Cancer Science最新文献

Gastric cancer is a prevalent and clinically significant gastrointestinal malignancy worldwide. Gastric cancer is characterized by limited treatment efficacy and a high recurrence rate. In this study, we found that LGALS9 was highly expressed in gastric cancer and may contribute to disease progression by modulating the infiltration of CD8⁺ T cells. Genetic knockout of LGALS9 reversed T cell function, attenuated immunosuppression, and enhanced the cytotoxic activity of T cells to kill gastric cancer cells. Furthermore, miR-491-5p was identified as a potential suppressor in gastric cancer. The microRNA miR-491-5p regulated T cell-mediated immunity by targeting and inhibiting LGALS9, which was similar to the effect of LGALS9 knockout. Overall, the key target LGALS9 and its inhibitor miR-491-5p represent promising potential for treating gastric cancer.

Based on mRNA Expression Profiles of 57 Patient-Derived Colorectal Cancer Stem-Like Cell (CRC-SC) Lines Compared With Normal Colonic Epithelial Stem-Like Cells (NCE-SCs), we Identified Five CRC Subtypes. The First Subtype of CRC-SCs Showed Markedly Increased Expression of MUC12, PIGR, PLA2G2A, SLC4A4, and ZG16, Which Were Barely Detectable in the Other Subtypes. Importantly, Their Expression Correlated With Favorable Outcomes in Both the Discovery Cohort and Independent Two Test Cohorts From Public Databases. The Remaining Four Subtypes Showed High Expression of DEFA6, BST2, MAGEA6, or IGF2 Compared With NCE-SCs. Although the Expression of Each Gene Individually Influenced Patient Outcomes, Additional Co-Expressed Genes Within Each Subtype Were Also Associated With Prognosis. Furthermore, Integrating the Five Subtype-Specific Signatures Produced a Practical Prognostic Indicator, Designated as the General Colorectal Cancer Signature (GCS), and Provided Individualized Predictive Signatures for Each Patient. The Clinical Significance of GCS Was Further Validated in a Novel Orthotopic Xenograft Mouse Model, Which Recapitulated Patient Outcomes: CRC-SCs With Low GCS Scores Developed Distinct Liver and Lung Metastases, Whereas Those With High Scores Did Not. Apparent Associations Were Observed Between Activating RAS/RAF Mutations and BST2 Expression, and Between the Absence of SMAD4 Mutation and IGF2 Expression, but These Had no Significant Impact on Patient Survival, Suggesting That Driver Gene Mutations May Not Directly Influence GCS. Collectively, Our Findings Provide a Comprehensive Overview of Clinically Relevant Molecular Subtypes of CRC-SCs, Representing the Current Landscape of CRC Molecular Expression Subtypes. They Also Enable Rapid, Low-Cost Outcome Prediction and Suggest Potential Targets for Therapeutics Development.

Cancer-associated fibroblasts (CAFs) play important roles in the progression of hepatocarcinoma, while the mechanism underlying the pro-invasive transformation of normal fibroblasts (NFs) to CAFs remains poorly defined. lncDILC is a long non-coding RNA previously identified to be downregulated in liver cancer stem cells. Here, we found that lncDILC was also significantly downregulated in liver cancer CAFs compared with NFs. Knockdown of lncDILC in NFs facilitated their conversion into CAFs, and enhanced the ability to promote the migration and invasion of liver cancer cells. Conversely, overexpression of lncDILC in CAFs ameliorated their invasive characteristics, and suppressed cancer cell metastasis. Moreover, we found miR-6071 acted as a target of lncDILC, and functioned as a transcriptive suppressor of zinc finger protein 395 (ZNF395), which exhibited an inhibitory effect on the pro-invasive conversion of fibroblasts. Overexpression of ZNF395 reversed the pro-invasive effects induced by lncDILC knockdown. These results elucidate a pathway of lncDILC-miR-6071-ZNF395 that suppresses the NF-CAF conversion, suggesting new therapeutic targets for the strategies for the treatment of liver cancer.

BRAF V600E-mutant colorectal cancer (CRC) represents a distinct molecular subtype with considerable heterogeneity in tumor biology and therapeutic response. Although gene expression-based classifications (BM1/BM2 subtypes) provide valuable insights into underlying molecular and immune features, their clinical application is limited by the need for high-throughput sequencing. This study aims to establish an immunohistochemistry (IHC)-based classification system to enable practical subtype stratification and aid prognostic and therapeutic evaluation. Using two independent cohorts (public dataset, n = 218; institutional cohort, n = 122), we performed differential expression analysis, machine learning modeling, and clinical feasibility evaluation. Fourteen candidate markers were identified, and a decision tree algorithm selected CD8 and ARHGEF17 as optimal classifiers. Based on these markers, two IHC-based subtypes were established: iBM1 (CD8⁺/ARHGEF17⁻) and iBM2 (CD8⁻ with any ARHGEF17 expression or CD8⁺/ARHGEF17⁺). The IHC-based subtypes showed concordance with transcriptomic BM subtypes (training: 82.69%, κ = 0.55; validation: 72.22%, κ = 0.44; prospective: 83.33%, κ = 0.57). Transcriptomic profiling revealed enrichment of immune activation and epithelial–mesenchymal transition in iBM1, and cell cycle-related pathways in iBM2. In clinical validation, iBM1 was associated with poorer survival but greater sensitivity to immune checkpoint inhibitors. This IHC-based classification provides a practical and accessible approach for BM subtype stratification, reflecting underlying molecular and immune characteristics, and may support prognostic assessment and therapeutic decision-making in BRAF V600E-mutant CRC.

Investigating the phenotypic contribution of gene-spliced isoforms to tumor cellular heterogeneity can facilitate the development of innovative strategies for precision medicine. Serine protease 3 (PRSS3), a trypsin-like protease with four spliced variants (PRSS3-SVs: PRSS3-V1 to V4), plays diverse biological roles in cancer progression. Herein, we systematically analyzed the expression patterns and functional implications of PRSS3-SVs in gastric cancer (GC) using an integrative approach that combined bioinformatic analyses, CpG site-specific methylation detection, splice-specific qPCR, isoform-based methodologies, and multiple functional assays. Our findings revealed that differentially expressed PRSS3 isoforms, predominantly PRSS3-V1 and PRSS3-V2, are regulated by intragenic methylation and exert pleiotropic roles in GC. Overexpression of PRSS3 transcripts suppressed GC cell proliferation via the NF-κB signaling pathway, while exerting distinct effects on matrix metalloproteinase-associated cell migration and invasion. Clinically, patients with low PRSS3-V1 or high PRSS3-V2 expression exhibited poorer survival outcomes, and the expression difference between these two transcripts was identified as an independent prognostic indicator for GC patients. Epigenetically, differential methylation patterns within PRSS3 enabled stratification of GC patients into subgroups characterized by either high-methylation with low-expressed PRSS3-SVs or low-methylation with high-expressed PRSS3-SVs. The UHRF1/DNMT1 complex was found to mediate CpG site methylation and regulate PRSS3 transcripts, particularly silencing PRSS3-V1 through intragenic CpG methylation. This methylation pattern was associated with reduced survival rates and further validated its correlation with tumor metastasis in an independent cohort (n = 243). Our study elucidates that methylation-regulated alternative splicing contributes to phenotypic heterogeneity in GC, highlighting its potential advantage over differentially expressed genes in improving stratification strategies for precision oncology.

EXPRESSION OF CONCERN: M. Xue, H. Pang, X. Li, H. Li, J. Pan and W. Chen, “ Long Non-coding RNA Urothelial Cancer-associated 1 Promotes Bladder Cancer Cell Migration and Invasion by Way of the hsa-miR-145–ZEB1/2–FSCN1 Pathway,” Cancer Science 107, no. 1 (2016): 18–27, https://doi.org/10.1111/cas.12844.

This Expression of Concern is for the above article, published online on 06 November 2015 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editor-in-Chief, Masanori Hatakeyama; the Japanese Cancer Association; and John Wiley & Sons Australia Ltd. The Expression of Concern has been agreed upon due to several instances of image duplication identified between Figures 3b, 3f and 3 g of this article and images published in another paper by a different group of authors. These duplicated images were used to represent different scientific contexts. Although this article was published earlier, the authors did not respond to requests for comments or original data, therefore the authenticity of the images could not be verified. Furthermore, concerns were raised regarding Figures 2c, 2e, 4f and 5 g, where the western blot backgrounds appear unusually clean, deviating from typical experimental results. Due to the nature of these concerns and the absence of author response, the journal has decided to issue an Expression of Concern to inform and alert readers.

Obesity is a known risk factor for breast cancer, particularly in postmenopausal women. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) associated with body mass index (BMI). We conducted a case–control study with 1273 breast cancer cases and 4816 controls to examine whether five BMI-associated SNPs (rs939584 [TMEM18], rs4409766 [BORCS7-ASMT], rs6265 [BDNF], rs1927790 [HS6ST3], rs1421085 [FTO]) influence breast cancer risk through BMI-dependent or -independent pathways using mediation analysis. For postmenopausal breast cancer, rs6265 (C > T) exhibited a carcinogenic direct effect (odds ratio [OR] = 1.18, 95% confidence interval [CI]: 1.04–1.34) along with a protective indirect effect through changes in BMI (OR = 0.98, 95% CI 0.96–0.99), while rs1421085 (T > C) showed a carcinogenic indirect effect (OR = 1.03, 95% CI 1.00–1.05). No significant associations were observed for any SNPs in premenopausal breast cancer. These findings suggest that two BMI-associated genetic variants, rs6265 and rs1421085, influence postmenopausal breast cancer risk through changes in BMI, and that rs6265 also exerts a direct effect through pathways independent of BMI, providing insight into a previously uncharacterized association between obesity-related genetic factors and breast cancer and highlighting the potential utility of genetic profiling in personalized risk assessment.

Disruptions in lipid metabolism can hasten disease progression and impose a heavier burden on patients with nasopharyngeal carcinoma (NPC). We previously observed a positive correlation between zinc finger and BTB domain-containing protein 7A (ZBTB7A) and the long non-coding RNA antisense non-coding RNA in the INK4 locus (ANRIL), indicating a potential link between NPC and lipid metabolism; however, the underlying mechanism remains unclear. This study investigated primary NPC tissues that had significantly lower ZBTB7A expression than that in normal nasopharyngeal epithelium. Subsequent results confirmed that ANRIL promoted ZBTB7A expression by sponging miR-339-5p. ZBTB7A directly promoted ANRIL expression but inhibited SREBP1 and FASN expression. Thus, the ANRIL/miR-339-5p/ZBTB7A axis creates a positive feedback loop that suppresses the lipid pathway. Combining stable ANRIL overexpression with ZBTB7A shRNA effectively reduced lipid metabolism and the migratory, invasive, and metastatic capacities of NPC cells in vitro and in vivo. Furthermore, the SREBP inhibitor, fatostatin, enhanced the suppression of NPC metastasis. Our results indicated that interventions targeting ANRIL-shZBTB7A and SREBP inhibitors can effectively disrupt lipid metabolism and impair the invasive and metastatic properties of NPC cells. These findings provide valuable insights into the potential experimental strategies for inhibiting NPC metastasis.

WJOG15221M is Japan's first fully remote, investigator-initiated oncology trial, successfully enrolling 28 patients—36% remotely—by integrating trial access into the national CGP program and leveraging existing healthcare infrastructure without new digital tools. Targeting rare ALK fusion-positive tumors, the trial demonstrated that decentralized models can improve equity, efficiency, and continuity of care, offering a scalable path for future precision oncology trials.

Next-generation sequencing-based comprehensive cancer genomic profiling is promising in cancer management; however, most studies rely on tumor-only DNA panels from single institutions. In 2023, Japan introduced an insurance-covered cancer genomic profiling test—the GenMine TOP Cancer Genome Profiling System—a dual DNA–RNA panel with matched tumor–normal testing. This study evaluated its utility compared to a conventional DNA-only test (FoundationOne CDx) in managing sarcoma patients using a nationwide genetic profiling database provided by the Center for Cancer Genomics and Advanced Therapeutics. This study included 1046 patients registered between August 2023 and October 2024. The dual DNA–RNA test identified significantly more fusion genes (20.3% vs. 7.4%, p < 0.001) and therapeutically targetable kinase fusions (3.5% vs. 1.2%, p = 0.019) than the DNA-only test. Among patients with translocation-related sarcomas, histology-specific fusion genes were identified in 77.5% using the dual panel, compared to 40.0% with the DNA-only panel (p < 0.001). In non-gastrointestinal stromal tumor sarcomas, the dual test showed a trend toward higher rates of genotype-matched therapy (4.3% vs. 2.6%, p = 0.25) and a significantly higher rate of molecular targeted therapy (4.3% vs. 1.5%, p = 0.03). Additionally, 5.7% of patients had pathogenic germline variants identified through tumor–normal matched analysis. These findings suggest that a dual DNA–RNA panel with matched tumor–normal testing may improve diagnostic accuracy and inform treatment decisions in the routine clinical management of sarcoma.