Journal of Cancer最新文献

Background: Melanoma is a highly malignant and difficult-to-treat skin cancer. Many researchers are exploring natural products for its treatment. Lentinan (LNT), extracted from Lentinus edodes, exerts strong anti-tumor effects. In this study, we aimed to establish a new approach for melanoma treatment by analyzing the pharmacological properties of LNT. Methods: A tumor-bearing mouse model was established to assess tumor growth. Cell survival was analyzed using the cell counting kit-8 assay. Molecular localization and expression were assessed via western blotting, histological staining, and cell staining. Results: LNT significantly inhibited the growth and proliferation of melanoma cells. In vitro, LNT inhibited the proliferation of B16F10 cells. It also decreased the expression levels of the proliferation-related molecules, poly (ADP ribose) polymerase 1 and proliferating cell nuclear antigen, in B16F10 murine melanoma cells. Moreover, LNT decreased the expression of the orphan nuclear receptor, Nur77, but increased that of the apoptosis-related protein, Bcl-2. LNT promoted the interaction between nuclear receptor Nur77 and mitochondrial apoptosis-associated protein Bcl-2, thereby inducing apoptosis in melanoma cells. Small-interfering RNA-mediated Nur77 knockdown revealed that LNT promoted melanoma cell apoptosis via the Nur77/Bcl-2 pathway. Furthermore, AKT played key roles in the cell apoptosis-inducing and anti-tumor effects of LNT via the Nur77/Bcl-2 pathway. Conclusion: Overall, LNT inhibited tumor growth and promoted apoptosis by regulating the AKT/Nur77/Bcl-2 pathway in melanoma cells. Our findings highlight the potential of LNT for drug development and clinical treatment of melanoma.

Background: Relevant studies have demonstrated that plasma metabolites and immune cell characteristics are closely related to colorectal cancer (CRC). However, the causal relationship among these factors remains unclear, particularly regarding whether immune cell traits mediate the causal link between plasma metabolites and CRC. Methods: This study employed a two-step, two-sample Mendelian randomization (MR) using summary data from genome-wide association studies (GWAS) to assess causal associations between 1,400 plasma metabolites, 731 immune cell traits, and CRC. Additionally, it evaluated the mediating effect of immune cell traits and utilized single-cell RNA sequencing (scRNA-seq) to analyze immune cells infiltration in CRC, assess their metabolic functional changes and their interactions with CRC cells. Results: Univariable two-sample MR analysis revealed causal relationships between 49 plasma metabolites and CRC, as well as between 36 immune cell traits and CRC. Two-step MR analysis revealed that two plasma metabolites (Sphingomyelin (d18:1/22:1, d18:2/22:0, d16:1/24:1) and 16α-hydroxy-DHEA-3-sulfate) influence CRC through two immune cell traits (SSC-A on CD14+ monocyte and CD3 on CD28- CD8+ T cell). Among these, SSC-A on CD14+ monocyte exhibited the highest mediating effect proportion, at 11.723%. scRNA-seq analysis further confirmed the increased infiltration of CD28- CD8+ T cells and CD14+ monocytes in CRC, along with upregulated sphingolipid metabolism and steroid biosynthesis. These cells were also found to interact with CRC cells, contributing to tumor initiation and progression. Conclusion: This study provides new evidence for the causal relationship between plasma metabolites and CRC, and it identifies immune factors with potential mediating roles. These findings offer new insights for further exploration of the mechanisms underlying the development of CRC.

Background: Rechallenge with immune checkpoint inhibitors (ICI) shows promise in various cancers, but data in esophageal squamous cell carcinoma (ESCC) is limited. This study aimed to evaluate the efficiency and safety of ICI rechallenge in ESCC. Materials and Methods: This multicenter study analyzed ESCC patients rechallenged with ICI from January 2020 to March 2023 across two medical institutions. Patients were divided into rechallenge (R) and non-rechallenge (NR) groups. Key outcomes studied were progression-free survival (PFS), overall survival (OS), and safety. Results: Among 329 included ESCC patients, 211 were in the R group and 118 in the NR group, with a median follow-up of 17.1 months. The R group exhibited significantly prolonged median PFS (4.7 vs. 3.2 months; p <.001) and OS (9.3 vs. 6.2 months; p <.001) compared to the NR group. Notably, for patients who initially received radiotherapy, the R group showed significantly longer mPFS (5.1 vs. 3.2 months; p <.001) and mOS (10.4 vs. 5.9 months; p <.001). Incidences of all-grade (64.5% vs. 66.1%; p = .764) and grade ≥3 adverse events (17.5% vs. 18.6%; p = .802) did not significantly differ between groups. Conclusion: ICI rechallenge demonstrates efficacy and manageable safety in ESCC, particularly post-radiotherapy.

Background: Killer Cell Lectin Like Receptor D1 (KLRD1) plays a crucial role in antitumor immunity. However, its expression patterns across various cancers, its relationship with patient prognosis, and its potential as an immunotherapy target remain inadequately understood. Methods: We analyzed KLRD1 expression across various cancer types using multi-omics data from The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Gene Expression Omnibus (GEO) databases, correlating it with patient prognosis. Single-cell RNA sequencing data were employed to further explore KLRD1 expression in natural killer (NK) cells and exhausted CD8+ T cells (CD8Tex). Functional enrichment analyses using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) identified the biological processes and pathways associated with KLRD1. Immune infiltration analysis, conducted via CIBERSORT, assessed the relationship between KLRD1 expression and immune cell infiltration within the tumor microenvironment. Furthermore, the Tracking Tumor Immunophenotype (TIP) meta-server and Easier tool were employed to assess the role of KLRD1 in the cancer immunity cycle and to predict immunotherapy responses. Drug sensitivity was predicted using tools like CellMiner and the Genomics of Drug Sensitivity in Cancer (GDSC) database to explore the link between KLRD1 expression and responsiveness to various anticancer drugs. Results: KLRD1 exhibits significant differential expression and strong prognostic value across cancers, particularly as an independent prognostic factor in head and neck squamous cell carcinoma (HNSC). Single-cell analysis revealed high expression of KLRD1 in NK and CD8Tex cells, indicating its critical role in antitumor immune responses. Functional enrichment analyses showed that KLRD1 is involved in several immune-related signaling pathways, including NK cell-mediated cytotoxicity and T cell receptor pathways. Immune infiltration analysis further confirmed a positive correlation between KLRD1 expression and the infiltration of various immune cells. Moreover, higher KLRD1 expression in HNSC is associated with enhanced immune pathway activity, increased sensitivity to cell division inhibitors, and the identification of arachidonyltrifluoromethane as a potential compound to counteract its oncogenic effects. Conclusion: In HNSC, KLRD1 is a key prognostic marker and potential target for personalized immunotherapy.

Objective: The TP53 mutation is a poor prognostic factor for malignant tumors in a number of organs. The present study primarily aimed to clarify the impact of the mutant pattern of p53 on the prognosis and recurrence of gastric cancer. Methods: For this purpose, 519 patients who underwent radical gastrectomy for cancer were enrolled in the present study. Immunohistochemistry (IHC) was used to examine p53 expression in tissues and a three-stage classification system was used to divide the patient tissues into three groups according to the expression of p53: Heterogeneous (wild-type), absent and overexpression (mutant). Results: After 5 years of follow-up, recurrence and metastasis occurred in 38.7% of patients with stomach cancer, with a p53 mutant pattern in 48.4% of these patients. Patients with a p53 mutant pattern had lower recurrence-free and overall survival rates at 5 years compared with those who were p53 wild-type (P<0.001). It was found that the p53 pattern differed significantly (P<0.001) between the wild-type and mutant patterns, including the pN0 and pN+ gastric cancer subgroups (P<0.001 and P=0.014, respectively). The p53 mutant pattern was also significant in the determination of the recurrence-free survival of patients with progressive stomach cancer (P<0.0001). The 5-year overall survival rates were 71.7 and 36.2%, and the recurrence-free survival rates were 71.2 and 35.2% in the pN0 and pN+ groups, respectively (P<0.001). The mutant pattern of p53 was a significant prognostic factor for both distant metastasis [relative risk (RR)=2.881, P<0.001] and overall survival (RR=2.809, P<0.001) in the univariate Cox regression analysis. In the multivariate analysis, distant metastasis (RR=2.767, P<0.001) remained significant in the mutant pattern of p53 staining. After propensity score matching, 189 patients with a p53 wild-type and 189 patients with a p53 mutant pattern were extracted for analysis. The 5-year overall survival rate in patients with the p53 mutant pattern (n = 189) was worse than that in the patients with p53 wild-type (n = 189) and with significant differences (log-rank P<0.01). The study was statistically significant after Cox univariate and multivariate regression analysis, which revealed that the mutant pattern of p53 is an independent prognostic factor impacting distant metastases following curative gastrectomy for advanced-stage gastric cancer (p = 0.48).

Purpose: Multimorbidity among colon cancer survivors reflected the coexistence of multiple chronic conditions. This study aimed to understand the comorbidity risks for long-term colon cancer survivors using a real-world population database. Methods: Taiwan cancer registry from 2016 to 2021 identified patients diagnosed with colon cancer, selecting those who survived beyond five years. Charlson Comorbidity Index (CCI) was used to assess the level of comorbidities, categorizing patients into no (CCI=0), mild (CCI=1-2), and severe (CCI≥3) comorbidity groups, for estimating the impact on survival. Cox regression model was applied to estimate risk factors associated with comorbidities among long-term colon cancer survivors. Results: In this cohort study of 13,209 colon cancer survivors, most had no comorbidity (82.23%), following as mild (10.03%) and severe (7.74%) comorbidity. Our study revealed the significant association between higher CCI scores and increased mortality risk. Compared with patients without comorbidities, mild comorbidities patients exhibited a significantly higher risk of mortality (HR:4.56; 95% CI:3.93-5.28), and those with severe comorbidities had an increased risk (HR:12.67; 95% CI:11.15-14.40) after adjusting potential confounders. Subgroup of sex, age, clinical stage, and treatment types show that colon cancer survivors with mild/severe comorbidities had significant higher mortality risk than those without comorbidities. Conclusion: This study indicated the critical role of comorbidity management may improve the survival outcomes for colon cancer patients, particularly those with high-risk factors and severe comorbidities.

Chemotherapy-induced diarrhea (CID) is a common and harmful side effect of chemotherapy, greatly impacting patients' quality of life and potentially compromising their chances of survival. Disruption of the balance in intestinal microbiota and compromised integrity of the intestinal barrier are key factors contributing to CID caused by mucositis. This paper investigated the mechanism through which intestinal microbiota activate Toll-like receptors and STING pathways to mediate intestinal mucosal inflammation resulting from immune responses in the gut, uncovering a novel mechanism of intestinal microbiota in chemotherapy-induced diarrhea, and suggesting innovative approaches for the prevention and management of CID.

NCAPG promotes the progression of endometrial cancer (EC) through PI3K-AKT pathway and has potential as a novel tumor marker. However, the precise regulatory mechanism of NCAPG remains inadequately understood. In this study, we applied Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-Seq) analysis combined with chromatin immunoprecipitation-qPCR (CHIP) and Co-Immunoprecipitation (CoIP) analysis to analysis for the first time that NCAPG promotes EC cell proliferation, migration and invasion by affecting the binding of LEF1 to chromatin, thereby affecting the transcription of downstream SEMA7A. Mechanistically, SEMA7A regulated the PI3K-AKT signaling pathway by binding to the PI3K regulatory subunit p85, exerting its biological function. The NCAPG/LEF1/SEMA7A axis promoted EC tumorigenesis and progression by activating the PI3K-AKT signaling pathway. Additionally, LEF1 and SEMA7A were associated with the FIGO stage, pathological grade, and myometrial invasion in EC patients. The expressions of NCAPG, LEF1, and SEMA7A were highly consistent. Targeting this cascade may provide effective antitumor strategies to delay the progression of EC.

Cancer research has been significantly advanced by the integration of transcriptomic data through high-throughput sequencing technologies like RNA sequencing (RNA-seq). This paper reviews the transformative impact of transcriptomics on understanding cancer biology, focusing on the use of extensive datasets such as The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). While transcriptomic data provides crucial insights into gene expression patterns and disease mechanisms, the analysis is fraught with technical and biological biases. Technical biases include issues related to microarray, RNA-seq, and nanopore sequencing methods, while biological biases arise from factors like tumor heterogeneity and sample purity. Additionally, misinterpretations often occur when correlational data is erroneously assumed to imply causality or when bulk data is misattributed to specific cell types. This review emphasizes the need for researchers to understand and mitigate these biases to ensure accurate data interpretation and reliable clinical outcomes. By addressing these challenges, the paper aims to enhance the robustness of cancer research and improve the application of transcriptomic data in developing effective therapies and diagnostic tools.

Wilms tumor, also known as nephroblastoma, is the most common kidney cancer in children. The miR-196a2 rs11614913 T>C polymorphism has been identified as a susceptibility locus in various adult cancers. However, it is unclear whether this polymorphism also increases the risk of pediatric cancer. In this study, we examined the genotypes of miR-196a2 rs11614913 T>C in 416 pediatric patients with Wilms tumor and 936 age- and gender-matched healthy controls of Chinese Han ethnicity using the TaqMan technology. The association between rs11614913 T>C polymorphism and the susceptibility to Wilms tumor was analyzed by univariable and multivariable logistic regression analyses, and the odds ratio (OR) and 95% confidence interval (CI) were calculated. Overall analysis indicated that the miR-196a2 rs11614913 T>C was associated with an increased risk of Wilms tumor in the homozygous (adjusted OR (AOR)=1.58, 95% CI=1.14-2.21, P=0.007), additive (AOR=1.26, 95% CI=1.06-1.49, P=0.007), dominant (AOR=1.33, 95% CI=1.02-1.74, P=0.034), and recessive (AOR=1.38, 95% CI=1.05-1.81, P=0.023) models. Stratification analysis further demonstrated that the association was dependent on age and tumor stages rather than gender. Furthermore, miR-196a2 rs11614913 T>C was significantly associated with the disease risk only in children older than 18 months and those with III+IV stage tumors. The expression quantitative trait locus (eQTL) analysis showed that rs11614913 T>C was associated with decreased expression of HOXC-AS1 and increased expression of GPR84 and HOXC8. Our results provide evidence that miR-196a2 rs11614913 T>C may confer genetic susceptibility to Wilms tumor. These findings warrant validation in larger cohorts and across different ethnicities.