American journal of cancer research最新文献

Pancreatic cancer, a lethal malignancy with a 5-year survival rate below 9%, is characterized by an immunosuppressive tumor microenvironment that facilitates immune evasion. Despite the clinical urgency, the molecular mechanisms driving the scarcity of cytotoxic T lymphocyte (CTL) infiltration, a hallmark of its immunologically 'cold' phenotype, remain poorly defined, which represents a critical barrier to developing effective immunotherapies. In this study, we identify ubiquitin-specific peptidase 18 (USP18) as a critical regulator of major histocompatibility complex I (MHC-I) degradation that enables immune evasion in pancreatic ductal adenocarcinoma (PDAC). In clinical PDAC samples, USP18 protein levels were significantly elevated and inversely correlated with MHC-I expression, independent of transcriptional regulation. Functionally, USP18 knockdown enhanced MHC-I surface expression, promoted CD8⁺ T cell activation, and sensitized PDAC cells to immune-mediated killing, while USP18 overexpression suppressed MHC-I expression and facilitated immune escape. Mechanistically, USP18 accelerated the lysosomal degradation of MHC-I through selective autophagy, a process dependent on the neighbor of BRCA1 gene 1 (NBR1). USP18 directly bound and stabilized NBR1 by deubiquitinating it, thereby inhibiting its proteasomal degradation. Collectively, our findings unveil the USP18-NBR1-MHC-I axis as a central mechanism driving immune evasion in PDAC and highlight USP18 as a promising therapeutic target for overcoming resistance to immunotherapy.

Background: The incidence of brain metastases is increasing, and surgical resection remains a key treatment modality. However, postoperative intracranial recurrence - including local recurrence (LR), distant brain recurrence (DBR), and leptomeningeal disease (LMD) - significantly impacts patient prognosis. Previous studies have predominantly focused on single tumor types and lacked systematic analyses of recurrence patterns and risk factors.

Objectives: This study aimed to investigate the incidence, temporal distribution, and independent risk factors associated with distinct postoperative recurrence patterns.

Methods: Demographic, imaging, surgical, pathological, and post-treatment data from 198 patients who underwent resection of brain metastases were retrospectively analyzed. Kaplan-Meier and Fine-Gray models were used to evaluate recurrence timing, and a multinomial logistic regression model (using the non-recurrence group as reference) was applied to identify risk factors. A cause-specific Cox proportional hazards model was further employed to analyze recurrence timing while considering death as a competing risk.

Results: Intracranial recurrence occurred in 119 patients (60.1%). LR was the most frequent type (47.1%), whereas LMD developed latest (median 14.6 vs. 9.1 months for LR, P<0.05). Independent risk factors for LR included tumor size >3 cm, proximity to the ventricle or dura mater, intraoperative tumor rupture, and omission of cavity radiotherapy. DBR was associated with ≥3 brain metastases, extracranial metastases, and lack of whole-brain radiotherapy. LMD was linked to primary breast cancer, intraoperative rupture, meningeal invasion, and delayed radiotherapy (≥4 weeks). The areas under the curve (AUCs) of predictive models were 0.78 for LR, 0.74 for DBR, and 0.81 for LMD. Stratified analysis by tumor type revealed that lung cancer most commonly exhibited LR (30.0%), followed by DBR (21.7%), with LMD being least frequent (5.8%); breast cancer demonstrated the highest incidence of LMD (21.4%). Multivariable analysis identified tumor size >3 cm and ventricular/dural proximity as independent risk factors for LR in lung cancer, while ≥3 metastases predicted DBR. In breast cancer, human epidermal growth factor receptor 2 positivity and delayed radiotherapy (≥4 weeks) were associated with LMD. Predictive model AUCs ranged from 0.65 to 0.83, indicating that recurrence patterns and risk factors are tumor type-specific.

Conclusion: Postoperative intracranial recurrence after surgical resection of brain metastasis demonstrates distinct incidence rates, temporal profiles, and independent risk factors. These recurrence patterns and associated risks are highly dependent on the tumor type.

Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cancer and is characterized by high aggressiveness and a propensity for metastasis. Although the targeted therapeutic drug sorafenib has achieved significant progress in the treatment of ccRCC, drug resistance remains a major challenge. We found that NRP2 is significantly upregulated in sorafenib-resistant ccRCC cells and is highly expressed in ccRCC tissues, where it promotes cell proliferation, migration, and invasion. These effects are mediated through the NRP2/NF-κB/TNFα axis, which also underlies NRP2-induced sorafenib resistance. Targeting this axis with the TNF-α inhibitor adalimumab effectively reversed sorafenib resistance in ccRCC, suggesting a promising therapeutic strategy.

Objective: To investigate the predictive value of serum soluble T-cell immunoglobulin and mucin domain-3 (sTIM-3), transforming growth factor-beta 1 (TGF-β1), and vasohibin-1 in the lymphatic metastasis of oral squamous cell carcinoma (OSCC).

Methods: A total of 220 OSCC patients admitted to Shanxi Provincial Cancer Hospital between January 2022 and December 2024 were included in this retrospective study. The patients were divided into training and validation sets at a 7:3 ratio (154 and 66 patients, respectively). Baseline characteristics, blood test results, and tumor marker levels were compared between the two groups. Predictors were screened, and column-line graphical models were constructed using Least Absolute and Residual Selection Operator (LASSO) regression and multifactorial logistic regression. The performance of the model was then evaluated using ROC curves, calibration curves, and decision curve analysis.

Results: LASSO regression identified the following variables as predictors: clinical stage, tumor diameter, squamous cell carcinoma antigen (SCC-Ag), and carcinoembryonic antigen, sTIM-3, TGF-β1, and vasohibin-1. Multifactorial logistic regression analysis revealed that clinical stage, SCC-Ag, sTIM-3, TGF-β1, and vasohibin-1 were independent predictors of lymphatic metastasis. The AUC of the nomogram model was 0.868 in the training set and 0.863 in the validation set, indicating strong discriminatory ability. Calibration curves showed good agreement between predicted and actual values, with p-values for goodness of fit of 0.865 (training set) and 0.872 (validation set). Decision curve analysis demonstrated significant clinical benefit, with maximum benefit rates of 39.41% in the training set and 37.80% in the validation set.

Conclusion: sTIM-3, TGF-β1, and vasohibin-1, along with clinical stage and SCC-Ag, are independent predictors of lymph node metastasis in OSCC patients. The risk prediction model based on these variables demonstrates strong predictive ability.

Objective: To validate the anti-hepatocellular carcinoma (HCC) efficacy of Coreopsis tinctoria Total Flavonoids (CTFs) and explore its underlying mechanisms using a comprehensive approach integrating network pharmacology and experimental verification, thereby supporting its potential as a multi-target therapeutic agent for liver cancer.

Methods: Potential targets of CTFs were retrieved from Traditional Chinese Medicine Systems Pharmacology (TCMSP) Database, while HCC-related targets were collected from GeneCards, OMIM, and DrugBank. Common targets were identified using VENNY2.1, and protein-protein interaction (PPI) networks were constructed via STRING. Functional Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using DAVID. A "CTFs-HCC-target-pathway" network was built with Cytoscape to identify key components and core targets. Molecular docking was performed using Autodock Vina. The Differential expression of key targets between HCC and normal tissues was visualized using boxplots, and prognostic relevance was evaluated by Kaplan-Meier survival analysis. In vitro assays, including CCK-8, live/dead staining, colony formation, flow cytometry, qPCR, were used to evaluate proliferation, viability, reactive oxygen species (ROS) levels, cell cycle distribution, and gene expression. A zebrafish xenograft model was established to determine the minimum toxic concentration (MTC) and evaluate tumor inhibition through fluorescence imaging and HE staining.

Results: Network analysis identified 27 bioactive components and 318 putative targets of CTFs, with 32 associated with HCC. Core targets included Caspase-3, P53, MAPK1, Bcl-2 and Bax, primarily interacting with quercetin, (-)-Epigallocatechin (EGCG), fisetin, acacetin, luteolin, and kaempferol. Molecular docking confirmed strong binding affinities between these compounds and core targets. Pro-apoptotic genes (Bax, Caspase-3, P53) were upregulated in HCC tissues, and low expression of Bax/Caspase-3 correlated with poor survival. CTFs treatment further enhanced expression of Bax, p53 and Caspase-3, suppressed Bcl-2 while increased the Bax/Bcl-2 ratio. In vitro, CTFs inhibited HepG2 proliferation, promoted LO2 growth, induced ROS production, G₂/M and S-phase arrest and apoptosis. In vivo, CTFs significantly suppressed tumor growth in zebrafish xenografts.

Conclusion: CTFs exert anti-HCC effects through multi-target regulation of apoptosis-related genes and multiple signaling pathways, effectively inhibiting cancer cell proliferation.

Myeloproliferative neoplasms are clonal hematopoietic disorders characterized by excessive mature blood cells production, dysregulated JAK-STAT signaling, and increased angiogenesis. Current therapies, such as ruxolitinib, improve symptoms but lack disease-modifying effects. This study aimed to evaluate the cytotoxic and mechanistic effects of STK405759, a fully synthetic microtubule targeting agent in myeloproliferative neoplasms models. Three representative myeloproliferative neoplasms cell lines (HEL, SET-2, MEG-01) were treated with STK405759 as a single agent or in combination with ruxolitinib. Cytotoxicity was evaluated by XTT assays, apoptosis via Annexin V/propidium iodide staining, and cell cycle distribution by flow cytometry. Microtubule dynamics were examined by immunoblotting and immunofluorescence. Apoptosis-related proteins, cytokine secretion and JAK-STAT pathway activation were analyzed using antibody arrays. STK405759 showed potent cytotoxicity in JAK2 V617F-positive HEL and SET-2 cells and BCR-ABL1-positive MEG-01 cells. Combination with ruxolitinib yielded synergistic effects in HEL and SET-2 cells. Mechanistically, STK405759 disrupted microtubule organization, reduced α- and β-tubulin polymerization and acetylated α-tubulin, leading to G2/M arrest and apoptosis. In SET-2 cells, STK405759 significantly increased STAT1 phosphorylation while causing its retention in the cytoplasm. Treatment also decreased VEGF secretion in both monocultures and HS-5 stromal co-cultures and induced IL-1β in co-cultures. These findings demonstrate that STK405759 exerts potent cytotoxic activity, disrupts microtubules, modulates STAT1 signaling, reduces VEGF secretion, and induces a distinct cytokine profile, while synergizing with ruxolitinib, supporting its further preclinical development as a potential therapeutic strategy in myeloproliferative neoplasms.

This study aimed to explore the predictive value of contrast-enhanced ultrasound (CEUS) parameters combined with inflammatory-nutritional indices for recurrence and survival following radiofrequency ablation (RFA) in early-stage hepatocellular carcinoma (HCC). It also sought to provide evidence-based personalized treatment strategies for clinical practice. A retrospective analysis was conducted on the clinical data of 263 HCC patients who underwent RFA at Henan Provincial People's Hospital from January 2021 to June 2022. Comprehensive data on tumor angiogenesis and hemodynamics were collected using CEUS, and the Prognostic Inflammatory and Nutritional Index (PINI) was calculated. Multivariate Cox analysis was performed to assess the predictive efficacy of these parameters for tumor recurrence and long-term survival. The study found that a low PINI score was associated with a higher risk of postoperative tumor recurrence and mortality. Among the CEUS parameters, time to peak, peak intensity, enhancement rate, and PINI were significantly correlated with tumor recurrence and patient survival. The combined scoring system, integrating CEUS parameters and PINI (CEUS-PINI), effectively distinguished different risk groups and was significantly associated with both recurrence-free survival and overall survival. In conclusion, the combination of CEUS parameters and PINI provides a simple, non-invasive prognostic tool that helps predict recurrence risk and survival outcomes following RFA in early-stage HCC. This combined assessment system can aid in the early identification of high-risk patients and facilitate the development of postoperative monitoring and management strategies.

In Taiwan, approximately half of ovarian cancer cases are diagnosed at an early stage. Although platinum-based adjuvant chemotherapy is recommended for high-risk early-stage epithelial ovarian cancer (EOC), the optimal regimen remains uncertain. Paclitaxel (PTX) is widely used based on evidence from advanced-stage disease, yet data comparing PTX and cyclophosphamide (CTX) in early-stage settings are limited. We retrospectively reviewed medical records of FIGO stage I-II EOC patients with high-risk features who received post-operative platinum-based chemotherapy with either PTX or CTX at Kaohsiung Chang Gung Memorial Hospital from January 2011 to December 2018. We analyzed associations between clinical characteristics, chemotherapy regimen, and survival outcomes. Baseline characteristics were compared using Chi-square tests for categorical variables and independent two-sample t-tests for continuous variables. Survival analysis was conducted using Kaplan-Meier and Cox regression methods. A total of 125 patients were included (mean age: 50.0 years), of whom 27.2%, 48.8%, and 24.0% were diagnosed with FIGO stage IA/IB, IC, and II, respectively. Clear cell (37.6%) and endometrioid (27.2%) carcinomas were the most common histologies. Eighty-one patients (64.8%) received PTX, and 44 (35.2%) received CTX. Multivariate analysis identified FIGO stage as the only independent predictor of disease-free survival (DFS; HR, 3.39; P = 0.046), while the chemotherapy regimen was not significantly associated with DFS (HR 2.58; P = 0.111). Since stage I patients constituted the majority of the cohort, we performed a subgroup analysis restricted to stage I patients, which similarly demonstrated no significant DFS difference between the two chemotherapy regimens (P = 0.377). CTX demonstrated comparable DFS outcomes to PTX in high-risk early-stage EOC. These findings support the use of CTX as a viable adjuvant chemotherapy alternative to PTX, particularly in Asian populations where clear cell and endometrioid histologies are more prevalent.

Anastomotic leakage is one of the most severe postoperative complications following esophagectomy for esophageal carcinoma. This study compared the incidence of postoperative anastomotic leakage after esophagectomy between a novel oblique-to-side esophagogastric anastomosis and the conventional end-to-side esophagogastric anastomosis. Clinical data from 318 patients with esophageal carcinoma (106 cases treated with the new anastomosis and 212 with the conventional approach) who underwent radical esophagectomy between January 2018 and November 2021 were retrospectively collected. Propensity score matching (PSM) was applied to balance baseline characteristics, yielding 188 matched patients (94 in each group). The primary outcome was the incidence of anastomotic leakage, while secondary outcomes included anastomotic stenosis, incisional infection, and pulmonary, cardiovascular, and digestive complications. After PSM, the new anastomosis group showed a significantly lower incidence of anastomotic leakage than the conventional group (6.4% vs. 22.3%, P=0.002). Besides, the incidence of postoperative fever was lower in the new anastomosis (10.6% vs. 27.7%, P=0.003). No significant differences were observed between the groups regarding anastomotic stenosis, incisional infection, or other systemic complications. Multivariate analysis identified the new oblique-to-side esophagogastric anastomosis as an independent protective factor against leak (OR=0.294, P=0.020). In conclusion, the oblique-to-side anastomosis effectively reduces postoperative anastomotic leak after radical esophagectomy without increasing other postoperative complications, demonstrating both safety and clinical efficacy.

Multiple Myeloma (MM) is the second most common hematological malignancy, with its pathogenesis involving complex cytogenetic variations, tumor clonal evolution, and dynamic interactions between tumor cells and bone marrow stromal microenvironment. Recent studies highlight the role of the intestinal microbiota, a key component of the tumor-associated microenvironment, in regulates MM occurrence, progression, and treatment response via the "gut-bone marrow axis". Under physiological conditions, it protects the local microenvironment by regulating host metabolism and maintaining immune homeostasis. However, intestinal dysbiosis causes metabolic disorders and immune surveillance defects, promoting tumor growth, drug resistance, and poor prognosis. Though traditional treatments such as chemotherapy and hematopoietic stem cell transplantation have been optimized, chemotherapy disrupts intestinal mucosal integrity and impairs immunity, significantly increasing post-chemotherapy infections. These infections can interrupt treatment, worsen conditions, and reduce quality of life, leaving MM still intractable. Notably, microbiota-targeted interventions (e.g., probiotics, fecal microbiota transplantation [FMT]) have shown potential to reduce infection risk by restoring microbiota balance and repairing intestinal barriers. These interventions may also exert potential anti-tumor effects through immune microenvironment regulation and alleviate chemo/radiotherapy-related adverse reactions (e.g., nausea, diarrhea), offering a new direction for relapsed/refractory MM. This article summarizes the molecular regulatory network of the intestinal microbiota in the pathogenesis of MM and the research progress of microbiota-based interventions, aiming to provide a foundation for developing novel microbiome-oriented precision treatment regimens and improving chemotherapy tolerance and patient prognosis.