Cancer Science最新文献

The Epstein-Barr virus (EBV) has two life cycles: latent and lytic. Previously, the latent cycle had been considered more relevant to EBV-associated epithelial malignancies, including nasopharyngeal carcinoma (NPC), whereas the lytic cycle, which ultimately leads to the death of host cells, had not been considered. However, recent studies have revealed that abortive lytic infections, in which the lytic cycle halts midway, avoids host cell death and contributes to tumorigenesis and tumor growth. However, the progression of the lytic cycle in NPC and its association with viral replication remain unclear. This study aimed to perform morphological analyses of EBV-positive NPC cell lines and clinical NPC biopsy samples using transmission electron microscopy, NanoSuit-correlative light and electron microscopy, and scanning ion conductance microscopy. Virion-like particles were observed in lytically induced EBV-positive NPC cell lines using time-lapse imaging to capture their release. These particles were also detected in clinical NPC samples using electron microscopy. Immunohistochemical analysis with the glycoprotein B (gB) antibody revealed a strong association between gB expression and poor prognosis. In conclusion, lytic infections with EBV replication occur in NPC, and the frequency of EBV replication is significantly associated with poor prognosis.

CD8⁺ T cell infiltration is essential for antitumor immunity across cancers while its clinical significance in gastric cancer (GC) remains unclear. This reflects molecular heterogeneity of GC, as defined by The Cancer Genome Atlas (TCGA) into four subtypes: Epstein-Barr virus (EBV)-positive, microsatellite instability (MSI), chromosomal instability (CIN), and genomically stable (GS), each with distinct immune features. We aimed to characterize distribution, clinical relevance, and immune associations of CD8⁺ T cell infiltration within this molecular framework. TCGA (n = 336) and Zhongshan Hospital (ZSHS, n = 455) cohorts were analyzed. CD8⁺ T cell infiltration and immune features were compared across TCGA subtypes. Prognostic and predictive significance of CD8⁺ T cells was evaluated in ZSHS cohort. CD8⁺ T cell infiltration was elevated in the EBV-positive and MSI subtypes (ZSHS: p = 0.026; TCGA: p < 0.001). In ZSHS cohort, high CD8⁺ T cell infiltration was associated with better overall survival (p = 0.040), particularly in the EBV-positive (p = 0.036) and CIN (p = 0.065) subtypes, but not in MSI (p = 0.440) or GS (p = 0.860). Notably, low CD8⁺ T infiltration predicted superior response to adjuvant chemotherapy in MSI patients (HR = 0.210, p = 0.022). Immune profiling revealed associations of CD8⁺ T cells with antigen presentation in EBV-positive, tertiary lymphoid structure signatures in CIN, and podoplanin+ cells in GS tumors, instead of neoantigen burden in MSI or pan-fibroblast TGFβ response signature in GS. CD8⁺ T cell infiltration demonstrates subtype-specific prognostic and therapeutic significance in GC-beneficial in EBV-positive and CIN tumors, and predictive of chemotherapy response in MSI with low infiltration, which accompanied by divergent immune features, reflecting heterogeneous immunological landscape of GC.

Retraction: A. Ghosh, S. Ghosh, G.P. Maiti, M.G. Sabbir, E.R. Zabarovsky, A. Roy, S. Roychoudhury, and C.K. Panda, "Frequent Alterations of the Candidate Genes hMLH1, ITGA9 and RBSP3 in Early Dysplastic Lesions of Head and Neck: Clinical and Prognostic Significance," Cancer Science 101, no. 6 (2010): 1511-1520, https://doi.org/10.1111/j.1349-7006.2010.01551.x. The above article, published online on 19 May 2010 in Wiley Online Library (http://onlinelibrary.wiley.com/), has been retracted by agreement between the journal Editor-in-Chief, Masanori Hatakeyama; the Japanese Cancer Association; and John Wiley & Sons Australia, Ltd. A third party contacted the journal with concerns about duplicated images in the figures. Following an investigation, multiple duplications were found throughout Figures 2A, 3B, 4B, and supporting information Figure 2. Additionally, portions of some figures were duplicated in later articles by some of the same authors: Figure 2A in Dasgupta et al. 2016 (https://doi.org/10.2217/fon-2016-0289); Figures 2A and 3A in Ghosh et al. 2011 (https://doi.org/10.1245/s10434-011-1991-x); and Figure 3A in Bhattacharya et al. 2013 (https://doi.org/10.1245/s10434-012-2715-6). Due to the scope of the errors, the editor has lost confidence in the results reported, and therefore the article must be retracted. The authors have been informed of this decision.

The incidence of early-onset cancers, commonly defined as cancers diagnosed before age 50 years, has been increasing globally over recent decades. In particular, the incidence of several early-onset digestive system cancers, including cancers of the esophagus, stomach, colorectum, liver, extrahepatic bile duct, gallbladder, and pancreas, has been reported to be increasing in multiple regions. To elucidate carcinogenic mechanisms and develop effective prevention, earlier detection, and treatment strategies, further evidence is needed on risk factors and clinical, pathological, and molecular characteristics. In this review, we summarize the current evidence on these characteristics, highlight shared and distinct features across organ sites, and discuss research opportunities to address the rising burden of early-onset digestive system cancers.

Osteosarcoma, the most common primary malignant bone tumor with poor prognosis, underscores the need for a deeper understanding of its molecular mechanisms. Recent studies have highlighted the importance of RNA modifications, including 5-methylcytosine (m5C), in cancer progression, yet the m5C modification landscape in osteosarcoma remains unexplored. Here, we performed transcriptome-wide profiling of m5C modifications in osteosarcoma using meRIP-seq and RNA-seq, analyzing four pairs of osteosarcoma and adjacent normal tissues. Furthermore, through conjunction analyses of meRIP-seq and RNA-seq data, we identified 637 genes with significant changes in both the m5C modification and mRNA levels. Among these, GPRC5B emerged as a key prognostic gene, with its high expression and m5C hypermethylation significantly associated with poor survival in osteosarcoma patients. Functional experiments demonstrated that GPRC5B suppresses apoptosis and promotes osteosarcoma cell proliferation and migration. Mechanistically, NSUN2-mediated m5C modification upregulates GPRC5B expression, and the anti-apoptotic effects of NSUN2 are primarily dependent on its ability to modulate GPRC5B m5C modification and expression. Knockdown of GPRC5B partially rescues the anti-apoptotic effects of NSUN2, highlighting the critical role of GPRC5B in osteosarcoma survival. Our study identified an m5C-dependent NSUN2-GPRC5B regulatory axis, providing insights into osteosarcoma progression and revealing its therapeutic potential.

The clinical significance of comprehensive genomic profiling (CGP) has been established in metastatic castration-resistant prostate cancer (PC). However, the role of genomic profiling in localized PC remains unclear. In this exploratory study, we evaluated somatic genomic alterations in localized PC using an in-house CGP platform to examine their associations with biochemical recurrence (BCR) and recurrence-free survival (RFS) after radical prostatectomy. DNA extracted from surgical specimens of 314 patients with localized PC was analyzed for alterations in 164 cancer-related genes. Six genes (PTEN, BRCA2, POLD1, ERBB3, MYC, and SETD2) were more frequently altered in patients who developed BCR in exploratory analyses. Patients harboring alterations in any of these genes (n = 96) showed higher pathological T stage, increased BCR rates (27.1% vs. 6.4%), and inferior RFS compared with alteration-negative patients (n = 218; p < 0.001). In multivariate analysis, the presence of these alterations was independently associated with worse RFS. Among individual genes, BRCA2 alteration, and particularly BRCA2-SETD2 co-alteration, were associated with unfavorable outcomes, although the latter finding was based on a limited number of cases. In patients who developed BCR, alterations were associated with shorter PSA doubling time and poorer outcomes after salvage radiotherapy, particularly in margin-negative cases; however, these subgroup analyses were based on small numbers and should be interpreted as hypothesis-generating. These findings suggest that somatic genomic alterations identified at prostatectomy are associated with early recurrence in localized PC. Further validation in independent cohorts is required to determine whether genomic profiling may contribute to future risk stratification and management strategies.

HER2-positive gastric cancer represents a distinct molecular subtype characterized by chromosomal instability, variable HER2 amplification, and substantial intratumoral heterogeneity. Although HER2-targeted therapies have improved clinical outcomes, therapeutic resistance commonly develops and limits long-term benefit. Established resistance mechanisms include bypass signaling through alternative receptor tyrosine kinases, reactivation of downstream pathways such as PI3K-AKT and MAPK, and dynamic changes in HER2 expression during treatment. These findings underscore the complexity of signaling regulation in HER2-driven tumors and indicate that mechanisms beyond receptor-level inhibition contribute to persistent oncogenic signaling. In this review, we examine the concept of transcriptional reinforcement within the HER2-RAS signaling network and discuss RUNX-dependent regulation of SOS1 as a downstream mechanism that may sustain signaling activity. We position this regulatory axis within the broader landscape of established resistance mechanisms and emerging therapeutic strategies, including antibody-drug conjugates, kinase inhibitors, and rational combination approaches. By integrating canonical resistance pathways with transcriptional regulation, this review provides a balanced perspective on how downstream regulatory processes may influence therapeutic response in HER2-positive gastric cancer.

Ovarian cancer is one of the most prevalent gynecologic malignancies worldwide. Dysregulated cell proliferation and angiogenesis are well-recognized to be involved in the pathogenesis of ovarian cancer. Nucleolar Protein 7 (NOL7), a novel RNA-binding protein, has been identified as a tumor suppressor and a key anti-angiogenetic factor. However, the function of NOL7 and its underlying molecular mechanisms in ovarian cancer remain unclear. In this study, we demonstrated that NOL7 expression was down-regulated in ovarian cancer tissues, and low NOL7 expression was associated with poorer prognosis in patients with ovarian cancer. Overexpression of NOL7 decreased cell viability, inhibited cell cycle entry and proliferation, and promoted apoptosis in OVCAR-3 and SKOV-3 cells. Additionally, NOL7 overexpression decreased VEGF-A level, increased TSP-1, and suppressed angiogenesis of human umbilical vein endothelial cells (HUVECs). Conversely, knockdown of NOL7 in ovarian cancer cells enhanced cell proliferation and angiogenesis, while reducing apoptosis. In vivo experiments further confirmed that NOL7 overexpression inhibited tumor growth and angiogenesis. Mechanistic studies revealed that NOL7 could bind to the 3'UTR of growth arrest and DNA damage inducible alpha (GADD45A), and overexpression of NOL7 up-regulated GADD45A expression by stabilizing GADD45A mRNA in ovarian cancer cells. The anti-cancer effects of the NOL7/GADD45A were mediated by inhibiting the phosphorylation of STAT3 at Ser727. Collectively, our findings indicate that NOL7 functions as a tumor suppressor in ovarian cancer and provide a novel therapeutic target for the treatment of ovarian cancer.

Chronic inflammation is a fundamental driver of cancer development, linking persistent immune activation to genomic instability, microenvironmental remodeling, and malignant transformation. In inflammation-associated malignancies such as colitis-associated cancer (CAC) and metabolic dysfunction-associated fatty liver disease-related hepatocellular carcinoma (MAFLD-HCC), sustained inflammatory signaling integrates tissue injury with oncogenic pathways to promote tumor initiation and progression. Importantly, these cancers arise through prolonged preneoplastic stages, during which dysregulated immune and inflammatory responses not only drive malignant transformation but also create opportunities for cancer prevention and early disease interception. CAC and MAFLD-HCC share convergent mechanisms, including IL-6/STAT3 and NF-κB activation, cytokine-driven survival signaling, and cooperation with genetic alterations in APC, KRAS, and TP53. A critical but often underappreciated dimension of this process is the failure of endogenous immunoregulatory systems that normally restrain excessive inflammation. Among these, the negative regulator of immune cells TIPE2 plays an important role in limiting inflammatory signaling, and its reduced activity contributes to the persistence of a tumor-promoting inflammatory microenvironment that supports both disease initiation and progression. This review synthesizes the shared inflammatory, immunologic, and microenvironmental mechanisms underpinning CAC and MAFLD-HCC, with a particular emphasis on how impaired immune regulation drives the transition from chronic inflammation to cancer. We further highlight therapeutic and preventive strategies targeting inflammation-driven pathways, underscoring the dual relevance of immune modulation for cancer prevention in chronic inflammatory disease and for the treatment of established malignancy.

Patients with triple-negative breast cancer (ER^-, PR^-, and HER2^-) are routinely treated with chemotherapies that induce DNA damage. However, around 30% of patients display resistance, owing largely to increased DNA repair mechanisms, upregulated to allow cancer cells to escape such therapies. PRMT1 and PRMT5, the two main protein arginine methyltransferases, are involved in several biological pathways, including DNA repair signaling, where they contribute to ensuring DNA integrity. We then speculated that targeting their enzymatic activity may sensitize TNBC cells to chemotherapeutic agents inducing DNA double-strand breaks. Here, we showed that PRMT1 and PRMT5 are recruited to DNA double-strand breaks upon doxorubicin or carboplatin treatment, two chemotherapies currently used to treat TNBC patients, and are preferentially involved in the homologous recombination pathway. By combining PRMT inhibitors with doxorubicin or carboplatin, we increased DNA double-strand breaks and impaired TNBC cell proliferation and clonogenicity in vitro and sensitized patient-derived models of TNBC to carboplatin treatment. These preclinical data provide a rationale for the clinical evaluation of PRMT inhibitors as combinatorial agents to improve chemotherapy efficacy for TNBC patients.