Translational Oncology最新文献

Objectives: Alpha fetoprotein(AFP) overexpression connecting with macrophage dysfunction remain poorly defined. In this study, explore AFP regulates macrophage immunomodulation in hepatocellular carcinoma(HCC) through comprehensive in vitro and in vivo studies.

Methods: Immunohistochemical and immunofluorescence staining was used to analyze the relativity of AFP and cellular membrane CD47 expression in clinical 30 HCC tissues, and the expression of AFP and CD47 in HCC cells. The intelligent living-cell high-throughput imaging analyzer was applied to dynamically track and image of macrophages to phagocytize HCC cells. The effect of AFP on regulating the level of CD47 in cellular membrane and growth of tumor in vivo was performed by animal experiment. The association of AFP and CD47 in HCC cells was detected by single cell analysis.

Results: The present results indicated that AFP upregulated the localization of CD47 on the HCC cell surface. CD47 overexpression stimulates HCC to escape immune surveillance by transmitting "don't eat me" signals to macrophages, lead to inhibit macrophage to phagocytize HCC cells. Mechanistically, the results demonstrated that AFP enhanced CD47 membrane translocation by interacting with Hu-Antigen R(HuR), an RNA-binding protein that regulates mRNA stability and translation. AFP alters the subcellular distribution of HuR, increasing its cytoplasmic accumulation and binding to CD47 transcript.

Conclusions: AFP enhanced CD47 membrane translocation by interacting with HuR. These findings proved that AFP could inhibit macrophage to phagocytize HCC cells by upregulating the localization of CD47 on the HCC cell surface. Combination of AFP with CD47 blockade may be a potential therapeutic strategy for HCC treatment.

Background: Prostate cancer stands as the second most common malignancy among men, notorious for its intricate heterogeneity, especially evident in metastatic disease. This complexity presents substantial challenges in treatment efficacy and patient prognosis.

Objective: This study endeavors to elucidate the multifaceted roles of cancer-associated fibroblasts within the tumor microenvironment of prostate cancer, with a focus on their implications for disease prognosis and the potential for novel immunotherapeutic strategies.

Methods: Leveraging advanced single-cell RNA sequencing technology, we meticulously characterized the diverse CAF subpopulations within prostate cancer samples. Our analysis identified four predominant subsets: C0 IER2+, C1 ABCA8+, C2 ABI3BP+, and C3 MEOX2+. We conducted comprehensive gene expression profiling to construct a robust prognostic model reflecting the clinical relevance of these subpopulations.

Results: C1 ABCA8+ fibroblasts demonstrated heightened proliferative activity, underscoring their pivotal role in fostering tumor growth and metastasis via intricate signaling pathways. In vitro experiments verified that the T transcription factor NFAT5 of C1 ABCA8+ fibroblasts subpopulation was knocked down in LNCaP clone FGC and 22Rv1 cell lines, which was closely related to the proliferation of PC. Moreover, we identified key genes linked to patient outcomes and immune landscape alterations, reinforcing the prognostic significance of CAF characteristics in this context.

Conclusion: This investigation illuminates the critical potential of targeting CAFs to augment immunotherapeutic approaches in prostate cancer. Our findings contribute to a deeper understanding of the TME's complexity, advocating for further exploration into CAF-targeted therapies aimed at enhancing treatment responses and ultimately improving patient outcomes.

5-Methylcytosine (m5C) is a ubiquitous RNA modification that is closely related to various cellular functions. However, no studies have comprehensively demonstrated the role of m5C in hepatocellular carcinoma (HCC) progression. In this study, six pairs of HCC and adjacent tissue samples were subjected to methylated RNA immunoprecipitation sequencing to identify precise m5C loci. Non-negative matrix factorization (NMF) was used to identify HCC subtypes in TCGA-LIHC cohort. Immune, metabolic, and tumor-related pathways in HCC subtypes with differences in methylation status were analyzed and a prognostic model based on m5C-related genes was constructed. Finally, using RIP and molecular interaction analysis, we demonstrated that YBX1 binds to TPM3 in an m5C dependent manner and regulates HCC progression. Widespread m5C sites were identified and found to be differentially distributed in HCC compared with adjacent tissues. Metabolic processes were inhibited in hypermethylated HCC, whereas immune checkpoint and multiple classical tumor pathways were significantly upregulated. More importantly, we have identified an m5C dependent regulatory axis. The m5C reader YBX1 binds to TPM3 in an M5C dependent manner and promotes the progression of hepatocellular carcinoma. These results provide new evidence for further understanding the comprehensive role of m5C in HCC and the regulatory mechanism of m5C.

The low expression of period circadian regulator 3 (PER3) in head and neck squamous cell carcinoma is closely correlated with tumor size and invasion depth. Hypoxia-inducible factor 1 subunit alpha (HIF-1α) regulates epithelial-mesenchymal transition (EMT) transcription factors, activates EMT, and promotes tumor metastasis. Here, we investigated the role and molecular mechanism of PER3 in regulating HIF-1α and metastasis in oral squamous cell carcinoma (OSCC) by using bioinformatics analyses and in vitro and in vivo experiments. PER3 expression was decreased in OSCC, and PER3 expression was significantly negatively correlated with T stage, N stage, clinical classification, and survival time. PER3 overexpression inhibited, while PER3 knockdown prompted EMT and metastasis of OSCC cells. HIF-1α reversed the effects of alterations in PER3 expression on OSCC metastasis. Mechanistically, PER3 bound to HIF-1α via the Per-ARNT-Sim 1 domain and promoted its ubiquitination degradation. Hypermethylation at CpG site cg12258811 of PER3 promoter inhibited PER3 expression and prognosis of OSCC. Decitabine combined with LW6 upregulated PER3, downregulated HIF-1α, and inhibited lymph node metastasis of OSCC in nude mice. Our findings reveal the role and mechanism of HIF-1α regulation by PER3 and support the potential clinical application of targeting PER3 in treating OSCC metastasis.

Background: Glucose metabolism in breast cancer has a potential effect on tumor progression and is related to the immune microenvironment. Thus, this study aimed to develop a glucose metabolism-tumor microenvironment score to provide new perspectives on breast cancer treatment.

Method: Data were acquired from the Gene Expression Omnibus and UCSC Xena databases, and glucose-metabolism-related genes were acquired from the Gene Set Enrichment Analysis database. Genes with significant prognostic value were identified, and immune infiltration analysis was conducted, and a prognostic model was constructed based on the results of these analyses. The results were validated by in vitro experiments with MCF-7 and MCF-10A cell lines, including expression validation, functional experiments, and bulk sequencing. Single-cell analysis was also conducted to explore the role of specific cell clusters in breast cancer, and Bayes deconvolution was used to further investigate the associations between cell clusters and tumor phenotypes of breast cancer.

Results: Four significant prognostic genes (PMAIP1, PGK1, SIRT7, and SORBS1) were identified, and, through immune infiltration analysis, a combined prognostic model based on glucose metabolism and immune infiltration was established. The model was used to classify clinical subtypes of breast cancer, and PMAIP1 was identified as a potential critical gene related to glucose metabolism in breast cancer. Single-cell analysis and Bayes deconvolution jointly confirmed the protective role of the PMAIP1+ luminal cell cluster.

Ataxia Telangiectasia Mutated (ATM) is a protein kinase traditionally known for its role in DNA damage response and cell cycle regulation. However, emerging research has revealed its multifaceted and crucial functions in the immune system. This comprehensive review explores the diverse roles of ATM in immune regulation, from lymphocyte development to its involvement in cancer immunotherapy. The review describes ATM's critical functions in V(D)J recombination and class switch recombination, highlighting its importance in adaptive immunity. It examines ATM's role in innate immunity, particularly in NF-κB signaling and cytokine production. Furthermore, the review analyzes the impact of ATM deficiency on oxidative stress and mitochondrial function in immune cells, providing insights into the immunological defects observed in Ataxia Telangiectasia (A-T). The article explores ATM's significance in maintaining hematopoietic stem cell function and its implications for bone marrow transplantation and gene therapy. Additionally, it addresses ATM's involvement in inflammation and immune senescence, linking DNA damage response to age-related immune decline. Finally, this review highlights the emerging role of ATM in cancer immunotherapy, where its inhibition shows promise in enhancing immune checkpoint blockade therapy. This review synthesizes current knowledge on ATM's functions in the immune system, offering insights into the pathophysiology of ATM-related disorders and potential therapeutic strategies for immune-related conditions and cancer immunotherapy.

Background: Colorectal cancer (CRC) presents significant challenges in chemotherapy response prediction due to its molecular heterogeneity. Current methods often fail to account for the complexity and variability inherent in individual tumors.

Methods: We developed a novel approach using matched CRC tumor and organoid gene expression data. We applied Consensus Weighted Gene Co-expression Network Analysis (WGCNA) across three datasets: CRC tumors, matched organoids, and an independent organoid dataset with IC50 drug response values, to identify key gene modules and hub genes linked to chemotherapy response, particularly 5-fluorouracil (5-FU).

Findings: Our integrative analysis identified significant gene modules and hub genes associated with CRC chemotherapy response. The predictive model built from these findings demonstrated superior accuracy over traditional methods when tested on independent datasets. The matched tumor-organoid data approach proved effective in capturing relevant biomarkers, enhancing prediction reliability.

Interpretation: This study provides a robust framework for improving CRC chemotherapy response predictions by leveraging matched tumor and organoid gene expression data. Our approach addresses the limitations of previous methods, offering a promising strategy for personalized treatment planning in CRC. Future research should aim to validate these findings and explore the integration of more comprehensive drug response data.

Funding: This research was supported by US National Cancer Institute grant R37CA248289, and Sylvester Comprehensive Cancer Center. which receives funding from the National Cancer Institute award P30CA240139. This work was supported by National Institutes of Health (NIH) under the following grants: T32CA009501-31A1 and R37CA248289. This work was also supported by the MSK P30CA008748 grant.

Metabolic reprogramming is a hallmark of cancer. The"Warburg effect", also known as aerobic glycolysis, is an essential part of metabolic reprogramming and a central contributor to cancer progression. Moreover, hypoxia is one of the significant features of pancreatic ductal adenocarcinoma (PDAC). Under hypoxic conditions, the "Warburg effect" occurs to meet the nutrient and energy demands of rapid genome replication, remodeling the tumor microenvironment (TME) and influencing tumor immunity. α-Enolase (ENO1) is a multifunctional protein, acting as a glycolytic enzyme that catalyzes the conversion of 2-phosphoglyceric acid to phosphoenolpyruvic acid. ENO1 was found to be overexpressed in multiple types of cancers. Here, we investigated the role of ENO1 in modulating the PDAC microenvironment. Using bioinformatic analyses, we demonstrated that ENO1 was highly expressed in PDAC patients, which was related to a poor prognosis. In vitro, Eno1 knockdown resulted in reduced PDAC cell proliferation and colony formation, along with enhanced apoptosis in PDAC cells. In vivo, tumorigenesis was suppressed in mouse PDAC models by Eno1 knockdown. Flow cytometry analysis revealed that high expression of Eno1 altered the tumor immune microenvironment (TIME), particularly the impaired tumor infiltration and function of CD8⁺ T cells. Mechanistic studies revealed that ENO1 upregulated PD-L1 to prevent CD8⁺ T cells infiltration through the hypoxia-inducible factor (HIF)-1α signaling pathway, leading to PDAC progression. In conclusion, our findings indicate that ENO1 might serve as a potential biomarker for PDAC and a novel onco-immunotherapeutic target via its role in altering the TIME.

Introduction: Laryngeal cancer (LC) presents a significant health challenge globally, with smoking being a major risk factor. Interestingly, LC incidence in females is significantly lower than in males; however, female smokers are more likely to develop Reinke edema (RE) than LC. This study sought to investigate whether autophagy, a major mechanism for RE development, acts as a defense mechanism in laryngeal tissue against cigarette exposure and suppresses LC development in females who smoke.

Methods: This study analyzed the National Health Insurance Service (NHIS) data of South Korea to explore sex differences in LC incidence and clinical outcomes. Protein expression was compared between tissues from LC and RE patients. The changes in autophagy-related markers were analyzed after exposure to human vocal fold fibroblast (hVFF) and cigarette smoke extract (CSE). In addition, to explore the relationship between the level of autophagy-related gene expression and clinical features, female LC patients were compared with male patients through an analysis of data from The Cancer Genome Atlas (TCGA).

Results: In the NHIS data analyses, male LC patients had an 11 times higher incidence than female patients, even after adjusting for smoking and age. Additionally, female LC patients had significantly better survival rates. RE tissues exhibited increased autophagy-related protein expression compared with LC tissues. hVFFs after CSE exposure demonstrated elevated autophagy markers along with protein expression similar to RE tissue, suggesting autophagy's role in RE development over LC. The TCGA data analysis did not find a significant difference in autophagy-related gene expression, which would explain the favorable female clinical outcomes, between male and female LC patients.

Conclusions: This study implies autophagy activation by cigarette smoke is a crucial mechanism for lower LC incidence and better outcomes in females, highlighting the potential for autophagy-targeted LC prevention and treatment strategies.