Translational cancer research最新文献

Background: Because of the high malignancy and subtle early symptoms of hepatocellular carcinoma (HCC), most patients lose the opportunity for surgery and opt for drug therapy. However, the current drugs for HCC treatment remain suboptimal, underscoring the urgent need to develop a novel anti-HCC agent. Curcumin is a natural chemical compound that has anti-cancer effects on various tumor cells, attracting sustained attention from researchers and clinicians. The present study aims to further elucidate curcumin's anti-HCC mechanisms, thereby offering a promising therapeutic candidate for HCC patients.

Methods: The viability of HCC cells was evaluated by Cell Counting Kit-8 (CCK-8) assay. The levels of glutathione (GSH), malondialdehyde (MDA), and total iron in the cells were detected by biochemical kits. The levels of reactive oxygen species (ROS) and Fe²⁺ in the cells were detected by fluorescent probes. The protein expressions of protein kinase RNA-like endoplasmic reticulum kinase (PERK), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and glutathione peroxidase 4 (GPX4) in the cells were detected by western blotting.

Results: Curcumin exerted a notably suppressive impact on HCC cells, which could be reversed by ferrostatin-1 (Fer-1) and desferrioxamine (DFO). By detecting cellular metabolic products, we observed an increase in total iron, Fe²⁺, MDA, ROS, and a reduction in GSH levels in HCC cells after treatment with curcumin, and these effects could be attenuated by Fer-1. Western blot analysis showed that curcumin significantly downregulated GPX4 levels in HCC cells while upregulating PERK, Nrf2 and HO-1 expression. Additionally, using PERK inhibitor, HO-1 inhibitor, and endoplasmic reticulum (ER) stress inhibitor could partially reverse the inhibition of HCC cells viability by curcumin and alleviate the reduction of GPX4 expression caused by curcumin.

Conclusions: Curcumin may induce ferroptosis in HCC cells through the PERK/Nrf2/HO-1 signaling pathway, thereby exerting its anti-cancer effects, suggesting that curcumin could potentially be used as a drug for treating HCC.

Background: Lung adenocarcinoma (LUAD), recognized as one of the most lethal variants of lung cancer, presents significant treatment challenges and is associated with a poor prognosis. In this study, we used data from The Cancer Genome Atlas (TCGA) to investigate the functional implications of N6-methyladenosine (m6A)-related genes in LUAD.

Methods: The clinical characteristics and RNA-sequencing data of patients with LUAD were obtained from the TCGA-LUAD database. Through a comprehensive analysis, we identified the genes related to m6A modifications and with prognostic value for patients with LUAD.

Results: In this study, we found that 10 out of 13 m6A genes (including WTAP, ZC3H13, FTO, RBM15, METTL14, METTL3, HNRNPC, KIAA1429, YTHDF1, and YTHDF2) exhibited differential expression in patients with LUAD. Our objective was to determine the correlation between m6A methylation-related genes. Notably, coexpression patterns were observed between FTO and YTHDC2, while RBM15 demonstrated a significant positive correlation with the reader gene KIAA1429. In contrast, a negative correlation was identified between the methylation eraser FTO and the reader HNRNPC. We retrieved expression profiles of these genes from samples available in TCGA database. Through multivariate Cox regression analysis, we identified three m6A methylation-related genes (HNRNPC, KIAA1429, and RBM15) and included them in a prognostic model.

Conclusions: In patients diagnosed with LUAD, there is a significant correlation between m6A-related gene expression and tumor classification. Our study constructed a novel signature associated with m6A modifications, which can serve as a promising prognostic indicator for LUAD. These findings may provide valuable insights into diagnosis and therapeutic strategies for patients with LUAD.

Background: Cholecystectomy is widely used to treat gallbladder disease, but its link to colorectal cancer (CRC) remains controversial. This study aimed to assess the association between cholecystectomy and CRC by combining cross-sectional analysis with Mendelian randomization (MR).

Methods: We analyzed 12,490 adults from the National Health and Nutrition Examination Survey (NHANES) 2017-2023 for the association between cholecystectomy and CRC. Weighted logistic regression models with progressive adjustments were applied: Model 1 was unadjusted, Model 2 accounted for sociodemographic factors, while Model 3 was further controlled for lifestyle, diet, and comorbidities. Subgroup and sensitivity analyses were conducted to evaluate the results' robustness. MR analysis further complemented the observational analysis and evaluated potential causality.

Results: In the NHANES sample, cholecystectomy was not significantly associated with CRC after full adjustment [Model 3: odds ratio (OR) =2.06; 95% confidence interval (CI): 0.93-4.55; P=0.07], although crude and partially adjusted models showed positive associations (Model 1: OR =3.77, 95% CI: 2.08-6.83, P<0.001; Model 2: OR =2.35, 95% CI: 1.23-4.51, P=0.01). The association remained non-significant across multiple sensitivity analyses and was consistent across population subgroups. MR analysis further indicated no causal link between cholecystectomy and CRC risk.

Conclusions: No statistically significant overall association was observed between cholecystectomy and CRC in our analysis.

Background: Currently, immune checkpoint inhibitors (ICIs) and other immune-activating strategies represent the main approach to cancer treatment; however, immune resistance in many solid tumors limits the immune therapy response and can cause strong toxic side effects. In solid tumors, the development of effective anti-tumor immune responses is hindered by limited immune cell infiltration and an immunosuppressive tumor microenvironment (TME). To overcome current immunotherapy challenges, we proposed a novel approach providing local and stable treatment levels to activate or revitalize anti-tumor immunity, to achieve the effect of TME infiltration and sustained presence in solid tumors.

Methods: Using genetic engineering methods to synergistically activate immunity in the TME, we programmed macrophages to express therapeutic payloads, including interleukin (IL)-12 and the signal regulatory protein alpha-Fragment crystallizable fusion protein (SIRPα-Fc), a CD47 ICI. Co-culture studies were performed to evaluate the effects of the genetically engineered macrophages (GEMs) on the T cells and GEMs themselves in vitro. We evaluated the tumor response, cellular response, and cytokine response. The GEMs were administered to a mouse model of tumor-cell transplantation, where they were retained and expressed as lentiviral payloads.

Results: The IL-12 secreted by the GEMs provided effector signals for T cells, thereby enhancing the tumor resident anti-tumor macrophages and CD8⁺T-cell populations. In addition, the secretion of SIRPα-Fc enhanced the phagocytic activity of the macrophages toward tumor cells and promoted their antigen presentation function. The combination therapy of dual proteins produced significant synergistic effects in solid tumor models and further enhanced memory immunity. The GEMs also improved the efficacy of ICIs in the ICI-resistant gene engineering tumor models and demonstrated significant anti-tumor efficacy in the metastasis models.

Conclusions: Our study showed the potential clinical application of GEMs in the treatment of tumors.

Background and objective: Immune checkpoint inhibitors (ICIs) have transformed the treatment of advanced renal cell carcinoma (aRCC), leading to the adoption of combination regimens. Either dual ICI regimens or ICI plus tyrosine kinase inhibitor (TKI) are now established as the first-line standard treatment. While phase III trials have demonstrated significant survival benefits of ICI combination therapy over TKI monotherapy, real-world reports, particularly from Japan, have revealed variable outcomes influenced by patient and tumor characteristics. Treatment-related adverse events (TRAEs), including immune-related adverse events (irAEs), are increasingly recognized not only as safety concerns but also as potential predictive biomarkers. In this review, we aimed to compare the clinical trials and real-world outcomes of combination immunotherapy with a focus on Japanese patients, and to examine the prognostic significance of TRAEs.

Methods: A narrative literature review was conducted using PubMed and Scopus for English-language studies published between April 2018 and August 2025. Search terms included the following MeSH terms: kidney neoplasm, carcinoma, renal cell, immunotherapy, nivolumab, ipilimumab, pembrolizumab, avelumab, axitinib, cabozantinib, lenvatinib, and biomarkers; and free-text terms: advanced, combination immunotherapy, irAEs, and TRAEs. Phase III trials and retrospective/prospective real-world studies were included, and abstracts and case reports were excluded.

Key content and findings: Nivolumab plus ipilimumab (NIVO + IPI) and various ICI + TKI regimens (avelumab + axitinib, pembrolizumab + axitinib, nivolumab + cabozantinib, pembrolizumab + lenvatinib) have shown superior efficacy to sunitinib in pivotal trials. Real-world Japanese cohorts often include older patients with poor performance status and non-clear cell RCC (ncc-RCC), leading to shorter overall survival (OS) and progression-free survival (PFS), despite comparable objective response rates (ORRs) to trials. Several studies on patients treated with NIVO + IPI have demonstrated that TRAEs/irAEs are associated with improved ORR and OS, with multivariate analyses identifying them as independent, favorable prognostic factors. However, this correlation was less consistent in ICI + TKI regimens, in which toxicity may be derived from either component.

Conclusions: Combination immunotherapy offers substantial benefits for aRCC; however, real-world outcomes can differ from trial data owing to patient heterogeneity. TRAEs show promise as prognostic markers in NIVO + IPI but require further validation in ICI + TKI. Prospective multicenter registries with standardized adverse event reporting, coupled with translational studies, are needed to refine regimen selection and personalized therapy.

The proliferation of publicly available imaging datasets, combined with widespread access to computational power, has boosted research in neuroscience, neurobiology, and systems biology while inspiring projects centered on building atlases. Atlases are methodological tools that provide global overviews of detailed thematic information, are usually organized in grids with assigned resolution to facilitate inference, and offer a reliable knowledge base from multimodal evidence data. Two critical goals have been generally addressed through atlases: (I) warehousing baseline information of normal anatomical structures under physiological (i.e., non-pathological) conditions; and (II) establishing a reference for typical anatomy across demographic groups by aggregating high-resolution imaging data that cover extensively diverse populations. Compared to more traditional atlases often referring to homogeneous groups of populations, the recent atlas developments have leveraged data multimodality and utilized machine learning (ML) and artificial intelligence (AI) tools for inference purposes. Together with the possibility of representing normal variation within specific demographic cohorts and gaining usability and reliability in clinical applications, data multimodality is particularly impactful in precision oncology and personalized therapy. This review discusses the translational potential of atlases in cancer studies through their property of integrating multiple types of cancer data and inspiring predictive learning algorithms that account for the correlations between anatomical and imaging features with genetic and omics markers.

Background: This study investigates the expression of ubiquitin-conjugating enzyme E2S (UBE2S) as a significant prognostic marker for skin cutaneous melanoma (SKCM) and its association with the tumor microenvironment (TME). The research aimed to advance precision oncology by identifying novel therapeutic targets for SKCM.

Methods: UBE2S expression in normal skin and SKCM tissues was analyzed using Sangerbox, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and DiSignAtlas databases. Its relationship with SKCM prognosis was examined through GEPIA2, Sangerbox, Ualcan, and TISIDB. The Human Protein Atlas (HPA) database assessed UBE2S protein expression and localization in cancerous and adjacent tissues, normal skin single-cell subgroups, and various cell lines. The CellTracer database explored UBE2S expression and cell differentiation in SKCM single-cell subgroups. CancerSEA and CellTracer databases were utilized to explore UBE2S's role in SKCM single-cell analysis, while TISIDB examined its correlation with the TME.

Results: Data from various databases showed significantly higher UBE2S messenger RNA (mRNA) and protein levels in cancer tissues compared to normal tissues. UBE2S, mainly found on the cell membrane, is linked to poor patient prognosis (P<0.05). UBE2S was highly expressed in normal skin, SKCM immune cells, and non-immune cell subpopulations, with a strong correlation to immune-related indicators in the SKCM TME (P<0.001). The A-431 and SK-MEL-30 cell lines ranked 7th and 12th in UBE2S expression among all cell lines. UBE2S expression was also positively linked to proliferation, invasion, metastasis, cell cycle, and quiescence (P<0.05).

Conclusions: UBE2S has the potential to serve as a prognostic biomarker for SKCM, demonstrating a strong correlation with cellular infiltration within the SKCM TME and the functional status of individual cells.

Background: Pan-cancer analyses focused on the immunological significance and therapeutic potential of microspherule protein 1 (MCRS1) remain unreported. This study aims to define the pan-cancer immunological significance and therapeutic potential of MCRS1, with focused mechanistic dissection of its epigenetic-driven roles in hepatocellular carcinoma (HCC) progression.

Methods: An integrated multi-omics approach was employed, encompassing bulk transcriptomics, single-cell RNA-sequencing (scRNA-seq), and functional validation. Data from public repositories including The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and the Human Protein Atlas (HPA) were analyzed using tools such as SangerBox, University of Alabama at Birmingham Cancer (UALCAN), Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier plotter, and Tumor Immune Estimation Resource (TIMER). Expression patterns, prognostic significance, epigenetic regulation, interactions with immune infiltrates, and functional impact of MCRS1 on HCC malignant phenotypes were comprehensively assessed.

Results: MCRS1 was upregulated in 24 malignancies (including HCC) and correlated with advanced stage, poor differentiation, and reduced survival (P<0.001). Hypomethylation of the MCRS1 promoter drove its overexpression in HCC, strongly associating with tumor progression. MCRS1 recruited M2-polarized macrophages (Rho =0.423, P=1.90e-16) and myeloid dendritic cells (Rho =0.560, P=7.87e-30). Spatial mapping confirmed MCRS1⁺/CD68⁺ macrophage colocalization in tumor niches. MCRS1 knockdown suppressed HCC proliferation, migration, and invasion. scRNA-seq revealed MCRS1 enrichment in immunosuppressive clusters expressing VEGFA/TGFB1.

Conclusions: Our pan-cancer analysis identifies MCRS1 as a key node linking epigenetic dysregulation and immunosuppression in HCC. Its promoter hypomethylation-driven overexpression is associated with an M2 macrophage-polarized, immune-resistant niche. These findings suggest that targeting MCRS1 may represent a strategy to overcome resistance to current immunotherapies.

Background: Breast cancer is a common malignant tumor posing a serious threat to women's health, with persistently high incidence and mortality rates. Among its subtypes, human epidermal growth factor receptor 2 (HER2)-positive breast cancer is highly invasive, prone to recurrence, and associated with a poorer prognosis. The aim of this study was to evaluate the real-world efficacy and safety of pyrotinib in the treatment of HER2-positive advanced breast cancer in the Xinjiang Uygur Autonomous Region of China.

Methods: A total of 81 patients with HER2-positive advanced breast cancer who received first-line treatment of pyrotinib in the Affiliated Tumor Hospital of Xinjiang Medical University from May 2019 to January 2024 were included in this study. The patients' progression-free survival (PFS), objective response rate (ORR), and drug-related adverse events (AEs) were retrospectively analyzed and evaluated.

Results: The median PFS (mPFS) of the patients was 20.5 months [95% confidence interval (CI): 18.98-22.02], and the median overall survival (OS) was not reached. The mPFS of the patients without brain metastases was 20.7 months (95% CI: 19.18-22.21), the mPFS of the patients with untreated or active brain metastases was 22.0 months (95% CI: 18.56-25.43), and the mPFS of patients with treated and stable brain metastases was 11.1 months (95% CI: 9.06-13.14). The differences between the three groups were statistically significant (P<0.001). The mPFS of the patients with an Eastern Cooperative Oncology Group (ECOG) performance score of 0 was 21.0 months (95% CI: 20.31-21.69), whereas for those with a score of 1 or higher, it was 13.1 months (95% CI: 11.37-14.83), representing a statistically significant difference (P=0.002). The main AE was diarrhea, with an incidence of 71.6% (58/81), with grade 1 accounting for 34.6% (28/81), grade 2 for 27.2% (22/81), and grade 3 for 9.9% (8/81). No grade 4 diarrhea was observed.

Conclusions: Pyrotinib showed good antitumor activity in the treatment of patients with HER2-positive advanced breast cancer and displayed a degree of efficacy in patients with brain metastases. The main adverse reaction was diarrhea, which was mostly low to moderate in severity, and the incidence of high-grade AEs was generally low, with controllable toxicity.

Background: Colorectal cancer is a leading cause of cancer-related mortality worldwide, with liver metastases occurring in nearly 50% of patients during the disease course. This study aims to compare survival outcomes, including overall survival (OS) and disease-free survival (DFS), and tumor recurrence risks between thermal ablation and surgical resection for colorectal liver metastases (CRLMs), incorporating recent randomized trial data to provide updated recommendations.

Methods: Searches were performed across PubMed, Embase, and Web of Science to identify relevant studies comparing thermal ablation with surgical resection for CRLM. Meta-analyses were performed using random-effects models for pooled hazard ratios (HRs) and risk ratios (RRs) with corresponding 95% confidence intervals (CIs). Heterogeneity was assessed using I² statistics, and publication bias was evaluated using funnel plot asymmetry and Egger's regression test.

Results: A total of 29 studies involving 5,719 patients were included in the analysis. Thermal ablation was associated with significantly worse OS compared to surgical resection (HR =1.56; 95% CI: 1.25-1.94). Subgroup analyses revealed that radiofrequency ablation (RFA) notably increased mortality risk (HR =1.63; 95% CI: 1.26-2.51), whereas microwave ablation (MWA) demonstrated non-inferiority to surgical resection. For tumors <3 cm, no significant survival difference was observed between the interventions, but for lesions ≥3 cm, surgical resection showed improved survival (HR =1.49; 95% CI: 1.16-1.91). DFS analysis showed a higher recurrence risk with thermal ablation (HR =1.93; 95% CI: 1.45-2.57). Local tumor recurrence was over three times more frequent following ablation compared to resection (RR =3.03; 95% CI: 1.99-4.61), while distal recurrence rates did not differ significantly. Heterogeneity was substantial for survival outcomes (I²=68.0%) and recurrence outcomes (I²=74.9%).

Conclusions: Surgical resection remains superior to thermal ablation in terms of OS and DFS, particularly for larger lesions (>3 cm). While thermal ablation, especially MWA, offers a promising alternative for smaller lesions, its increased risk of local recurrence warrants careful patient selection and precise procedural execution. These findings underscore the need for personalized, lesion-specific approaches to CRLM management, integrating advancements in ablation technology and hybrid surgical-ablation strategies.