-3p.
Colorectal cancer (CRC) is a serious malignancy. Retinoic acid (RA) can inhibit cancer cell growth, promote cancer cell apoptosis, and hold significant importance for tumor prognosis. We utilized TCGA public data to screen RA-related genes linked with survival. Based on RA-related genes, the CRC prognostic model was generated by Cox regression analysis. Subsequently, immune infiltration analysis, functional enrichment analysis of differentially expressed genes (DEGs), tumor mutation analysis, and drug prediction were carried out based on the high-risk (HR) and low-risk (LR) groups identified in the prognostic model. We identified 10 RA-related genes associated with CRC. A prognostic model was constructed based on RA-related genes. CRC patients were divided into HR and LR groups. Immune infiltration analysis demonstrated that cells such as B cells, iDCs, and mast cells had higher infiltration levels in the LR group (P < 0.05). The results of DEG enrichment analysis of HR and LR groups uncovered that DEGs were mainly enriched in Alcoholism, regionalization, nucleosome, DNA packaging complex, and other biological processes. Drug sensitivity prediction results revealed that AZ628, CGP-082996, CKM, Dasatinib, GNF-2, Saracatinib, Sorafenib, WH-4-023, and WZ-1-84 were more sensitive for patients in the HR group. AKT inhibitor VIII, Gemcitabine, JW-7-52-1, Mitomycin, NSC-87877, PAC-1, Pyrimethamine, QS11, and Roscovitine were more sensitive for those in the LR group. Our project identified correlations between RA-related genes and CRC. The model genes identified are essential indicators for evaluating CRC prognosis and further treating CRC.
The incidence of breast cancer, a malignant tumor that causes more harm to women, is increasing year by year, affecting women at a younger age. This paper describes the possible practical significance of lncRNA EBLN3P (EBLN3P) in predicting the prognosis of invasive breast cancer. EBLN3P and miR-144-3p levels in tissues and cells were detected by real-time quantitative PCR (RT-qPCR). The association between EBLN3P expression and prognosis of invasive breast cancer was investigated using Cox multivariate regression and Kaplan-Meier curve. The growth efficacy of EBLN3P expression on invasive breast cancer cells was evaluated by Cell Counting kit-8 (CCK-8) method and Transwell method, and the mechanism of EBLN3P targeting miR-144-3p was further studied. EBLN3P was elevated in invasive breast cancer, whereas survival rates were lower in patients with high EBLN3P level. EBLN3P directly targeted miR144-3p to participate in the mechanism of invasive breast cancer, and EBLN3P knockdown had an inhibitory effect on tumor cells. Silencing EBLN3P inhibited the advancement of invasive breast cancer and was expected to be a promising therapeutic target for clinical intervention and prognosis.
Noncoding RNA regulatory networks play crucial roles in human breast cancer. The aim of this study was to establish a network containing multi-type RNAs and RBPs in triple-negative breast cancer (TNBC). Differential expression analyses of lncRNAs, miRNAs, and genes were performed using the GEO2R tool. Downstream RBPs and miRNAs were identified using respective databases. GO, KEGG, and protein-protein interaction were predicted. Expression of mRNAs, lncRNAs, and miRNAs were examined using TCGA and ENCORI. TMEM161B-AS1-miR-3646-SERPINB5 axis was validated with the expression level and cell function. TMEM161B-AS1-RBFOX1-SER-PINB5 axis was validated using RIP assays. A lncRNA-miRNA-mRNA network, a lncRNA-RBP-mRNA network, and a lncRNA-miRNA/RBP-mRNA network were constructed. Alterations in the expression levels of TMEM161B-AS1, miR-3646, and SERPINB5 were confirmed by real-time polymerase chain reaction as downregulation, upregulation, and downregulation, respectively. TMEM161B-AS1 inhibited TNBC cell proliferation, migration, and invasion. miR-3646 reversed the inhibitory effect of TMEM161B-AS1 on cell function, while SERPINB5 offset the miR-3646 effect. RB-FOX1 bound to SERPINB5 mRNAs, and TMEM161B-AS1 was involved in their interaction. This study revealed the ln-cRNA-miRNA/RBP-mRNA network in TNBC, providing more directions to study the molecular mechanism of TNBC.
Breast cancer (BC) is one of the main causes of cancer-related death in women. The purpose of this study was to evaluate the expression of miR-605-5p in BC and its diagnostic and prognostic value. BC patients and healthy individuals who met the study criteria were included. Real-time fluorescence quantitative PCR (RT-qPCR) was used for the detection of miR-605-5p expression in BC patients and BC cell lines. The ROC curve was used for the assessment of the diagnostic value of miR-605-5p. The Kaplan-Meier survival curve was used to assess the prognostic value of miR-605-5p. CCK-8 and Transwell assays were performed to detect the effect of miR-605-5p on BC cell activity. The results of this study showed that miR-605-5p was markedly downregulated in BC and correlated with the clinicopathological features of the patients. The expression level of miR-605-5p has high diagnostic accuracy for distinguishing BC patients from healthy individuals. Low expression predicts an unfavorable prognosis for BC patients, while up-regulation of miR-605-5p inhibited the activity of BC cells. In summary, miR-605-5p has the potential to serve as an important molecular marker for prognostic analysis and prediction of BC patients.
Neuro-oncology is the study of brain and spinal cord neoplasms. Molecular targets and signaling pathways are pivotal in advancing modern healthcare, particularly in personalized medicine. Signaling pathways, which regulate cellular processes such as growth, division, and survival, are frequently dysregulated in cancer. Targeting these pathways has enabled the development of personalized therapies that improve efficacy while minimizing side effects. This approach has led to significant improvements in patient outcomes, reduced treatment toxicity, and a shift toward precision medicine, driving innovation in drug discovery. The integration of molecular targets and signaling pathways into clinical practice highlights their importance for enhancing patient care.
Numerous genes have been associated with colorectal cancer (CRC) treatment in prior studies, but the impact of radiotherapy-related autophagy genes (RRAGs) on CRC remains largely unexplored. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were implemented to screen out RRAGs significantly associated with survival, and a prognostic model was constructed. Samples were categorized into high- and low-risk groups with median riskscore. Immunomicroenvironment analysis, immunotherapy response prediction, enrichment analysis, tumor mutation analysis and drug prediction were performed in risk groups. Expression of signature genes in CRC cells was examined using quantitative reverse transcription polymerase chain reaction (qRT-PCR). There were 10 CRC-related RRAGs found. Prognostic models were built with RRAGs. Based on immune infiltration analysis, low-risk populations showed significantly greater levels of immune infiltration (P < 0.05) among immune cells, including dendritic cells (DCs), induced DCs (iDCs), and natural killer (NK) cells. They also had significantly higher levels of HLA-DRA and HLA-DMB expression (P < 0.05). Enrichment analysis presented that biological processes such as neuroactive ligand-receptor interaction, neutrophil extracellular trap formation, and signaling receptor activator activity were the primary areas of enrichment for differentially expressed genes in both groups. In the high-risk one, the ARHGEF17 mutation rate was 6%. Medications such as CGP-082996, Dasatinib, Erlotinib, and Salubrinal were more sensitive to high-risk group, whereas drugs such as FTI-277, DMOG, and Crizotinib were more sensitive to low-risk group. UGT1A6 and IRGM were significantly upregulated in tumor group as revealed by qRT-PCR. This study constructed a new prognostic model for CRC patients based on RRAGs, and a series of analysis results is conducive to providing more theoretical references and new insights into precision treatment of CRC patients.
Targeting PI3K/AKT/MTOR (PAM) signaling pathway may be a strategy at the fore for treating lung squamous cell carcinoma (LUSC). However, relationships of PAM pathway-related genes (PAGs) with LUSC prognosis are unknown. Therefore, identifying the prognostic significance of PAGs for LUSC is innovative and feasible. Transcriptomic data, clinical features, and PAGs of LUSC were obtained from public databases (TCGA, GEO). A PAGs-based prognostic model was built using regression analysis in TCGA-LUSC. Gene levels were assessed via qRT-PCR. Predictive performance was verified through multiple datasets. Differences in immune infiltration and anti-tumor immunity between risk groups were assessed by R packages. Sensitivity to common anti-cancer agents was tested using oncoPredict package. We identified a Riskscore model containing 11 PAGs. Patients were assigned into groups of high risk (HR) and low risk (LR) per median Riskscore. CAB39L, CDKN1A, and ITPR2 were significantly underexpressed in LUSC cells. TRAF2 and TRIB3 were significantly enhanced in LUSC cells. The LR group had a longer survival time. Prognostic values of one-, three-, and five-year ROC curves were good. Results were verified in GEO. Patients in LR group had higher immune infiltration levels of B cells and Tfh cells, and higher ssGSEA scores for APC_co_inhibition and T_cell_ co_stimulation. LR group had lower TIDE scores and lower IC50 values (Alpelisib, Ibrutinib, Sapitinib, and Savolitinib). We successfully built a reliable 11-gene Riskscore prognostic model. Patients in LR group had potential advantages in survival, immune response, and drug sensitivity. In summary, the results offered new insights into prognosis prediction, immunotherapy, and personalized treatment of LUSC.
Invasive ductal carcinoma (IDC) is a major type of breast cancer. The utilization of inhibitors targeting histone methyltransferases introduces novel therapeutic avenues for the treatment of cancer. Immunohistochemistry, Western blot, and reverse transcription quantitative polymerase chain reaction experiments were applied to assess the levels of EHMT2 in IDC and adjacent tissues. HCC70 cells were treated with EHMT2 inhibitors (UNC0646 and BIX-01294), and assessed using Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and transwell assays to evaluate cell viability, apoptosis, and migratory capacity, respectively. The reactive oxygen species (ROS) levels were assessed using the 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescent probe. The expressions of Hippo pathway were analyzed via Western blot assay. Immunofluorescence staining was employed to detect the subcellular localization changes in YAP expression. A xenograft tumor model of HCC70 cells was applied to validate the tumor-suppressive influences of EHMT2 inhibitors in vivo. We observed significant upregulation of EHMT2 in both IDC clinical samples and IDC cell lines, with high EHMT2 expression correlating with poor prognosis. After treatment with EHMT2 inhibitors UNC0646 or BIX-01294, HCC70 cells exhibited inhibition of proliferation and migratory capacity, alongside an increase in apoptosis rate and ROS production levels. UNC064 or BIX-01294 promoted the phosphorylation levels of MST1, LATS1, MOB1A, and YAP, indicating the activation of the Hippo pathway by EHMT2 inhibitors. Moreover, UNC0646 and BIX-01294 enhanced the cytoplasmic expression of YAP while inhibiting its nuclear localization, preventing its nuclear activation. EHMT2 was upregulated in IDC, and EHMT2 inhibitors suppressed IDC progression by modulating the Hippo signaling pathway.
BACKGROUND:Lung adenocarcinoma (LUAD) is one of the most malignant tumors with significant implications for population health and life. Nicotinamide metabolism may play a pivotal part in influencing the prognosis of LUAD. This study aimed to figure out the potential value of nicotinamide metabolism-related genes (NMRGs) in LUAD prognosis. METHODS:Forty-two NMRGs were obtained from the Molecular Signatures Database and intersected with differentially expressed genes (DEGs) in LUAD from The Cancer Genome Atlas. Unsupervised consensus clustering was conducted based on the intersecting genes, followed by identification of DEGs between clusters. Enrichment analyses and LASSO-Cox regression analyses were conducted. Immune cell infiltration was calculated using the ssGSEA algorithm. Wilcoxon test was conducted on the TIDE scores of different risk groups. Targeted small molecule drug prediction was performed on the DEGs in groups. RESULTS:A total of 10 nicotinamide metabolism-related differentially expressed genes (NMRDEGs) were identified for LUAD clustering. LUAD patients were divided into two clusters. Cluster 1 had considerably higher overall survival rates compared to cluster 2. Differential genes between clusters were mainly enriched in hormone metabolic processes and the neuroactive ligand-receptor interaction pathway. An 11-gene prognostic model was established to predict the overall survival of LUAD patients. The validation set showed that the model had a good prognostic effect. Analysis of immune cell infiltration demonstrated that in the high-risk (HR) group, infiltration levels of mast cells and neutrophils were considerably lower than low-risk (LR) group, while infiltration levels of NK cells and Th2 cells were considerably higher than LR group. TIDE scores indicated a lower likelihood of immune evasion and a potentially better response to immunotherapy in LR patients. Drug prediction showed that FGIN-1-43, deferiprone, and griseofulvin were potential drugs. CONCLUSION:We successfully developed a predictive model for the survival and immunotherapy response of LUAD patients.
Microplastics (MPs), pervasive environmental pollutants, have raised significant concerns regarding their potential impact on human health, particularly in relation to cancer. This review examines the current evidence linking MPs to various cancers, including ovarian, gastric, blood, brain, colorectal, lung, liver, breast, and cervical cancers. Recent studies indicate that MPs, including polystyrene nanoparticles (PS-NPs) and microplastics (PS-MPs), can exacerbate tumor progression through mechanisms such as oxidative stress, inflammation, and endocrine disruption. For instance, in ovarian cancer, PS-NP exposure has been shown to accelerate tumor growth, while in gastric cancer, PS-MPs alter gene expression to promote cancer progression. Blood cancer research highlights the presence of MPs in human blood, suggesting their potential systemic distribution and impact. MPs' ability to cross the blood-brain barrier raises concerns about brain cancer, where they may induce neurotoxicity. Similarly, MPs contribute to colorectal cancer by causing intestinal inflammation and gut microbiota alterations. Inhalation of MPs is linked to lung cancer due to chronic inflammation and oxidative stress. In liver cancer, MPs induce hepatic toxicity and promote carcinogenesis. Breast and cervical cancers are associated with MPs endocrine-disrupting properties, leading to increased cell proliferation and migration. This review underscores the urgent need for further research to elucidate the mechanisms through which MPs contribute to cancer and to inform public health strategies and regulatory policies aimed at mitigating the risks of microplastic exposure.
Despite advancements in systemic therapy, the mortality rate for patients with metastatic melanoma remains around 70%, underscoring the imperative for alternative treatment strategies. Through the establishment of a chemoresistant melanoma model and a subsequent drug investigation, we have identified pacritinib, a medication designed for treating myelofibrosis and severe thrombocytopenia, as a potential candidate to overcome resistance to melanoma therapy. Our research reveals that pacritinib, administered at clinically achievable concentrations, effectively targets dacarbazine-resistant melanoma cells by suppressing IRAK1 rather than JAK2. Notably, melanoma-resistant cells exhibit elevated p-IRAK1 levels, while there is no discernible difference in p-JAK2 levels between sensitive and resistant cells. Additionally, analysis of melanoma patients indicates a higher expression of IRAK1, correlating with a significantly improved survival rate. Furthermore, the depletion of IRAK1 not only reduces cell viability in melanoma cells but also enhances the effectiveness of dacarbazine treatment. In a dacarbazine-resistant melanoma model, pacritinib demonstrates significant inhibition of tumor growth in mice, leading to enhanced overall survival. In the dacarbazine-sensitive melanoma model, the combination of pacritinib and dacarbazine is more effective than dacarbazine alone in reducing tumor growth and improving overall survival in mice. In summary, our findings highlight IRAK1 as a promising therapeutic target to overcome melanoma resistance, and pacritinib emerges as a valuable addition to the treatment armamentarium for melanoma.
