Journal of environmental pathology, toxicology and oncology : official organ of the International Society for Environmental Toxicology and Cancer最新文献

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 ȕ 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.

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.

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.

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.

Background: Circular RNAs (circRNAs) play a pivotal part in the advancement of multiple tumors. Nonetheless, the influence of Helicobacter pylori (H. pylori) infection on the expression of circRNA in gastric cancer remains less studied.

Aim: The objective of this research is to clarify the function and underlying mechanism of circ_0075829 in the context of gastric cancer and its relation to H. pylori infection.

Methods: The circ_0075829 expression in tissue specimens and cells was evaluated utilizing quantitative real-time PCR (RT-qPCR). H. pylori infection and transfection were treated in gastric cancer cells to measure circ_0075829 expression changes and their effects on cellular behaviors. Kaplan-Meier curve was conducted to assess the clinical prognostic performance of circ_0085729 in patients with gastric cancer. Bioinformatics and dua-luciferase reporter assay were performed to validate the downstream miRNA and mRNA. CCK-8 proliferation assay and transwell experiments were carried out to investigate the influence of circ_0075829-miR-149-5p-AGO1 on cellular activities.

Results: Circ_0075829 expression was increased in gastric cancer and correlated with several clinical characteristics and shorter overall survival. Besides, H. pylori infection increased circ_0075829 expression in cancer cells. miR-149-5p was a direct target miRNA of circ_0075829 and was downregulated in gastric cancer. Downregulation of circ_0075829 could repress the proliferative abilities, migratory capacities, and invasion potential of cancer cells by mediating miR-149-5p to regulate AGO1 expression.

Conclusion: Circ_0075829 seems to play an oncogenic role in H. pylori-associated gastric malignancies and may serve as a promising indicator for predicting outcomes in gastric cancer, which underpins a more theoretical basis for the progression of new therapeutic approaches to treating gastric cancer.

Bladder cancer (BCa) is approximately the fourth most prevalent diagnosed cancer in men and is three times less common in women. Therefore, identifying biomarkers, developing more effective therapeutic strategies, and understanding the mechanisms underlying BCa tumor growth and progression are urgently required to improve survival rates. Therefore, we aim to investigate the expression of PTEN/Akt in tissue samples of both non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC) patients (n = 70) and human BCa cell lines T24 and 5637, along with the potent role of ellagic acid (EA) in the modulation of the PTEN/Akt pathway and the resulting therapeutic potential. Results showed low-intensity nuclear or cytoplasmic PTEN staining or loss of PTEN expression in tumor cells and overexpression of p-Akt (Ser-473) with high intensity in the nucleus or cytoplasm. EA treatment of T24 and 5637 cells reduced cell viability, inflammation (NF-κB, COX-2), invasion (MMP-9), induced the caspase (cas-3 and cas-9) cascade signaling pathway, and induced cell apoptosis along with the suppression of the PI3K/PTEN/Akt signaling pathway after 48h in a dose-dependent manner. Thus, these data suggested that the EA showed a strong potential anti-cancer effect in T24 and 5637 cells. In conclusion, the expression of PTEN/p-Akt and the inverse relation indicated an alteration of the PTEN/Akt pathway, and such cases could benefit from treatment with EA in BCa.

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.