Hereditas最新文献

Background & objectives: Non-small cell lung cancer (NSCLC) represents a malignant neoplasm exhibiting high incidence and mortality rates, marked by diminished patient survival probabilities and an unfavorable prognosis. The primary objective of this research is to investigate the prognostic value of miR-4701-3p in NSCLC and its regulatory role in tumor progression.

Methods: In this study, a cohort comprising 105 patients with NSCLC was enrolled. Expression levels of miR-4701-3p in tissues and cell lines were assayed using RT-qPCR. To investigate the correlation between miR-4701-3p and clinicopathological features, the χ2 test was applied. Additionally, Kaplan-Meier survival analysis alongside Cox regression modeling were performed to evaluate the prognostic significance of miR-4701-3p.

Results: miR-4701-3p was markedly upregulated in NSCLC tissues and cells. miR-4701-3p was significantly correlated with TNM stage and lymph node metastasis (LNM) in NSCLC patients. The group exhibiting high miR-4701-3p expression demonstrated a markedly decreased 5-year survival rate in comparison to the low expression group. According to Cox regression analysis, miR-4701-3p expression, TNM stage, and lymph node metastasis (LNM) emerged as independent predictors of the 5-year survival rate among NSCLC patients. By downregulating miR-4701-3p, a substantial inhibition of NSCLC cell proliferation, migration, and invasion was observed, accompanied by enhanced apoptotic activity. Conversely, overexpressing miR-4701-3p can enhance cell proliferation, invasion, and migration abilities while inhibiting cell apoptosis.

Conclusion: The elevated expression of miR-4701-3p in NSCLC tissues has certain predictive value for poor prognosis in patients and may be involved in malignant behaviors of NSCLC cells.

Bladder cancer (BLCA) is the predominant type of urothelial carcinoma in urinary system, and resistance to cisplatin-based chemotherapy substantially worsens clinical outcomes, presenting a major therapeutic obstacle. In this study, we integrated genome-wide association study (GWAS) data with expression quantitative trait loci (eQTL) analyses, and applied Mendelian randomization (MR) to assess the causal effects of eQTLs from 19,942 genes on BLCA. By incorporating scRNA-seq data, our study also identifies differentially expressed genes (DEGs) in cisplatin-resistant BLCA cells and examined their causal associations with BLCA, aiming to elucidate genetic drivers of chemoresistance and tumor progression. Through this integrated approach, we identified the eQTL of the ARHGEF12 gene as a key mediator of cisplatin resistance. Bioinformatic analysis revealed that elevated ARHGEF12 expression was strongly associated with activation of the PI3K/Akt signaling pathway. To define ARHGEF12's role in cisplatin resistance, we established a cisplatin-resistant UM-UC-3/DDP model. Silencing ARHGEF12 markedly reduced chemoresistance, increased apoptotic cell death, and induced pronounced morphological changes. Pharmacological modulation with the ROCK inhibitor Y-27632 and a rescue assay with the Akt activator SC79 supported a model in which ARHGEF12 drives chemoresistance via RhoA/ROCK-dependent activation of the PI3K/AKT axis. This study is the first to integrate MR with single-cell transcriptomics to explore the genetic contribution to cisplatin resistance in BLCA. Our results uncover a novel mechanistic role of ARHGEF12 in BLCA progression and chemoresistance and suggest it as a potential therapeutic target for precision treatment strategies.

Background: As the fifth most common cancer worldwide, hepatocellular carcinoma (HCC) is a highly malignant disease with a formidable prognosis. Within the tumor microenvironment, cancer-associated fibroblasts (CAFs) play a paramount role in tumorigenesis and progression by providing a supportive environment for cancer cells. This research aims to elucidate the regulatory mechanisms of CAFs and salmonella pathogenicity island 1 (SPI1) in HCC progression.

Methods: Protein and mRNA expression levels were determined by western blot and reverse-transcription quantitative polymerase chain reaction (RT-qPCR), respectively. The ability of glycolysis was detected using the glucose consumption and lactate production test kit. Cell proliferation was examined using colony formation assay. Cell migration and invasion were assessed via wound healing and transwell assays, respectively. The cell apoptosis was examined by flow cytometry and terminal deoxynucleotidyl transferase dUTP Nick-End Labeling (TUNEL).

Results: The CAFs and para-cancer fibroblasts (PAFs) were successfully separated. CAFs under hypoxic stress (H/CAFs) promoted glucose consumption and lactate production in HCC cells (Huh7 and Hep3B). CAFs conditioned medium (CAFs-CM) facilitated HCC cell proliferation, migration, invasion, glucose consumption, and lactate production. CAFs-CM facilitated programmed cell death 1 ligand 1 (PD-L1) and CD8⁺T apoptosis and hindered proliferation of CD8⁺T. SPI1 was identified as the common target of the differentially expressed genes (DEGs) in CAFs (GSE192912) and transcription factors (TF). The mRNA and protein expression of SPI1 was increased in CAFs. SPI1 knockdown suppressed PD-L1 expression levels, glucose consumption, lactate production, proliferation, invasion, and immune escape in CAFs-CM-cultured HCC cells.

Conclusions: SPI1 derived from CAFs facilitates the malignant behaviors of HCC cells by up-regulating v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) expression. This study enriches our understanding of HCC at the molecular level and may pave the way for the development of a novel strategy for the treatment of HCC.

Background: Erectile dysfunction (ED) and Parkinson's disease (PD) are prevalent conditions that considerably impair patients' quality of life. Emerging evidence suggests a potential relationship between ED and PD, possibly mediated by shared biological mechanisms. This research seeks to examine shared transcriptomic alterations and the underlying biological pathways associated with ED and PD.

Methods: Gene expression profiles related to ED and PD were derived from the Gene Expression Omnibus database, specifically the GSE2457 and GSE7621 datasets. Differentially expressed genes (DEGs) between patients and controls were identified through differential expression analysis. Functional enrichment analyses, including Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology analyses, were carried out to uncover the biological roles of the identified DEGs. To refine and validate potential key genes, machine learning algorithms, such as support vector machine-recursive feature elimination and LASSO regression, were employed. Immune infiltration analysis was carried out to examine potential immune responses related to the identified genes. Additionally, miRNA-gene and protein-protein interaction networks were established. Finally, the reliability of the selected genes was validated through external and experimental verification.

Results: In total, 25 overlapping DEGs were identified between ED and PD. Functional enrichment analysis demonstrated that these DEGs were involved in such biological processes as redox homeostasis and neuronal cell body function. KEGG pathway analysis indicated significant enrichment in pathways such as adrenergic signaling, cGMP-PKG signaling. Machine learning algorithms further refined the candidate genes, with SHOX2 and PIK3R6 demonstrating strong diagnostic potential. Immune infiltration analysis demonstrated correlations between the gene expression levels and various immune cell types. The constructed miRNA-gene regulatory networks revealed possible post-transcriptional regulatory mechanisms that modulated the expression of these genes. Finally, the diagnostic performance of these genes was verified in external datasets, with their performance further confirmed by ROC analysis and experimental verification.

Conclusion: This study identified the shared biological target between ED and PD through bioinformatics analyses. The key genes SHOX2 and PIK3R6 may serve as potential biomarkers. These results may offer new insights into the molecular mechanisms linking ED and PD.

Background: Coptisine (COP) is a natural compound extracted from Rhizoma Coptidis, and it represses the malignant biological behaviors of bladder cancer cells. However, the underlying molecular mechanism has not been fully elucidated. The aim of this study was to clarify the downstream mechanism by which COP treats bladder cancer.

Materials and methods: SwissTargetPrediction, STITCH, SymMap, ETCM, TCMSP, CTD databases were used to collect the related targets of COP. GeneCards, DisGeNET, TTD and OMIM databases were used to obtain the related targets of bladder cancer. A Venn diagram was used to identify the potential targets of COP in bladder cancer treatment. The protein-protein interaction network was constructed using STRING database, and Cytoscape 3.9.0 software was used to screen the hub targets. The binding relationship between COP and the hub targets was verified by molecular docking and molecular dynamics simulation. After the bladder cell lines T24 and BIU-87 were treated with different doses of COP, the regulatory effects of COP on PI3K/AKT pathway were investigated with western blotting. Additionally, the tumor-suppressive properties of COP on bladder cancer cells were validated with tumorigenesis model and metastasis model in nude mice.

Results: RAC-alpha serine/threonine-protein kinase 1 (AKT1), glycogen synthase kinase 3 beta (GSK3B), caspase-3 (CASP3), tumor necrosis factor (TNF) and cyclin D1 (CCND1) were identified as the main hub targets of COP in bladder cancer treatment. PI3K/AKT pathway was predicted to be a crucial pathway regulated by COP. The binding affinities between COP and AKT1, GSK3B, CASP3, TNF and CCND1 were high. COP treatment markedly repressed the phosphorylation level of ERK1/2, AKT1, PI3K p85 and mTOR in T24 and BIU-87 cells, and repressed the tumorigenesis and lung/liver metastasis of T24 cells in vivo.

Conclusion: COP may be a natural inhibitor for AKT1, GSK3B, CASP3, TNF and CCND1. COP represses PI3K/AKT pathway to suppress the progression of bladder cancer.