Translational cancer research最新文献

Background: There is growing evidence that long non-coding RNA long iatrogenic non-protein-coding RNA p53-induced transcript (LINC-PINT) is highly expressed in cancer tissue and is associated with the prognosis of cancer patients. The present study systematically analyzed the prognostic significance of LINC-PINT expression in cancer patients. We aimed to reveal the association between LINC-PINT expression and survival in cancer patients.

Methods: We collected eligible studies through the PubMed, Embase, and Cochrane library searches until February 1, 2024. We collected the following data from the enrolled studies: first author, publication year, country, cancer type, case number, cancer stage, detection method and cut-off value of LINC-PINT expression, follow-up period, and survival outcome. The prognostic significance of LINC-PINT expression was evaluated by conducting a meta-analysis. StataSE17 (Stata, College Station, TX, USA) was used for all analyses.

Results: Eleven eligible studies with 2,876 cancer patients were collected. The pooled results revealed that LINC-PINT expression was associated with favorable overall survival (OS) and disease-free survival (DFS) in cancer patients [for OS, hazard ratio (HR) =0.72, 95% confidence interval (CI): 0.64-0.80, P<0.001; for DFS, HR =0.70, 95% CI: 0.60-0.82, P<0.001].

Conclusions: LINC-PINT expression was associated with favorable OS and DFS, and it may serve as a valuable prognostic marker in cancer patients.

Background: Telomerase is activated in most cancer cells, and thus telomerase is an ideal target for cancer therapy. The human liver-associated candidate tumour suppressor LPTS/PinX1, is the only human protein reported to bind with the telomerase catalytic subunit telomerase reverse transcriptase (TERT) and inhibit telomerase activity. The C-terminal fragment of LPTS/PinX1 (LPTS/PinX1290-328) contains a telomerase inhibitory domain that is needed for inhibition of telomere elongation and induction of apoptosis. This study prepared the TAT-LPTS39 (TAT-LPTS/PinX1290-328) polypeptide and analysed its effect of the tumour growth.

Methods: LPTS/PinX1290-328 was fused with TAT [11 amino acid (aa) peptide of the HIV transactivator of transcription protein] to generate the recombinant protein GST-TAT-LPTS39 and was transduced into cells. Telomerase activity was identified by the telomeric repeat amplification protocol (TRAP) and the relative telomere length (RTL) was measured by quantitative real-time polymerase chain reaction (qPCR). The effects of the TAT-LPTS39 protein on cell growth and death were evaluated by 3-(4,5-dimethylthiazolyl)-2,5-diphenyltetrazolium bromide (MTT), cell culture doubling time and flow cytometry assays. The cell derived xenograft (CDX) model was used to examine tumour growth inhibition effect of TAT-LPTS39 polypeptide in vivo.

Results: We successfully expressed and purified the recombinant protein GST-TAT-LPTS39 in vitro. The GST-TAT-LPTS39 protein was efficiently delivered into cells, inhibited telomerase activity and the growth of the telomerase-positive liver cancer cells BEL-7404 and QGY7701, and induced the senescence and apoptosis in telomerase-positive Hela, BEL-7404 and QGY7701 cells, but was ineffective to telomerase-negative cells in vitro. The TAT-LPTS39 polypeptide without the GST tag similarly inhibited the growth of telomerase-positive cancer cells Hela and PLC-PRF-5 in vitro, BEL-7404 CDX tumour in vivo and shortened telomere length.

Conclusions: The TAT-LPTS39 polypeptide has the ability to inhibit telomerase activity and suppress the growth of all tested human telomerase-positive cancer cells in vitro and in vivo, suggesting a potential anticancer drug development.

Background: Low-grade glioma (LGG) is a tumor that includes World Health Organization (WHO) grade II and III glioma, the treatment of which consistently results in relapse and drug resistance. Transforming growth factor-beta (TGF-β) is a multifunctional cytokine that regulates various cellular processes, which is found to be abnormal in tumors and promotes glioma development and progression. In this study, we aimed to systematically evaluate the importance of the genes associated with TGF-β in LGG and discover the role of these genes in the prognosis and treatment response of LGG.

Methods: We used the "Bioconductor Limma" and "consensusClusterplus" R packages to screen differential and prognostic TGF-β-related genes. The R package "GSVA" was used to estimate the infiltration of immune cells and metabolism signature. The drug sensitivity for each TGF-β subtype was assessed by the R package "pRRophetic". The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to assess the copy number variation (CNV). The onco-print tool of the "complexheatmap package" was employed to visualize the somatic mutation and copy number alteration (CNA) among TGF clusters.

Results: We reported three subtypes (A, B, and C) of LGG according to the classification of TGF-β-related genes, where subtype A showed the best prognosis. Subtype B was highly enriched in immune cells. Somatic variations were observed to be diverse in all of the three TGF-β subtypes. Furthermore, another three genes (SHA, AC062021.1, and SNCG) related to TGF-β were identified, which can be a superior predictor of prognosis with a risk score.

Conclusions: LGG can be divided into three subtypes based on TGF-β signaling-related genes with distinct immune infiltration, metabolism, somatic variations, and prognosis.

Background: Gastric cancer ranks as the fifth most prevalent cancer and the third leading cause of cancer-related mortality worldwide, Statins, renowned for their cholesterol-lowering effects, have garnered interest for their potential roles in cancer prevention and treatment due to their pleiotropic effects, such as anti-proliferative, pro-apoptotic, and anti-inflammatory properties. This study aims to investigate the therapeutic potential of simvastatin, a widely prescribed statin, in the context of gastric cancer using Mendelian randomization (MR) to explore a possible causal relationship between simvastatin use and gastric cancer risk.

Methods: We conducted a two-sample MR analysis utilizing summary statistics from genome-wide association studies (GWAS). Data from the Integrative Epidemiology Unit (IEU) Open GWAS project included 462,933 participants and 9,851,867 single nucleotide polymorphisms (SNPs) for simvastatin, and 476,116 participants with 24,188,662 SNPs for gastric cancer. Instrumental variables screening criteria were stringent, resulting in 41 valid SNPs as instrumental variables. The MR analysis was performed using the inverse variance weighting (IVW), supplemented by MR-Egger, weighted median estimator (WME), weighted mode, and simple mode approaches. Heterogeneity and pleiotropy were assessed using IVW, MR-Egger tests, and the MR-PRESSO method.

Results: The IVW and WME analyses indicated a significant protective effect of simvastatin against gastric cancer [IVW: odds ratio (OR) =0.1459, 95% confidence interval (CI): -3.502 to -0.346, P=0.01; WME: OR =0.0347, 95% CI: -3.521 to 0.1610, P=0.03]. There was no significant difference between the results of the two MR analyses before and after the removal of outliers (P=0.76), and the Egger-intercept for horizontal pleiotropy testing was not significant (P=0.38). Leave-one-out sensitivity analysis supported the robustness of our findings.

Conclusions: This MR study provides evidence for a potential protective effect of simvastatin against gastric cancer, suggesting its consideration as an adjunct to traditional cancer therapies.

Background and objective: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the primary treatment for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations, significantly enhancing patient prognosis. Despite the efficacy of EGFR-TKIs, monotherapy faces challenges such as variability among individuals and early drug resistance. This article aims to explore the treatment strategies and influencing factors for advanced NSCLC patients treated with EGFR-TKIs, optimize treatment plans, and improve the prognosis of patients with advanced NSCLC.

Methods: We undertook a comprehensive, narrative review of the latest literature to define the current application and progress of EGFR-TKIs in treating patients with advanced NSCLC.

Key content and findings: The efficacy and promise of EGFR-TKIs, both as monotherapy and combined with other agents, for treating patients with advanced NSCLC are outlined. The study delves into the mechanisms of resistance and the ongoing development of EGFR-TKIs. Various factors influencing the treatment of advanced NSCLC patients with EGFR-TKIs are also examined.

Conclusions: EGFR-TKIs alone improve survival in patients with advanced NSCLC. Combined with other agents, some regimens have shown improved benefits in overcoming drug resistance and prolonging patient survival. It is imperative to focus on developing novel EGFR-TKIs and investigate innovative combination therapies to maximize patient benefit.

Background: Lymphoid enhancer-binding factor 1 (LEF1)/T cell factor (TCF) family members are key transcription factors in malignant tumors. In this study, the role of T cell factor 4 (TCF4) in the progression of gastric cancer (GC) cell migration and invasion was investigated.

Methods: Fifty-five pairs of GC tissues and adjacent non-tumor tissues were collected for evaluating the expression of LEF1/TCF family members, which were also evaluated by the Gene Expression Profiling Interactive Analysis (GEPIA) database, an online analysis platform based on The Cancer Genome Atlas and Genotype-Tissue Expression databases.

Results: Through GEPIA online analysis and our experimental specimens, we found that TCF4 messenger RNA (mRNA) expression was significantly upregulated in GC tissues compared with normal non-tumor tissues. The findings from protein-protein interaction (PPI) analysis suggested that myocyte enhancer factor 2C (MEF2C) may function as a regulatory gene for TCF4 and play a role in the progression of GC. A significant increase in TCF4 mRNA expression was observed in the GC cell lines. Silencing of TCF4 led to significant inhibition of the proliferation, migration, and invasion of the MGC-803 and SGC-7901 cells. TdT-mediated dUTP nick end labeling (TUNEL)-positive staining cells were significantly increased after transfection with TCF4 small interfering (si)-RNA into GC cells. In addition, patients with GC with high TCF4 expression were associated with poor T stage, pathologic stages, histologic grade, overall survival, and recurrence-free survival, indicating that TCF4 may be a potential prognostic marker of GC.

Conclusions: TCF4 potentially exerts a carcinogenic role in the progression of GC. TCF4 may serve as a prognostic indicator and therapeutic target for GC.

Background: 5-methylcytosine/N⁶-methyladenosine/N⁷-methylguanosine (m⁵C/m⁶A/m⁷G)-related genes play a critical role in tumor occurrence and progression, and non-apoptotic regulatory cell death (NARCD) is closely linked to tumor development and immunity. However, the role of m⁵C/m⁶A/m⁷G-related NARCD genes in hepatocellular carcinoma (HCC) remains unclear. We used m⁵C/m⁶A/m⁷G-related NARCD genes to construct a prognostic model of HCC for prognostic prediction and clinical treatment of patients.

Methods: We obtained transcriptome data for HCC from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). Using the least absolute shrinkage and selection operator (LASSO) regression, we identified m⁵C/m⁶A/m⁷G-related NARCD genes and constructed a prognostic model through multivariate Cox regression. Model performance was assessed using Kaplan-Meier and receiver operating characteristic (ROC) curves, with external validation using the ICGC. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses were used to study differentially expressed genes between high- and low-risk groups. We also examined immune cell infiltration, drug response, and cell communication between tumor cells and immune cells in high-risk groups.

Results: We identified 140 m⁵C/m⁶A/m⁷G-related NARCD genes, using five of them to build the prognostic model. Functional enrichment analysis revealed enrichment in tumor and immune-related pathways for risk genes. The high-risk group displayed increased immune cell infiltration and better responses to immune checkpoint inhibitors (ICIs). High-risk patients were more responsive to cisplatin, doxorubicin, and mitomycin C, while low-risk patients were more sensitive to erlotinib. Cell communication analysis indicated that high-risk tumor cells used insulin-like growth factor (IGF) and macrophage migration inhibitory factor (MIF) signaling pathways to send signals to immune cells and received signals through the bone morphogenetic protein (BMP) and lymphotoxin-related inducible ligand (LIGHT) pathways.

Conclusions: We have developed a prognostic model with m⁵C/m⁶A/m⁷G-related NARCD genes to predict the prognosis of HCC patients. This model can offer insights into the effectiveness of immunotherapy and chemotherapy for HCC patients.

Background: Ovarian cancer (OC) is the most malignant gynecologic cancer, and chemoresistance is a major cause of treatment failure in patients with OC. The understanding of microRNA (miRNA) in cancer is limited, and the role of miRNA (miR)-450b-5p in cancer drug resistance is unknown. In this study, we aim to evaluate the role of miR-450b-5p in drug-resistant OC and its underlying mechanisms.

Methods: MiR-450b-5p expression was assessed in drug-sensitive and resistant OC cells via quantitative real-time polymerase chain reaction. Cell viability was evaluated using the Cell Counting Kit-8 assay. Progression-free survival (PFS) and overall survival (OS) curves were generated using the Kaplan-Meier method and the log-rank test. Target genes of miR-450b-5p were identified from the Cancer MIRNome database. Co-expressed genes were obtained from The Cancer Genome Atlas and Cancer Genome cBioportal for pathway enrichment and functional clustering analysis.

Results: The miRNA-450b-5p expression was significantly increased in A2780 and SKOV3 OC-resistant cells and significantly increased by 17-fold in the A2780-CBP-Lv-miR-450b-5p cells compared to A2780-CBP and A2780-CBP-Lv-NC cells. The up-regulated expression of miR-450b-5p increased the cell viability and half maximal inhibitory concentration (IC₅₀) of A2780 platinum-resistant cells and was associated with poor OS. We obtained 33 potential target genes of miR-450b-5p and beta-actin (ACTB) might be a potential target of miR-450b-5p. Low expression of ACTB predicted poor OS and PFS. We obtained 362 common genes co-expressed with ACTB, which involved 4 critical pathways. PI3K acted as an upstream pathway of the other three pathways, which ultimately responded to drug resistance regulation in OC. The genes enriched in four pathways were cross-analyzed and 13 overlapping genes were obtained. These 13 genes were also significantly and positively co-expressed with ACTB at both protein and mRNA levels.

Conclusions: High expression of miRNA-450b-5p might affect drug resistance and prognosis in OC by targeting 13 co-expressed genes of ACTB directly through the PI3K/Akt signaling pathway. Thus, miR-450b-5p might provide a new therapeutic target for drug resistance in OC.

Background: The bortezomib (BTZ) resistance mechanisms in mantle cell lymphoma (MCL) are complex, involving various genes and signaling pathways. This study used bioinformatical tools to identify and analyze differentially expressed genes (DEGs) associated with BTZ resistance.

Methods: Gene chip datasets containing MCL BTZ-resistant and normal control cohorts (GSE20915 and GSE51371) were selected from the Gene Expression Omnibus (GEO) database. GEO2R was used to identify the upregulated DEGs in the microarray datasets, using a significance threshold of P<0.05. Subsequently, these DEGs were subjected to a Gene Ontology (GO) functional analysis, a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and a protein-protein interaction (PPI) network assessment. Additionally, 40 MCL patients who underwent second-line BTZ treatment were included in this study. The patients were categorized into resistant and sensitive groups based on treatment response. The enzyme-linked immunosorbent assay (ELISA) technique was employed to evaluate the expression levels of specific DEGs in the serum of the patients in both groups.

Results: In the GSE20915 dataset, 144 upregulated genes were identified as DEGs. Similarly, in the GSE51371 dataset, 219 upregulated genes were identified as DEGs. By employing a Venn diagram to compare the upregulated DEGs from both datasets, we identified 11 DEGs linked to BTZ resistance in MCL. The enrichment analysis of the KEGG signaling pathways revealed that the DEGs were predominantly enriched in key biological processes (BP), including the cell cycle, cellular senescence, the p53 signaling pathway, the interleukin 17 (IL-17) signaling pathway, and the nuclear factor kappa-B (NF-κB) signaling pathway. A distinct cluster was revealed by creating a PPI network and performing a module analysis of a set of typical DEGs. This cluster comprised four candidate genes; that is, cyclin-dependent kinase inhibitor 1A (CDKN1A), CDKN1C, midkine (MDK), and TNF alpha induced protein 3 (TNFAIP3). Among these genes, MDK was found to be the key gene. The serum concentration of MDK in the resistant group [1,539 (1,212, 2,023) ng/L] was significantly higher than that in the sensitive group [1,175 (786, 1,502) ng/L] (P<0.05).

Conclusion: Identifying the key gene MDK and its associated signaling pathways extends our understanding of the molecular processes that underlie resistance to BTZ in MCL. This discovery establishes a theoretical framework for future investigations of targeted therapy in clinical settings.