Cancer Science最新文献

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, highlighting the urgent need for improved therapeutic strategies. In this study, we identified zinc finger protein 282 (ZNF282), located on chromosome 7q, as a novel gene that contributes to CRC progression through comprehensive expression profiling using data from The Cancer Genome Atlas (TCGA) and single-cell RNA sequencing combined with spatial transcriptomics in clinical CRC datasets. ZNF282 was overexpressed in tumor cells. High ZNF282 mRNA expression was associated with distant metastasis and served as an independent poor prognostic factor in CRC. In vitro and in vivo experiments using CRISPR/Cas9-mediated ZNF282 knockout CRC cell lines demonstrated significantly reduced tumor growth and cell proliferation, which were reversed by reexpression of ZNF282. Mechanistically, ZNF282 knockout impaired the G1/S cell cycle transition and downregulated E2F1 and its downstream targets, CCNE1 and CCND1. These findings were supported by single-cell RNA sequencing analysis, which showed ZNF282 enrichment in malignant epithelial cells linked to cell cycle pathways. Motif scanning further identified a putative ZNF282 binding site upstream of the E2F1 transcription start site, suggesting that ZNF282 may enhance E2F1 expression by facilitating the activity of an upstream regulatory region. In conclusion, ZNF282 is a novel gene that promotes CRC progression in part by enhancing cell cycle progression possibly via E2F1 activation. Its high expression is associated with poor prognosis, supporting its potential as a prognostic biomarker and therapeutic target in CRC.

Tumor-associated neutrophils (TANs) play crucial roles in malignant tumors, and their polarization is considered a determining factor in cancer progression. However, knowledge concerning the molecular mechanisms that regulate the changes in the polarization phenotype of TANs and their impact on tumor biology is limited. Here, we demonstrate that tumor-derived prostaglandin E2 (PGE2) regulates the polarization of TANs toward the N2 phenotype within the tumor microenvironment, promoting tumor cell proliferation and migration. Mechanistically, PGE2 is released from the LDs of CRC cells into the TME, where the stimulation of ROS-mediated methylation increases through binding with the surface receptors prostaglandin E receptor 2 (EP2, PTGER2) and EP4 on TANs, resulting in a reduction in the expression of the transcriptional repressor FOXO3a and thereby eliminating its ability to bind to the promoter region of N2-associated molecules such as ARG1, MMP9, and BV8 in TANs and promote their production. In summary, PGE2-induced N2-type TAN polarization directly affects the malignant progression of tumors. Our research revealed that PGE2 could be a potential effective molecule for targeting TANs in antitumor immunotherapy for CRC.

Even after surgical resection, the prognosis is poor for patients with esophagogastric junction adenocarcinoma who develop upper mediastinal lymph node metastasis. Moreover, the current preoperative diagnostic accuracy for upper mediastinal lymph node metastasis remains inadequate, which complicates treatment planning. To enhance diagnostic precision and facilitate personalized therapeutic strategies, we aimed to develop a novel diagnostic model that integrates a DNA methylation panel with conventional clinical parameters. First, genome-wide methylation profiling of 69 tumors identified seven CpG sites significantly associated with upper mediastinal lymph node involvement. We then evaluated a methylation panel based on these markers in two independent cohorts comprising a total of 133 treatment-naïve patients. The methylation panel alone achieved moderate diagnostic performance (AUC 0.71, 95% CI 0.52–0.91), whereas its integration with clinical data substantially improved accuracy (training cohort: AUC 0.87, 95% CI 0.75–0.99). Applying the same model formula to an independent pretreatment validation cohort confirmed its robustness (AUC 0.85, 95% CI 0.70–1.00). Furthermore, the methylation panel was identified as an independent prognostic factor for overall survival (p < 0.01). Finally, to facilitate clinical implementation, the integrated model was formalized as a nomogram. In summary, this novel diagnostic model enables highly accurate detection of upper mediastinal lymph node metastasis in esophagogastric junction adenocarcinoma, with the potential to optimize treatment decisions and reduce the need for invasive procedures, thereby contributing to precision oncology.

Small cell neuroendocrine carcinoma of the cervix (SCNEC) is classified as a high-grade neuroendocrine carcinoma with a worse prognosis than other major histological types of cervical cancer. Identifying novel therapeutic targets based on its molecular characteristics is highly desirable but challenging due to the rarity of SCNEC and the resulting lack of research resources. In this study, we identified vaccinia-related kinase 1 (VRK1) as a potential therapeutic target for SCNEC. VRK1 was prioritized based on our previously reported proteomic analysis of patient-derived organoids. Immunohistochemistry of patient samples consistently revealed high VRK1 expression in SCNEC, as opposed to its variable expression in other cervical carcinomas. Although VRK1 knockdown in SCNEC had only a limited effect on cell proliferation in two-dimensional cultures, it significantly suppressed cell proliferation in three-dimensional cultures and inhibited xenograft tumor growth in vivo. Gene set enrichment analysis of RNA-sequencing data from mouse xenograft models demonstrated that VRK1 is associated with mitochondrial-related pathways. Furthermore, under oxidative stress conditions, VRK1 knockdown resulted in a reduction of mitochondrial membrane potential, an indicator of mitochondrial integrity, and decreased expression of cytochrome c oxidase subunit IV (COX IV), a nuclear-encoded subunit of cytochrome c oxidase, the terminal enzyme complex of the mitochondrial respiratory chain. These findings suggest that VRK1 knockdown indirectly impaired mitochondrial function. Collectively, these anti-tumor effects highlight VRK1 as a promising therapeutic target for SCNEC.

Watanabe, T., Kidoguchi, K. and Kimura, S. (2025), Treating Hematological Malignancies With OR-2100, an Orally Bioavailable Prodrug of Decitabine. Cancer Sci, 116: 853–861. https://doi.org/10.1111/cas.16452

In Table 1, the reference citations were incorrect. The correct table is shown below:

Figure 3 legend was incorrect. The correct legend is shown below:

FIGURE 3 OR-2100 prevents leukemogenesis associated with aberrant DNA methylation in AKR mice. Tumor cells isolated from AKR mice have hypermethylated proximal promoter regions compared with normal T cells (left panel). Kaplan–Meier survival curves of AKR mice treated with vehicle, OR-2100, or DAC (right panel) [48]. Part of material from: Yuta Yamamoto et al., DNA demethylating agents for chemoprevention of oncovirus-associated leukemogenesis, Leukemia, 2024, Springer Nature.

In the third paragraph of the section “2.3 OR21 Monotherapy in ATL,” the text “Several genes that negatively regulate T-cell receptor signaling, including THEMIS, LAIR1, and RNF130, were down-regulated through promoter hypermethylation in ATL cells [16].” was incorrect.

This should have read: “Several genes that negatively regulate T-cell receptor signaling, including THEMIS, LAIR1, and RNF130, were down-regulated through promoter hypermethylation in ATL cells [30].”

We apologize for these errors.

Clear cell renal cell carcinoma (ccRCC) with sarcomatoid differentiation is a rare histological type of ccRCC, characterized by aggressive clinical behavior and poor prognosis. However, the malignant characteristics of this disease have yet to be fully elucidated. Here, we performed single-cell RNA sequencing (scRNA-seq), single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq), and WES analysis on a single patient with sarcomatoid ccRCC. By integrating scRNA-seq and scATAC-seq data from 19 previous classical ccRCC samples (19,819 tumor cells and 21,684 nuclei), we firstly identified the transcriptional regulatory features of sarcomatoid differentiated tumor cells by scATAC-seq, primarily evidenced by active binding with FOS/JUND, FOSL1/JUN, and FOSL2. In addition, we identified DST, FRMD4A, and PREX2 as tumor markers for ccRCC with sarcomatoid differentiation, which were validated in a cohort study. Moreover, we determined that PREX2 played a malignant role in ccRCC with sarcomatoid differentiation in vitro and in vivo, facilitating tumor progression by inhibiting PTEN and activating the PI3K/AKT pathway. This study demonstrated the comprehensive gene expression and DNA regulation information of ccRCC with sarcomatoid differentiation, highlighting its malignant characteristics, thereby offering novel insights for the diagnosis and treatment of sarcomatoid ccRCC.

Microbiomes within the tumor microenvironment (TME) are intricately linked to the modulation of cancer cell properties and the prognoses of various types of cancer, including esophageal squamous cell carcinoma (ESCC). However, their contribution to the onset and advancement of ESCC is still not fully elucidated. We adopted single-cell RNA sequencing to investigate the effects of esophageal commensal bacteria during the development of mice's spontaneous ESCCs. By analyzing the single-cell transcriptomes of 54,562 cells across different ESCC pathological stages, commensal bacteria were observed to display a cellular heterogeneous distribution in the ESCC TME. These bacteria were associated with the malignant transformation of epithelial cells and the formation of inflammatory fibroblasts, contributing to a chronic inflammatory microenvironment. However, after depriving commensal bacteria with an antibiotic cocktail (ABX), infiltrations of inflammatory fibroblasts and anti-bacteria macrophages were lower than those in the control H₂O group, while the infiltration of regulatory Cd4⁺ T (Treg) cells was higher. Interactions between inflammatory fibroblasts and Treg cells were intensified in the ABX group, which exacerbated the immunosuppressive state in the TME and developed more invasive carcinomas. This study demonstrates the significant role of commensal bacteria in ESCC tumorigenesis and sheds light on the potential clinical applications of adjusting commensal bacteria for the prevention and treatment of ESCC.

Cellular senescence is a state of stable cell cycle arrest accompanied by heightened immune activity, contributing to aging and age-related diseases. Although once regarded as a terminal and static condition, cellular senescence is now recognized as a dynamic and highly regulated process controlled by complex molecular networks. In vitro, it can be triggered by a variety of stimuli, including telomere attrition, DNA damage, oncogene activation, mitochondrial dysfunction, and others. However, the precise in vivo triggers of cellular senescence remain unclear. Recent findings from our group demonstrate that plasma membrane damage can induce cellular senescence in cultured normal human fibroblasts. Notably, the gene expression profile of these cells shares key characteristics with the cells localized near fibrotic cutaneous wounds in humans. In this review, we highlight recent advances in understanding the diverse subtypes of cellular senescence and their underlying regulatory networks, their context-dependent roles in tumorigenesis, and the therapeutic potential and challenges associated with targeting senescent cells. Unraveling the heterogeneity of cellular senescence holds promise for harnessing the beneficial roles of cellular senescence while mitigating its pro-tumorigenic and pro-aging effects.

Glioblastoma (GBM) is an aggressive malignant brain tumor, characterized by a poor prognosis and a limited response to chemoradiotherapy and immunotherapy. Increasing evidence indicates that the extracellular matrix (ECM), particularly collagen proteins, contributes to tumor progression and immune evasion. In this study, we identified COL1A2, COL6A2, COL8A1, and COL8A2 as survival-related genes that were overexpressed in GBM and significantly upregulated in short-term survivors. Subsequently, COL6A2 was verified to be associated with chemotherapy and immunosuppression. Functional assays demonstrated that COL6A2 promotes GBM cell proliferation, invasion, and chemoresistance. Cytometry by time-of-flight (CyTOF) and Tumor Immune Estimation Resource (TIMER) analysis revealed that high COL6A2 expression correlates with immunosuppressive features in the tumor microenvironment, particularly the accumulation of immature dendritic cells (DCs) and impaired cytotoxic T-cell activity. Mechanistically, COL6A2 silencing restored DCs' activation and enhanced the infiltration and function of effector immune cells. Our findings highlight COL6A2 as a key oncogenic and immunomodulatory ECM component in GBM and suggest that targeting collagen-mediated immune suppression may improve therapeutic outcomes in GBM patients.

Actinin-4 (gene name: ACTN4) is an actin-bundling protein implicated in cancer invasion and metastasis. This study evaluated whether ACTN4 amplification and actinin-4 protein expression were associated with osimertinib efficacy in epidermal growth factor receptor-mutant non-small cell lung cancer. We retrospectively analyzed 63 patients with epidermal growth factor receptor-mutant non-small cell lung cancer treated with osimertinib as first-line treatment. Immunohistochemistry was performed for pretreatment tumor tissues. Actinin-4 immunohistochemistry positivity was defined as positive staining of ≥ 30% tumor cells. In positive cases, ACTN4 amplification was assessed via fluorescence in situ hybridization. Progression-free survival and overall survival were compared across groups. Among 63 patients (median age: 73 years, 52 with Eastern Cooperative Oncology Group performance status 0–1, 63 with adenocarcinoma; epidermal growth factor receptor mutations: 19del/L858R/uncommon = 32/24/7), there were 33 and 30 actinin-4 immunohistochemistry-positive and actinin-4 immunohistochemistry-negative cases, respectively. The propensity score-weighted overall survival and progression-free survival were significantly shorter for actinin-4 immunohistochemistry-positive patients than for actinin-4 immunohistochemistry-negative patients (overall survival: hazard ratio, 2.76; 95% confidence interval, 1.02–7.45; progression-free survival: hazard ratio, 1.91; 95% confidence interval, 1.03–3.54). Among the 33 actinin-4 immunohistochemistry-positive cases, four showed positivity in ACTN4 fluorescence in situ hybridization. Overall survival and progression-free survival were numerically shorter for patients with ACTN4 positivity than for those with ACTN4 negativity in fluorescence in situ hybridization. The findings suggest that ACTN4 amplification and actinin-4 protein expression are prognostic markers for poor osimertinib efficacy in epidermal growth factor receptor-mutant non-small cell lung cancer.