Translational cancer research最新文献

Background: Breast cancer (BRCA) is one of the most prevalent malignant tumors in women worldwide, characterized by significant heterogeneity. Fatty acid metabolism (FAM) plays a crucial biological role in the initiation and progression of cancer. This study aims to identify novel, effective biomarkers related to FAM for improved risk stratification and treatment selection in BRCA patients.

Methods: Gene expression data from 1,217 BRCA patients were obtained from The Cancer Genome Atlas (TCGA) database. A comprehensive machine learning approach, incorporating ten different methods, was used to develop a FAM-related gene prognostic model (FAMGM). The Kaplan-Meier method and correlation analysis were employed to assess differences in overall survival (OS) and immune characteristics between high- and low-risk groups. External validation was performed using independent datasets. Single-cell RNA sequencing (scRNA-seq) data from 26 BRCA patients were analyzed, and the potential functions and mechanisms of the model genes were investigated using single-sample gene set enrichment analysis (ssGSEA), CellChat, and other algorithms. Finally, spatial transcriptomics (ST) analysis was conducted to examine the expression of model genes in the malignant regions of tumors.

Results: The FAMGM, developed using CoxBoost and random survival forest (RSF) methods, was identified as the optimal prognostic model. FAMGM demonstrated stable and robust performance in predicting clinical outcomes for BRCA. The high-risk group showed poor survival prognosis, typically associated with advanced clinical stages, reduced immune cell infiltration, and increased tumor mutational burden (TMB). Model genes were predominantly enriched in macrophages and appeared to influence tumor progression through the upregulation of multiple signaling pathways. Additionally, these model genes exhibited higher expression in malignant tumor regions.

Conclusions: FAMGM holds significant potential as a prognostic marker and could be used in the subsequent diagnosis, treatment, prognostic prediction, and mechanistic research of BRCA.

University Town, Nanjing 210023, China; Faculty of Chinese Medicine and State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau University of Science and Technology, Macau, China. Email: njwych@126.com; Min Chen, PhD. Faculty of Chinese Medicine and State Key Laboratory of Mechanism and Quality of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China. Email: mchen@must.edu.mo.

Background: Accumulating evidence indicates that fermitin family member 1 (FERMT1) is closely related to various disease processes. However, its association with cancer prognosis, tumor microenvironment (TME), and metastatic progression remains unclear, particularly in lung adenocarcinoma (LUAD). We conducted a comprehensive pan-cancer analysis to evaluate the clinical relevance of FERMT1 expression in LUAD and its functional role in metastasis.

Methods: We conducted a multi-omics and functional analysis to evaluate FERMT1 expression across multiple cancer types using 11,069 patient datasets from 33 cancers via The Cancer Genome Atlas (TCGA) database and the University of California, Santa Cruz (UCSC) Xena platform. We assessed FERMT1 expression heterogeneity, prognostic significance, genomic alterations, immune infiltration, and drug sensitivity in pan-cancer and LUAD-specific contexts. Additionally, functional experiments were performed to investigate its role in LUAD cell lines (NCI-H441 and Calu-3).

Results: FERMT1 was significantly overexpressed in 13 tumors and downregulated in 3 compared to normal tissues. Its high expression correlated with poor prognosis in multiple cancers and influenced immune cell infiltration. Genomic alterations in FERMT1 were prevalent across cancers. Pan-cancer analysis revealed significant correlations between FERMT1 expression, TME, and stemness scores. In LUAD, FERMT1 expression was significantly associated with tumor T classification (P=0.001) and higher levels in tumor tissues than in normal tissues. Functional assays demonstrated that FERMT1 deletion reduced LUAD cell migration and invasion.

Conclusions: FERMT1 serves as a potential biomarker for LUAD prognosis and cancer immunotherapy, highlighting its role in tumor progression and therapeutic response.

Background: Growing evidence suggests that the imbalance of liquid-liquid phase separation (LLPS) can alter the spatiotemporal coordination ability of biomolecular condensates, thereby playing an important role in carcinogenesis and cachexia. Gastric cancer (GC), ranking as the fifth most prevalent malignancy globally, remains lacking in systematic analysis at the GC-LLPS level within current research. This study aims to identify differentially expressed LLPS-related genes (LLPSGs) in GC and elucidate the role of LLPS in the initiation and progression of GC. Identifying the role of LLPS in carcinogenesis facilitates the development of personalized treatment strategies.

Methods: The Cancer Genome Atlas of Stomach Adenocarcinoma (TCGA-STAD) dataset was employed as the training cohort, encompassing RNA sequencing data from 375 GC samples and 32 normal samples, along with comprehensive clinical information from 443 GC patients. Differentially expressed genes associated with GC were identified, and LLPS genes correlated with overall survival (OS) in GC patients were determined using the LLPS database. Univariate Cox analysis and least absolute shrinkage and selection operator (LASSO) Cox regression were applied to construct LLPS-based prognostic models, validated using the GEO15459 dataset containing clinical and gene expression data from 192 GC patients. Model accuracy was assessed via area under the curve (AUC) values. Multiple algorithms were employed to calculate immune cell infiltration scores for high- and low-risk groups. Finally, gene set enrichment analysis (GSEA) enrichment analysis was performed on the selected genes to explore biological processes and pathways.

Results: Through univariate Cox analysis and the LASSO Cox penalized regression analysis, six genes (VCAN, APOD, MYB, SNCG, F5, BRI3BP) associated with the OS of GC patients were found and an LLPSG prognostic model was constructed. In our LLPS-related prognostic model, GC patients in the high-risk group had a poorer OS rate than those in the low-risk group. For 1-, 3-, and 5-year survival rates, the AUC predictive values of the LLPSG nomogram were 0.63, 0.63, and 0.70, respectively. The GSE15459 cohort confirmed the favorable prognostic effect of our model. The predicted survival rates at 1-, 3-, and 5-year are 0.61, 0.64, and 0.66, respectively. There were also significant differences in immune cell infiltration between the high- and low-risk groups of the model. GSEA analysis showed that the six genes were differentially enriched in various cancer-related pathways.

Conclusions: Our research establishes and validates an LLPS-associated risk model centered on the genes VCAN, APOD, MYB, SNCG, F5, and BRI3BP. These genes are poised to be considered as potential therapeutic targets in the treatment of GC.

Background: Selenium (Se) compounds display selective cytotoxicity toward many tumors, yet their activity against cervical cancer is not well-established. This study evaluates the anti-cervical cancer effects of sodium selenite (SS) and clarifies the underlying mechanisms.

Methods: HeLa cells were treated with graded SS concentrations. Cell viability was measured using the Cell Counting Kit-8, apoptosis was analyzed by Annexin V/PI flow cytometry, and cell migration and invasion were evaluated by scratch assay and Matrigel-Transwell assay, respectively. Autophagic activity and Hippo signaling were analyzed by Western blotting and immunofluorescence. For in vivo validation, 5-week-old female BALB/c nude mice bearing subcutaneous HeLa xenografts received SS (6 mg/kg intraperitoneally, every other day) or saline. Tumor volume was recorded, and excised tumor tissues underwent histopathology.

Results: SS suppressed HeLa cell proliferation in a concentration- and time-dependent manner [24-h half-maximal inhibitory concentrations (IC₅₀) ≈4.9 µM], heightened apoptosis, and markedly reduced migration and invasion. Molecular assays showed increased LC3-II accumulation with concomitant p62 degradation, indicating enhanced autophagic flux. These changes coincided with elevated phosphorylation of LATS1 and YAP and a reduction in total YAP, signifying Hippo signaling pathway activation, which was further confirmed by YAP knockdown-mediated inhibition of SS-induced autophagy. In xenograft models, SS slowed tumor growth and lowered proliferative and YAP immunostaining without overt toxicity.

Conclusions: SS restrains cervical cancer progression by inducing apoptosis and accelerating autophagosome turnover through activation of the YAP-Hippo axis. These findings highlight SS and YAP-directed modulation in general, as promising avenues for future cervical cancer therapy development.

Background: For hormonal receptor-positive (HR⁺) breast cancer (BC), about 50% of recurrence occurs after 5-year adjuvant endocrine therapy (late recurrence). It is of great significance to identify the patients with a high risk of late recurrence who might benefit from extended endocrine therapy. This study aimed to construct a model predicting late recurrence of HR⁺/human epidermal growth factor receptor 2-negative (HER2^-) BC.

Methods: In this study, the female patients with HR⁺/HER2^- metastatic BC who were treated in the Department of Breast Oncology in Peking University Cancer Hospital were included. These patients were divided into the early recurrence group and the late recurrence group according to disease-free survival (DFS). Predictors for the recurrence time were identified and a nomogram was constructed and validated through concordance index (C-index), area under the curve (AUC), and calibration plots. The clinical data were collected from medical records.

Results: A total of 639 patients treated in the hospital between April 2007 and October 2019 were included. Median age of these patients at the initial diagnosis of primary tumors was 47 years old. Among them, 382 patients (59.8%) were presented with early recurrence (DFS ≤5 years), and 257 patients (40.2%) were presented with late recurrence (DFS >5 years). The median DFS was 50.0 months. Both univariate and multivariate analyses showed that a higher level of Ki-67 (P=0.005, 0.003) and more positive lymph nodes (P=0.003, 0.021) were associated with shorter DFS. A nomogram based on potentially associated clinicopathological factors was constructed and validation results showed that the nomogram was well-calibrated to predict the recurrence time of these patients (AUC =0.703, C-index =0.697).

Conclusions: A well-calibrated nomogram is constructed using the data of clinicopathological factors obtained from 639 HR⁺/HER2^- BC patients. Patients with premenopausal status at initial diagnosis, fewer positive lymph nodes and a lower level of Ki-67 were common factors for late recurrence. The nomogram could well predict the risk of late recurrence. Prospectively designed studies are needed to further validate the model.

Background: Small cell lung cancer (SCLC) is a subtype of lung cancer that is aggressive, progresses rapidly, and is prone to recurrence. The biological composition of SCLC is still under investigation. This study aims to characterize the intratumoral heterogeneity and immunosuppressive tumor microenvironment of SCLC using single-cell RNA sequencing (scRNA-seq), and to identify and validate the key genes BEX1 and MAP1b as potential therapeutic targets.

Methods: To comprehend the heterogeneity of SCLC and the tumor microenvironment, we used scRNA-seq to analyze the primary tumor and adjacent noncancerous tissue from a patient. The findings were tested with cell experiments.

Results: We observed that SCLC was mainly composed of neuroendocrine epithelial cells and displayed the immune-related cell failure state. The corresponding antitumor immune pathway activities were also downregulated, and the tumor microenvironment eventually showed immunosuppression. BEX1 and MAP1b were upregulated in most cell subtypes, which are verified by immunohistochemistry. In addition, downregulation of BEX1 in NCI-H209 and MAP1b in NCI-H82 significantly inhibited cell proliferation and migration, while increasing apoptosis. Based on preliminary data, BEX1 and MAP1b have been identified as promising candidates for the early diagnosis and therapy of SCLC; however, their clinical utility requires confirmation in subsequent studies. To investigate the heterogeneity and interaction among different cell types, we also constructed an intercellular communication network.

Conclusions: Our knowledge of the basic traits of SCLC is improved by this highly accurate single-cell study, which also offers fresh suggestions for potential future therapies.

Background: Circular RNAs (circRNAs) appear to exert critical functions in breast cancer (BC). The objective of this study is to explore the usefulness of circRNAs as potential diagnostic and prognostic biomarkers of BC.

Methods: The Gene Expression Omnibus (GEO) database was referenced to identify differentially expressed circRNAs in BC. Quantitative real-time polymerase chain reaction (qPCR) was used to detect the expression levels of hsa_circ_0001756 in both BC tissue samples and BC-derived cell lines. The functions of hsa_circ_0001756 were investigated both in vitro and in vivo. The luciferase reporter and rescue assays were used to clarify the molecular mechanisms of hsa_circ_0001756. Receiver operating characteristic (ROC) curve was established to evaluate the clinical value of hsa_circ_0001756 as a serum biomarker, and to investigate its potential correlation with the clinical pathological characteristics of BC patients by Chi-squared test.

Results: Hsa_circ_0001756 expression was upregulated in BC tissues and substantially correlated with tumor size and tumor-node-metastasis (TNM) stage. Knockdown (KD) of hsa_circ_0001756 markedly inhibited the malignant potential of BC both in vitro and in vivo. Mechanistically, hsa_circ_0001756 acted as a miR-584-5p sponge to regulate TRAF6 in BC cells. Serum levels of hsa_circ_0001756 were significantly higher in pre-operative BC patients than in healthy controls, fibroadenoma patients, and post-operative BC patients. Also, serum hsa_circ_0001756 was remarkably correlated with tumor size, patient age, metastasis state, and TNM stage. The combination of the traditional tumor markers carcinoembryonic antigen (CEA) and cancer antigen 15-3 (CA15-3) with hsa_circ_0001756 significantly improved the diagnostic accuracy of BC.

Conclusions: Our findings indicated that hsa_circ_0001756 could promote BC malignant progression through the miR-584-5p/TRAF6 signaling axis. Especially, hsa_circ_0001756 in serum holds promise as a biomarker for BC screening and diagnosis.

Background: Patients with acute leukemia are at increased risk of microbial infections due to factors such as the disease itself, intensive chemotherapy, and transplantation. Untimely or inadequate treatment can prolong therapy, raise costs, and even threaten patient survival, impacting overall cancer treatment outcomes. Traditional microbial identification relies on blood cultures (BCs), but their low positivity rate and lengthy processing time often hinder prompt diagnosis and the identification of the infecting pathogens. This study aimed to use droplet digital polymerase chain reaction (ddPCR), known for its sensitivity in single-molecule amplification, to detect pathogen DNA and drug-resistant genes in blood.

Methods: We included a total of 47 patients with hematologic malignancies who were over 18 years old and had neutropenia accompanied by fever [suspected bloodstream infection (BSI)] from August 2022 to November 2022. Patients who failed resuscitation after severe shock, with severe liver or kidney dysfunction, and in the terminal stage were excluded. We conducted ddPCR testing for bacteria/fungi/viruses with the patient's blood on the first day, third day, and fifth day of the occurrences of neutropenic fever with suspected BSI. In case of positive results indicating the presence of bacteria, we used the remaining nucleic acid samples to detect drug resistance genes.

Results: BC and ddPCR yielded positive results indicating the presence of bacteria in five patients (10.64%) and 14 patients (29.79%), respectively, with ddPCR demonstrating acceptable positive rate (81.44%). Regarding the breadth of detection, ddPCR identified 10 different pathogens, while only two pathogens went undetected. In contrast, BC detected only five different pathogens. In terms of the diversity of pathogens detected in single samples, among the 14 polymerase chain reaction (PCR)-positive patients, three had the presence of two different pathogens synchronously. Furthermore, ddPCR also revealed the presence of drug resistance genes. Among the 14 PCR-positive patients, four were found to have drug resistance genes, including one case of Klebsiella pneumoniae carbapenemase (rendering patients' immunocompromised system) and three cases of methicillin resistance determinant A (mecA).

Conclusions: ddPCR is a versatile and adaptable platform that can serve as a complement to traditional BCs.

Background: The signaling lymphocytic activation molecule family (SLAMF) members have recently been demonstrated to be potential targets in malignant tumors. The aim of this study is to explore the role of SLAMF member 9 (SLAMF9) in glioma.

Methods: Datasets from The Cancer Genome Atlas (TCGA) database were downloaded, and the correlation between SLAMF9 expression and the overall survival (OS) of glioma patients was analyzed. A tissue chip including 139 tumor tissues from glioma patients for immunohistochemistry (IHC) staining was used to detect the protein expression of SLAMF9, and the relationships between SLAMF9 expression and OS, disease-free survival (DFS), and clinicopathological features were analyzed. Multiplex immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry analysis, and bioinformatics analysis were used to detect the potential biological function of SLAMF9 in glioma.

Results: SLAMF9 expression was significantly higher in glioma tumor tissues than in normal tissues. High expression levels of SLAMF9 were correlated with shortened OS and DFS in glioma patients. Data from the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) glioma dataset revealed that the protein expression of CD68 and CD163 was positively related to SLAMF9 expression in the tissues of glioma patients. In vivo, the levels of CD80 and CD86 were significantly increased, whereas the level of CD163 decreased after SLAMF9 knockdown in human macrophages. Functional analysis revealed that the pathways enriched in glioma tissues with high SLAMF9 expression were associated with immune response-related pathways.

Conclusions: This study is the first to highlight the important clinical value of SLAMF9 in patients with glioma.