Translational cancer research最新文献

[This corrects the article DOI: 10.21037/tcr-24-269.].

Background: Bladder cancer is the most common malignancy of the urinary tract and one of the most common cancers in the world. Cuproptosis is a novel type of cell death associated with tumorigenesis. In this study, we assessed the correlation between cuproptosis-related genes and tumorigenesis. Moreover, we constructed a prognostic signature.

Methods: Pearson correlation analysis and univariate Cox regression were utilized to extract cuproptosis-related long non-coding RNAs (lncRNAs) predicting prognosis in The Cancer Genome Atlas (TCGA) database. The least absolute shrinkage and selection operator (LASSO) Cox regression was utilized to establish a cuproptosizs-related prognostic signature. A nomogram signature was generated to predict individual survival.

Results: We obtained 19 cuproptosis-related genes and 14 prognostic cuproptosis-related lncRNAs. We constructed a seven-prognostic risk signature. Time-dependent receiver operating characteristic (ROC) curves demonstrated good predictive power (1-, 3-, and 5-year survival rates of 0.711, 0.673, and 0.684, respectively). The high-risk group reported a worse prognosis than the low-risk group, and the risk signature was identified as an independent factor. The biological process of risk-related genes primarily involved tumorigenesis and migration. The high-risk group expressed high chemokines and T cell inhibition and low antigen-presenting cells.

Conclusions: Cuproptosis-related lncRNAs are central to tumorigenesis, providing a novel therapeutic target for patients with bladder cancer. We constructed an individualized predictive signature based on cuproptosis-related lncRNAs.

Background: Sini decoction (SND), a popular formula from traditional Chinese medicine (TCM), plays a critical role in the treatment of liver disease. Its protective effect for the heart against cardiovascular diseases is well documented. However, its effects and pharmacological mechanisms for the liver remain unclear. This study aimed to clarify the effect and mechanism of the SND-polysaccharide compound (SNDPC) on hepatocellular carcinoma (HCC).

Methods: Different genes affected by SNDPC in HCC were analyzed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Databases including Multi-Experiment Matrix (MEM), HCCDB, LinkedOmics, and Gene Expression Profiling Interactive Analysis (GEPIA) were used to determine the correlation between PHLDA2 and ANXA2. Cell proliferation and viability were identified using Cell Counting Kit-8 (CCK-8). Cell apoptosis was estimated using terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and Western blotting. Glycolysis was determined by measuring glucose uptake, lactate concentration, extracellular acidification rate (ECAR), and the expressions of LHDA, HK2, and PKM2. The binding between PHLDA2 and ANXA2 was identified by coimmunoprecipitation.

Results: SNDPC significantly weakened cell proliferation, facilitated cell apoptosis, and suppressed glycolysis by reducing glucose uptake, lactate concentration, ECAR, and the expressions of LDHA, HK2, and PKM2 in HCC cells. Furthermore, PHLDA2 was predicted to bind to ANXA2, which was confirmed by coimmunoprecipitation. SNDPC reduced the expressions of PHLDA2 and ANXA2 in HCCLM3 cells, and PHLDA2 silencing decreased the proliferation of cells, promoted cell apoptosis, and inhibited glycolysis of HCCLM3 cells while reversing the overexpression of PHLDA2.

Conclusions: SNDPC suppressed proliferation and glycolysis while accelerating the apoptosis of HCC cells through PHLDA2/ANXA2.

Background: Esophageal squamous cell cancer (ESCC) is the most common type of esophageal cancer. This study aimed to elucidate the role of Saccharomyces cerevisiae-like 4 (SEC14L4) in ESCC.

Methods: To elucidate the role of SEC14L4 in ESCC, this study analyzed the clinical data, gene sequencing data, and other relevant data retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) of the National Center for Biotechnology Information. The methodology involved several analytical approaches, including nomogram model analysis, co-expression analysis, gene set enrichment and variation analysis, weighted correlation network analysis, drug susceptibility analysis, and single-cell analysis. These methods were employed to evaluate the significance of SEC14L4 in ESCC. The expression of SEC14L4 was evaluated via quantitative real-time polymerase chain reaction (qRT-PCR).

Results: SEC14L4 expression (P<0.001) was significantly elevated in those with ESCC, especially in patients with locally advanced disease (P=0.005), and indicated a poor prognosis (P=0.045). Findings from the nomogram model analysis identified the contribution of clinical indicators to survival prediction with good efficacy. Subsequently, the single-nucleotide polymorphisms and co-expressed genes of SEC14L4 were identified. Furthermore, pathways associated with SEC14L4, including DNA metabolic process, transcription factor binding, apoptosis, and others, were examined. Notably, SEC14L4 expression was predominantly observed in monocytes. Drug sensitivity analysis indicated the association of SEC14L4 expression with sensitivity of ESCC to the common chemotherapy drugs AICAR, BMS.708163, GNF.2, Nutlin.3a, PD.0325901, and RDEA119. Verification of the high expression of SEC14L4 in KYSE520 and KYSE150 was conducted, thereby confirming the study's findings.

Conclusions: High expression of SEC14L4 is associated with poorer clinical outcomes, highlighting its potential as a therapeutic target and suggesting its involvement in the molecular mechanisms underlying ESCC.

Background and objective: Krukenberg tumours (KTs) are metastatic signet ring cell (SRC) adenocarcinomas of the ovary, arising from the stomach in most cases (70%). Other common primary sites are the colon, appendix and breast. The use of the term "Krukenberg tumour" is inconsistent in the literature which makes data interpretation difficult. Prognosis of KTs is dismal and, in the absence of randomised controlled trials, the best treatment strategies remain controversial. Evidence from retrospective studies suggests that metastectomy is associated with improved survival. Our narrative literature review set out to determine which patients gain maximal survival benefit from surgical management.

Methods: A comprehensive literature search was performed using PubMed and Google Scholar databases, from 1 January 2000 to 15 July 2024, with the terms 'Krukenberg', 'metastatic mucinous adenocarcinoma of ovary'. This search identified 20 full-text manuscripts, including data on 1,815 patients.

Key content and findings: We found that the overall prognosis of these patients remains poor, with a median overall survival (mOS) ranging between 9 and 50 months. Metastectomy is associated with survival benefit only when all visible disease is removed (R0): mOS in patients with microscopic residual disease (R1) or gross residual disease (R2) is similar to mOS in unresected patients (11 vs. 10 months). The following other factors have been identified as independent prognostic factors for survival in multivariate analyses: heated intraperitoneal chemotherapy (HIPEC), adjuvant chemotherapy, curative surgery for the primary tumour, i.e., gastrectomy, no ascites, non-gastric origin, a good performance status, less extensive metastatic disease, i.e., no extra-ovarian disease or no extra-pelvic disease, no peritoneal carcinomatosis or a low Peritoneal Cancer Index (PCI), smaller size of lesion, no SRC features, expression of oestrogen receptor-β (ER-β) and progesterone receptors (PR), metachronous tumours, linitis plastica, tumour grade.

Conclusions: Multiple retrospective analyses have demonstrated that metastectomy is associated with a survival benefit in patients with metastatic mucinous ovarian adenocarcinomas. However, patients with poor prognostic factors are less likely to benefit from surgery and should be counselled accordingly. Diagnostic laparoscopy could be considered before debulking surgery, to assess resectability of disease and to avoid a futile exploratory laparotomy. HIPEC after cytoreductive surgery (CRS) remains controversial, with possible survival benefit for KTs of gastric origin, particularly when peritoneal dissemination is present but the PCI is low.

Background: Gastric cancer, a prevalent and life-threatening malignancy, is believed to involve cancer stem cells (CSCs) as a contributing factor to tumor progression. Insulin gene enhancer binding protein-1 (ISL1) is a transcription factor, and it has not been elucidated how ISL1 regulates gastric carcinogenesis. The aim of this paper is to investigate the role of ISL1 in gastric cancer development.

Methods: In this study, we investigated the effects of ISL1 on the stem-like properties of human gastric cancer cells by applying transcriptional, flow, and immunofluorescence techniques.

Results: In human gastric cancer samples, there is an observed elevation in ISL1 expression, which correlates with the expression of stem cell markers, notably LGR5. Functionally, ISL1 fosters the self-renewal, cell proliferation, migration, and the clonogenic potential of gastric cancer cells in vitro. Furthermore, it enhances the ability of these cells to form tumors and metastasize in vivo. Additionally, ISL1 collaborates with AQP5, collectively intensifying the tumorigenicity of gastric cancer cells. Mechanistically, transcriptomic analysis of cells overexpressing ISL1 unveils a notable activation of the forkhead box O (FOXO) pathway. This activation leads to increased nuclear expression of forkhead box O3 (FOXO3), subsequently resulting in elevated expression of the stemness-associated gene CD44 in gastric cancer cells.

Conclusions: These findings shed light on the role of ISL1 in promoting the stem-like characteristics of gastric cancer cells and emphasize the connection between ISL1 and AQP5 as a novel therapeutic target for individuals with gastric cancer.

Background: Patients with biliary tract cancer (BTC) often have dismal outcomes due to the poor performance of traditional methods for early diagnosis. Recently, bile cell-free DNA (cfDNA) has been reported as a potential liquid biopsy material for BTC diagnosis. However, bile is a complex alkaline aqueous medium, and the proper storage conditions for bile remain to be explored. The aim of this study is to explore the effects of storing bile under various conditions on the stability of bile cfDNA and to determine the optimal conditions, thereby establishing a foundation for the subsequent application of bile cfDNA in liquid biopsy for early diagnostic and prognosis monitoring of patients with malignant BTC.

Methods: We evaluated the storage temperature and storage time for the preservation of bile samples. Bile samples were collected in cfDNA tubes with protectant covered inside or regular tubes without, and the stability of bile cfDNA was analyzed during 10 days at room temperature (RT) or after 2 months of storage at low temperatures.

Results: Bile cfDNA remained stable for bile samples being collected with cfDNA tubes and stored for 10 days at RT, while degraded with time for the case with regular tubes. When bile samples were collected with cfDNA tubes and stored for 2 months at 4 ℃, bile cfDNA remained stable, however, if collected with regular tubes, bile cfDNA exhibited a slight loss of integrity. No significant difference was observed for 2 months storage at -20 or -80 ℃.

Conclusions: Our findings suggested that for bile cfDNA research, bile samples should be collected with cfDNA tubes and it can be transported for short-term shipment at RT, and could be stored at 4 ℃ with cfDNA tubes, or frozen at -20 ℃ with regular tubes.

Background: Human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) is an increasingly common malignancy. We aimed to explore the immune heterogeneity of natural killer (NK) cells in HPV-positive HNSCC.

Methods: Single-cell RNA-sequencing (scRNA-seq) and bulk RNA-sequencing datasets of HPV-positive HNSCC data were obtained from the Gene Expression Omnibus (GEO) database. "Seurat", "harmony", and "SingleR" were used to perform the scRNA-seq analysis. Subsequently, the "cellphonedb" package was used for the cell crosstalk analysis, and the "clusterProfiler" package was used for the hallmark pathway enrichment analysis. Finally, the "gene set variation analysis" ("GSVA") package was used for the immune cell infiltration, Tumor Immune Dysfunction and Exclusion (TIDE), and risk-score analyses.

Results: A total of 30,562 cells were classified into 9 cell clusters that comprised 6 main cell types [i.e., T cells, natural killer T (NKT) cells, NK cells, B cells, plasma cells, and macrophages]. The NK cells were then further clustered into 3 tissue-resident NK (trNK0-2) and 2 tumor-associated NK (taNK0-1) cell types. The trNK0 cell type, which exhibited inhibitory cancer hallmark activity, appeared to exert potential anti-tumor effects via trNK0-macrophage crosstalk. The trNK score could serve as an independent and valuable prognostic classifier, as the patients with high-trNK scores had better outcomes, immune-infiltration levels, and immunotherapy effects.

Conclusions: Using an scRNA-seq analysis, we identified a specific type of tissue-resident NK cell (i.e., trNK-0) that was involved in the anti-tumor and immunotherapy response in HPV-positive HNSCC.

Background: Tumor-associated macrophages play a critical role in the progression and immune response of triple-negative breast cancer (TNBC). Our study aimed to explore the characteristics of tumor-associated macrophages (TAMs) in TNBC, construct a risk signature associated with TAM clusters, and verify its relationship with prognosis and immune-related characteristics.

Methods: Firstly, we identified four TAM clusters and determined prognosis-related clusters in TNBC based on the single-cell RNA sequencing (scRNA-seq) data. Subsequently, the TAM-related prognostic genes were obtained by the univariate Cox regression analysis and an 8-gene risk signature was then constructed by least absolute shrinkage and selection operator (LASSO) regression based on these TAM-related prognostic genes. Analyses of immune characteristics showed a significant association between the signature with stromal and immune scores, as well as some immune cells.

Results: Multivariate analysis revealed that the risk signature was an independent prognostic factor for TNBC, and its value in predicting immunotherapeutic outcomes was also confirmed. A novel nomogram integrating the stage and TAM-based risk signature was constructed, which exhibited favorable predictability and reliability in the prognosis prediction of TNBC. Finally, the increasing expression of GPR34 which is one of the eight hub genes was explored in TNBC by experiments including reverse-transcriptase polymerase chain reaction, western blot, and immunohistochemistry.

Conclusions: Our study may provide unique insights into obtaining independent prognostic factors, improving immunotherapeutic strategies, and identifying effective therapeutic targets for TNBC.

Background: Although signal sequence receptor subunit 1 (SSR1) has undergone thorough examination in different cancer types, its importance in hepatocellular carcinoma (HCC) remains largely uncharted and warrants further investigation. The aim of this study is to explore the role of SSR1 in HCC progression and to decipher its underlying molecular mechanisms.

Methods: We employed the ONCOMINE, Tumor IMmune Estimation Resource (TIMER), and The Cancer Genome Atlas databases to assess SSR1 expression levels within tumor tissues. Logistic and Cox regression analyses, Kaplan-Meier survival plots, nomograms, and forest plots were employed to establish correlation between SSR1 and prognosis. Receiver operating characteristic (ROC) curves demonstrated diagnostic utility of SSR1. Additionally, Gene Ontology (GO) and gene set enrichment analysis (GSEA) analyses were conducted to uncover relevant molecular pathways. TIMER was instrumental in elucidating the connection between SSR1 and immune cell infiltration. Actions of SSR1 in HCC proliferation and migration were investigated through quantitative real-time polymerase chain reaction, Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine cell proliferation assays, and Transwell migration and wound healing experiments.

Results: Elevated SSR1 levels were found to be correlated with clinical parameters such as age and pathologic stage, thereby predicting a reduced overall survival (OS) rate in HCC patients. Multivariate survival analysis underscored SSR1 as an independent prognostic marker for OS. A nomogram underscored SSR1's effectiveness as a predictive tool for HCC outcomes, while ROC analysis indicated its high diagnostic accuracy. GO and GSEA analyses suggested that elevated SSR1 expression may be associated with epithelial-mesenchymal transition (EMT) pathway. SSR1 exhibited a negative correlation with cytotoxic cells and a positive correlation with Th2 cells. Our in vitro experiments provided evidence that heightened SSR1 levels may impact HCC proliferation and migration through EMT pathway.

Conclusions: SSR1 surfaces as a new diagnostic and potentially prognostic biomarker, showing an association with immune cell infiltration and cell proliferation in HCC.