Translational cancer research最新文献

Background: Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. POC1 centriolar protein A (POC1A) is a gene encoding a protein that plays a key role in the centrosome, and is one of the two isoforms of POC1. To date, the expression of POC1A in HCC and its potential as a biomarker and tumor therapeutic target have not been examined. This study aimed to explore the effect of POC1A on patients with HCC and its potential mechanism.

Methods: This study investigated the role of POC1A in the occurrence and development of HCC. It analyzed the expression of POC1A in various types of HCC patients and its effect on survival using HCC patient information from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), the Human Protein Atlas (HPA), and the Hepatocellular Carcinoma Cell DataBase (HCCDB). It then explored the major enrichment pathways and gene functions of POC1A in HCC using the gene set enrichment analysis (GSEA) method and examined its protein-protein interactions (PPIs). Finally, it predicted the potential transcription factors (TFs) and target microRNAs (miRNAs) of POC1A, and analyzed the single nucleotide variation (SNV) and copy number variation (CNV) mutations of POC1A and the related genes in HCC, as well as their effects on immune cells.

Results: The results showed that POC1A was significantly overexpressed in HCC and was significantly associated with a poor prognosis. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses indicated that POC1A was mainly involved in the regulation of cell-cycle pathways and chromosome segregation functions. POC1A showed significant interactions with NUDC and PPARG, and they both had different numbers of SNV and CNV mutations in the HCC samples. In relation to immunity, the high expression of POC1A and its reciprocal genes may play an important role in B cells and macrophages.

Conclusions: In general, our findings suggest that POC1A overexpression could have an important effect on the development of HCC by regulating cell-cycle pathways, and that it could serve as a novel prognostic biomarker and a potential therapeutic target for HCC.

Background: Budding uninhibited by benzimidazole 1 (BUB1) is a highly conserved serine/threonine kinase, showing prominent importance for proper function during mitosis. However, little is known about BUB1 mRNA expression in breast cancer (BRCA) and its correlation with prognosis and immune infiltration. Hence, we aimed to unveil its potential as groundbreaking biomarkers for immunotherapy efficacy and the prognosis of BRCA.

Methods: Database for Annotation, Visualization, and Integrated Discovery (DAVID) is a potent tool for identifying significant clusters of genes and pathways in the resulting dataset. In this study, gene set enrichment analysis of BUB1 was conducted using DAVID. The clinical characteristics of patients with or without altered BUB1 mRNA expression were compared using cBioPortal. Tumor Immune Estimation Resource (TIMER) is a known as database for comprehensive analysis of tumor-infiltrating immune cells in various cancers. In the present study, the relationship between BUB1 expression and the abundance of immune infiltrates was explored using TIMER in BRCA. Immunohistochemistry staining was performed to analyze the protein expression of BUB1 in tumor tissue specimens. We used PrognoScan and Kaplan-Meier Plotter to evaluate the prognosis of patients with different BUB1 expression levels.

Results: The expression of BUB1 in various tumor tissues was higher than that in adjacent normal tissues. BUB1 was mainly localized to the nucleoplasm and additionally localized to the cytosol. Functional enrichment analyses revealed that the cell cycle was the most significant pathway. Abnormal BUB1 mRNA expression was more frequently detected in invasive ductal carcinoma with higher histological grades and BRCAs with estrogen receptor (ER)-negative, human epidermal growth receptor 2 (HER2)-negative, and basal-like phenotypes. The BUB1 expression was correlated positively with tumor purity, B cells, CD8⁺ T cells, CD4⁺ T cells, neutrophils, and dendritic cells, while BUB1 had no significant correlation with macrophages. The results of immunohistochemical staining from clinical samples further confirmed that BUB1 was overexpressed in BRCA compared to benign tumor (fibroadenoma of breast) (P<0.01). BRCA patients with lower BUB1 expression had a better prognosis than those with higher BUB1 expression in overall survival (OS) curves, distant metastasis-free survival (DMFS) curves, and relapse-free survival (RFS) curves (P<0.05).

Conclusions: Our results suggest that BUB1 is a potential molecular biomarker for evaluating the prognosis and predicting the effectiveness of immunotherapy for BRCA.

Background: Pleckstrin homology containing family A, number 4 (PLEKHA4) plays a role in a number of biological processes in human cells, including cell polarization, growth, and proliferation. However, the relationship between PLEKHA4 expression and survival in breast cancer (BC) remains unclear. The aim of this study is to investigate the potential of PLEKHA4 as a prognostic indicator in BC.

Methods: We obtained gene expression profiles of BC and normal tissues from the Tumor Immune Estimation Resource (TIMER), UALCAN web. Immunohistochemistry (IHC) staining was performed to investigate the protein expression and prognostic value of PLEKHA4 in BC patients. The prognostic value was analyzed using Kaplan-Meier curve analysis and Cox regression analysis in R software after downloading The Cancer Genome Atlas (TCGA) databases. The correlations between PLEKHA4 and tumor immune infiltrates were investigated via gene set variation analysis (GSVA). Signaling pathways related to PLEKHA4 expression were identified by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis.

Results: Both bioinformatics and IHC results showed that PLEKHA4 was expressed at low levels in BC tissues compared with the adjacent tissues. Furthermore, the expression of PLEKHA4 was negatively correlated with ages (χ²=6.394, P=0.01), molecular subtype (χ²=15.606, P=0.001), lymph node metastasis (χ²=13.753, P=0.004), tumor-node-metastasis (TNM) stage (χ²=22.616, P<0.001). Kaplan-Meier curves implicated low expression of PLEKHA4 was associated with worse survival of BC patients [hazard ratio (HR) =0.46, P=0.01]. Cox regression models showed that low PLEKHA4 expression could be an independent risk factor for BC (HR =0.911, P=0.006). The results of gene set enrichment analysis (GSEA) showed that cell cycle, Notch signaling pathway, nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway, and Rho GTPases were highly enriched in the low PLEKHA4 expression group, as identified by GO and KEGG. Additionally, in BC, PLEKHA4 expression displayed a positive correlation with the infiltration of natural killer (NK) cells (P<0.001), CD8⁺ T cells (P<0.001), B cells (P<0.001), neutrophils (P<0.001), and dendritic cells (DCs) (P<0.001).

Conclusions: The findings indicate that PLEKHA4 is an independent prognostic biomarker associated with key signaling pathways and immune infiltration in BC. Targeting PLEKHA4 may contribute to improving immunotherapy for BC.

Background: The transfer RNA (tRNA)-derived fragments, generated by the cleavage of mature and pre-tRNAs, play a vital role in the tumorigenesis and progression of hepatocellular carcinoma (HCC). However, the relationship between tRNA-derived fragments and the prognosis of patients with HCC has not been thoroughly studied. This study aims to discuss the relationship between tiRNA-Gly-GCC-002 and the prognosis of HCC patients and its role in guiding HCC treatment.

Methods: In this study, the differently expressed tRNA-derived fragments were screened out from the tumor tissues and paracancerous tissues. These tRNA-derived fragments were validated in the tissues and serum samples of patients with HCC by quantitative real-time polymerase chain reaction (qRT-PCR). The target genes of the tRNA-derived fragments were predicted with the microRNA target prediction database (miRDB), which was proceeded with gene set enrichment analysis (GSEA). After that, we analyzed the prognostic effect of the tRNA-derived fragment in relapse-free survival (RFS). Based on univariate and multivariate Cox regression analysis, independent prognostic factors for RFS were obtained. In addition, a column chart was constructed based on clinical pathological features and tiRNAGly-GCC-002.

Results: The tiRNA-Gly-GCC-002 was ultimately served as the candidate gene. Function analysis indicated that tiRNA-Gly-GCC-002 was primarily involved in adenyl nucleotide binding, cell cycle, cell cycle process and chromosome organization. We found that patients with high expression level of tiRNA-Gly-GCC-002 had worse prognosis than low expression level. The univariable and multivariable Cox regression analyses showed that tiRNAGly-GCC-002 was an important prognostic factor. Furthermore, the nomogram by combining tiRNA-Gly-GCC-002 expression level (P=0.03) and serum gamma-glutamyl transferase (GGT) level (P=0.001) was established to predict the prognosis of patients with HCC [concordance index (C-index): 0.789].

Conclusions: In summary, the tiRNA-Gly-GCC-002 can predict the outcome of patients with HCC, which may play a vital role in directing the treatment of HCC.

Background: One of the main challenges associated with the development of therapeutic and diagnostic strategies for patients with colorectal cancer (CRC) is the establishment of minimally invasive and efficient biomarkers. Pertinent genes in CRC have been identified through their functions in systematic mutagenesis screens. KRAS is considered a dominant mutated oncogene that contributes to pathogenesis of CRC. This study aimed to explore the genomic alternations of KRAS in a CRC population.

Methods: Sequencing data of 94 Chinese patients with CRC were prospectively collected and analyzed using next-generation sequencing (NGS). The influence of KRAS and its associated subtype co-mutations on the expression level of the tumor mutational burden (TMB) was investigated. The objective of our study was to assess the potential prognostic significance of KRAS and other driving oncogenes in determining the clinical efficacy of immunotherapy.

Results: The gene mutation rates of TP53, APC, and KRAS were 81.91%, 71.28%, and 43.62%, respectively. Additionally, KRAS G12D displayed a relatively higher mutation rate than other KRAS-mutant subtypes. Increased TMB was observed in cases of KRAS and BRAF mutation combined with APC single mutation; furthermore, the expression of TMB in G12V was the highest, and G12D presented the lowest TMB in single KRAS-mutant subtypes or the combination with APC mutations.

Conclusions: The TMB driven by KRAS co-mutations may have the potential to be used as a key biomarker for prediction of treatment outcomes of immune checkpoint inhibitors (ICIs) in patients with CRC, especially with APC co-mutation.

Background: Glioblastoma (GBM) is characterized by poor prognosis and a high malignancy. The competing endogenous RNA (ceRNA) network formed by long non-coding RNA (lncRNA) and microRNA (miRNA) can regulate the incidence of GBM. Therapeutic strategies targeting cuproptosis-related genes (CRGs) have helped reduce drug resistance in patients. However, the regulatory mechanism underlying the ceRNA network related to cuproptosis in GBM remains unclear. Therefore, we aim to explore the ceRNA regulatory axis associated with cuproposis in GBM and provide a new protocol for therapy.

Methods: The ceRNA network related to CRG was constructed by bioinformatics. Dual-luciferase reporter assay and other experiments were used to prove the conclusion.

Results: We found that the LINC00957/miR-17-5p axis drove nephronectin (NPNT) expression to promote the malignant progression of GBM. First, by measuring the copper ion concentration and reactive oxygen species (ROS) levels, we found that inhibiting NPNT could promote cuproptosis. Meanwhile, the results of enrichment analysis and phenotypic experiments demonstrated that the LINC00957/miR-17-5p/NPNT axis can regulate the cell cycle and migration in GBM. In terms of mechanistic evidence, findings from reporter gene experiments suggested that LINC00957 acted as a ceRNA to regulate the expression of NPNT via miR-17-5p. In addition, findings from rescue experiments confirmed that the regulation of malignant GBM progression by LINC00957 depended on NPNT to an extent.

Conclusions: Our findings indicate that the ceRNA regulatory network is related to cuproptosis in GBM and provide novel potential targets for the diagnosis and treatment of GBM.

Background: Ovarian clear cell carcinoma (OCCC) is a rare and distinct subtype of epithelial ovarian cancer (EOC). It is unique in several biological aspects. This study analyzes the clinicopathological features and survival outcome of patients with OCCC, aiming to identify factors affecting recurrence, progression-free survival (PFS) and overall survival (OS).

Methods: A retrospective study included 49 women with OCCC between January 2009 and December 2021 at Oxford Cancer Center. All demographic and pathological characteristics, pre-operative biomarkers, surgical procedure, complications, hospital stay, chemotherapy regimen, and disease status on follow-up, were collected from electronic medical records.

Results: No residual disease (R0) was achieved in 39 out of 49 women who underwent cytoreductive surgery. The follow-up time had a mean of 8.75 years. The 3-year OS was 73.4%, and the 3-year PFS was 81.3% [95% confidence interval (CI): 84.63-118.93]. Women with stage 1 disease had the best outcome. There was a marked difference (P<0.001) in OS in the presence of residual disease. No residual disease conferred a 3-year OS of 88.6% (95% CI: 108.6-141.8), compared to only 12.5% in the presence of residual disease (95% CI: 4.48-32.11). In multivariant analysis, the International Federation of Gynecology and Obstetrics (FIGO) stage was the only independent prognostic indicator of OS with (P<0.05), including carbohydrate antigen (CA) 125, hemoglobin, albumin, associated endometriosis, ascites, residual disease and FIGO staging.

Conclusions: Surgery to achieve no residual disease is necessary to improve the prognosis in advanced OCCC. The true challenge is to predict which patients with early-stage disease at higher risk of recurrence and would most benefit from adjuvant treatments.

Background: miR-103a-3p has been reported to be a factor leading to poor prognosis in several human malignancies, including nasopharyngeal carcinoma (NPC). Secreted microRNAs containing exosomes may mediate the communication between cancer and stromal cells. The purpose of the current work was to learn more about miR-103a-3p's function in NPC exosomes.

Methods: Transmission electron microscopy and NanoSight analysis were used to verify the existence of exosomes. To determine the relationship between exosomal miR-103a-3p and carcinogenesis in NPC, gain- and loss-of-function studies were carried out. Cell Counting Kit-8 (CCK8), 5-ethynyl-2'-deoxyuridine (EdU) cell proliferation assay, colony formation, flow cytometry, trans-endothelial invasion assays, endothelial permeability and cellular immunofluorescence were used to identify roles of exosomal miR-103a-3p in vitro. Zebrafish assay was used to disclose the effect of exosomal miR-103a-3p in vivo. Bioinformatics and dual-luciferase reporter assay were applied to clarify the mechanism of exosomal miR-103a-3p regulating the crosstalk between NPC cells and human umbilical vein endothelial cells (HUVECs).

Results: In the present study, we first demonstrated that the overexpression of exosomal miR-103a-3p improved NPC cell proliferation, migration, and the epithelial-mesenchymal transition (EMT) progression in vitro. Then, we verified that NPC cell-derived exosomal miR-103a-3p destroyed the integrity of the endothelial monolayer in vitro and in vivo by downregulating zonula occludens 1 (ZO-1) expression. Moreover, we revealed that miR-103a-3p containing exosomes facilitated NPC cell proliferation through lipid droplet accumulation by direct target to metabolic enzyme acyl-CoA oxidase 1 (ACOX-1).

Conclusions: Our data demonstrate that exosomal miR-103a-3p can facilitate the development of NPC by regulating the crosstalk between NPC cells and HUVECs. Exosomal miR-103a-3p could potentially serve as a therapeutic target for NPC.

Background: The prognosis of lung metastasis in primary limb bone tumors represents a pivotal yet challenging aspect of oncological management. Despite advancements in diagnostic modalities, the predictive accuracy for metastatic spread remains suboptimal. This study aims to bridge this gap by leveraging the Surveillance, Epidemiology, and End Results (SEER) database to construct a nomogram that forecasts the risk of lung metastasis, thereby enhancing clinical decision-making processes.

Methods: A retrospective cohort, including 1,822 patients with primary limb bony tumors from 2010 to 2015 in the SEER database, was extracted. Using precise inclusion and exclusion criteria, variables essential for predicting lung metastasis were identified through univariate and multivariate analyses, along with least absolute shrinkage and selection operator (LASSO) regression. These variables provided a solid basis for creating the multivariable nomogram, of which the discriminating power and utility were verified using receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis.

Results: The model incorporated seven key predicting variables, including age, histological type, surgery, radiation, chemotherapy, T stage, and N stage. The nomogram emerged as a cohesive whole with good discriminative power. The area under the curve (AUC) was 0.806 in the training cohort and 0.767 in the validation cohort. The calibration curves demonstrated the model's validity by showing a good match between the actual outcomes and the model-predicted probabilities of lung metastasis.

Conclusions: This study showed for the first time the reliability of the predictive model in translating the hard-to-interpret demographic, clinical, and pathologic data into a very usable predictive model. Thus, it represents a significant step toward demystifying the risk of lung metastasis in primary limb bone tumors. It is an invitation for a paradigm shift of oncology, to evidence-based, person-based oncology that is taking a new metric for cancer prognosis.