Translational cancer research最新文献

Background: Sarcopenia is increasingly recognized as a critical factor that can diminish treatment tolerance, exacerbate therapy-related toxicity, and ultimately impair clinical outcomes in cancer patients. This highlights the need to move beyond prognostic modeling and focus on its impact on treatment decisions and outcomes. Regarding head and neck squamous cell carcinoma (HNSCC), the association between sarcopenia and clinical outcomes is still not well characterized. Our study is therefore designed to bridge this gap and further explore the underlying multi-omics mechanisms, with the ultimate goal of informing treatment personalization and intervention strategies to improve therapeutic efficacy and patient survival in HNSCC.

Methods: A total of 167 HNSCC patients from The Cancer Genome Atlas (TCGA) with paired computed tomography (CT) imaging and genomic data were analyzed. Sarcopenia assessment was based on the measurements of skeletal muscle area at the level of the third cervical vertebra (C3) from baseline CT scans. Overall survival (OS) was compared using Cox regression. Multi-omics differences (gene expression, transcriptomics, and immune microenvironment) were examined. A Genetic Risk Score (GRS) derived via least absolute shrinkage and selection operator (LASSO) regression was validated in the Gene Expression Omnibus (GEO) database under accession number GSE65858.

Results: Patients with sarcopenia demonstrated significantly worse OS [hazard ratio (HR) =2.36; 95% confidence interval (CI): 1.33-4.19; P=0.003]. Transcriptomic profiling revealed distinct sarcopenia-associated gene signatures in HNSCC, with pathway enrichment analysis implicating inflammatory responses and metabolic dysregulation in disease pathogenesis. A robust four-gene prognostic signature comprising fibrinogen beta chain (FGB), kinesin family member 1A (KIF1A), hepatic leukemia factor (HLF), and yippee-like 1 (YPEL1) was derived from LASSO regression and demonstrated strong predictive value for survival (HR =2.86; 95% CI: 1.73-4.73; P<0.001), with subsequent confirmation in an independent validation cohort. Characteristic depletion of CD8⁺ and CD4⁺ T cell infiltration was observed in sarcopenic patients.

Conclusions: Sarcopenia is significantly associated with poorer prognosis in HNSCC. Sarcopenic patients exhibit distinct gene expression, transcriptomic profiles related to lipid metabolism, and immune infiltration levels compared to non-sarcopenic patients. A GRS model constructed with four genes demonstrated favorable performance in predicting prognosis in HNSCC.

Background: The recent identification of disulfidptosis, a novel form of cell death, offers significant potential for advancing cancer therapeutics. Osteosarcoma (OS) and rhabdomyosarcoma (RMS) are prevalent malignant sarcomas in children and young adults, yet their molecular underpinnings remain poorly understood, hampering treatment options. This study aimed to delineate the role of disulfidptosis in these malignancies and to identify key molecular determinants of prognosis.

Methods: We analyzed extensive RNA transcriptome data from the Gene Expression Omnibus (GEO) and the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) databases. Non-negative matrix factorization (NMF) clustering was employed to identify disulfidptosis-associated molecular subtypes. Furthermore, we integrated 100 machine-learning algorithms to pinpoint core prognostic genes.

Results: Based on disulfidptosis-related genes, we identified a distinct immunosuppressive subtype in both OS and RMS, characterized by significantly poorer immune cell infiltration. A robust prognostic signature comprising five genes (ACTN4, MYH9, FLNA, MYH10, and IQGAP1) was established, which effectively characterized the immunosuppressive subtypes and stratified patient risk. Notably, IQGAP1 emerged as an independent prognostic factor in RMS, highlighting its potential as both a therapeutic target and biomarker. Additionally, our analysis revealed a strong correlation between macrophage infiltration and disulfidptosis, suggesting a potential role in shaping the tumor immune microenvironment and influencing patient prognosis.

Conclusions: Our findings illuminate the landscape of disulfidptosis in OS and RMS, revealing a novel immunosuppressive subtype and a defined five-gene signature for risk stratification. The identification of IQGAP1 and the link to macrophages provides new insights for developing targeted therapies and immunotherapeutic strategies for these malignancies.

Background: Transforming acidic coiled-coil containing protein 1 (TACC1) is a key regulator of cellular differentiation, growth, and gene regulation. Despite the known interaction between full-length TACC1 and retinoic acid receptor alpha (RARα), the relationship between the short-form TACC1 variant 25 (TACC1v25) and RARα in head and neck squamous cell carcinomas (HNSCCs) remains unclear. This study aimed to evaluate the value of TACC1v25 on differentiation and invasion in HNSCC and its correlation with RARα.

Methods: We analyzed the interaction between TACC1v25 and RARα by co-immunoprecipitation (Co-IP). The effects of TACC1v25 associated with RARα on the differentiation and invasion in HNSCC were assessed by western blot and transwell assays. RNA sequencing (RNA-seq) profiling and orthotopic xenograft modeling further validated the results.

Results: TACC1v25 physically interacted with RARα. A portion of TACC1v25 and RARα was found at the same loci both in the nucleus and cytoplasm. After all-trans-retinoic acid (ATRA) treatment, TACC1v25 increased in the cytoplasm, whereas RARα increased in the nucleus (P<0.05). Overexpression of TACC1v25 significantly upregulated differentiation-related proteins in Cal27 and Fadu cells; however, ATRA treatment counteracted the pro-differentiation effect in Cal27-v25 cells (P<0.05). TACC1v25 overexpression inhibited cell invasion and migration, but similarly, ATRA-mediated RARα reversed these effects and counteracted the downregulated vimentin and p-AKT expression (P<0.05).

Conclusions: TACC1v25 may be involved in cell differentiation, invasion, and migration in HNSCC cells, and the dissociation of activated RARα from TACC1v25 might partially counteract the effects of TACC1v25 in HNSCCs. It is possible that ATRA induces conformational changes and/or promotes nuclear translocation of RARα, which in turn reduces its interaction with TACC1v25 and modulates the downstream transcriptional effects. This may provide new ideas for treating HNSCCs.

Background: Inflammatory myofibroblastic tumor (IMT) is a relatively rare mesenchymal tumor in clinical practice and is difficult to diagnose. At present, clinical reports on this disease are still relatively scattered. Especially for IMT occurring in special sites such as the nasal cavity, sacrum, and bladder, systematic reports on its clinical manifestations, treatment responses, and prognostic characteristics are still lacking.

Case description: This study retrospectively reported six patients with low-grade IMT diagnosed by pathology (three males and three females), aged 15 to 63 years (with an average age of 41.67 years). The maximum diameter of the tumors ranged from 2.0 to 9.5 cm (with an average of 4.4 cm), and the involved sites included the nasal cavity, upper limbs, chest wall, sacrum, and bladder. All patients underwent surgical treatment and were followed up for 13 to 33 months after the operation (with an average of 19.67 months). Among them, one patient with nasal IMT had local recurrence after the operation, one patient with sacral IMT was found to have multiple bone metastases throughout the body during the follow-up period, and no recurrence or metastasis was observed in the remaining four cases.

Conclusions: IMT is a tumor with "low malignant potential" or "borderline" characteristics. It is neither a typical benign tumor nor a highly malignant cancer, but occupies an intermediate gray zone. It can occur at multiple sites in the body, most commonly in the lungs, and has been reported across all age groups. Through the analysis of six cases of IMT with unusual primary sites, this study found that even with low-grade pathological features, the tumor can still exhibit aggressive biological behavior, including postoperative recurrence and distant metastasis, when arising in atypical locations such as the sacrum or nasal cavity. This suggests that the clinical management of IMT should not rely solely on pathological grading but should also involve a comprehensive evaluation incorporating the tumor's location and size. This case series contributes to broadening the understanding of the clinical spectrum of IMT, enhances awareness of IMT in rare sites, and provides important clinical rationale for long-term systematic follow-up and monitoring for all patients with IMT.

Background: The heat shock protein (HSP)/albumin (ALB) ratio, which measures the levels of plasma Hsp90α to ALB, is believed to be a sensitive prognostic biomarker for hepatocellular carcinoma (HCC); however, its prognostic value has not been clearly confirmed. The aim of our study was to assess the role of HSP/ALB as a prognostic factor in patients with HCC and further establish an interpretable predictive model using least absolute shrinkage and selection operator (LASSO)-Cox regression and SHapley Additive exPlanations (SHAP) value.

Methods: A total of 1,340 HCC patients were enrolled in this study. We measured the levels of HSP/ALB in HCC patients within a week before treatment. Then, we established the HSP/ALB ratio and assessed its correlation with prognosis. Finally, we use LASSO-Cox regression to incorporate HSP/ALB into the prediction model for visualization and risk stratification.

Results: The best cut-off value for HSP/ALB was determined to be 3.77 using the X-tile software. It was found that the median overall survival (mOS) of patients with HSP/ALB ≥3.77 (high) [8.3 months, 95% confidence interval (CI): 7.6-9.3] was significantly lower than that of patients with HSP/ALB <3.77 (low) (38.7 months, 95% CI: 35.8-45). In the training cohort, the mOS of patients with HSP/ALB ≥3.77 was 7.3 months (95% CI: 5.8-8.9), and that of patients with HSP/ALB <3.77 was 36.1 months (95% CI: 28.4-39.8). In the validation cohort, the mOS of patients with HSP/ALB ≥3.77 was 7.1 months (95% CI: 4.9-9.0), and that of patients with HSP/ALB <3.77 was 36.2 months (95% CI: 31.6-43.7). The subgroup analysis included four groups: transarterial chemoembolization (TACE) alone, TACE combined with operation, and radiotherapy (RT) group. The results showed that the patients with HSP/ALB <3.77 had longer mOS. We integrated HSP/ALB into the LASSO-Cox prediction model. Our findings showed that using HSP/ALB alone, the area under the curve (AUC) values for predicting 1-, 2-, and 3-year overall survival (OS) were 0.757, 0.731, and 0.713, respectively. However, after incorporating HSP/ALB into the prediction model based on LASSO-Cox regression, the AUC values for predicting 1-, 2-, and 3-year OS were 0.850, 0.842, and 0.810, respectively. Additionally, a nomogram was created based on this improved prediction model. Meanwhile, it was observed that the OS of the low-risk group significantly outperformed that of the medium-risk and high-risk groups. Finally, we ranked the importance of variables according to the SHAP value.

Conclusions: The integration of HSP/ALB into the LASSO-Cox prediction model improves its predictive performance, indicating that HSP/ALB can serve as a reliable prognostic predictor.

Background: Metastatic non-small-cell lung cancer (NSCLC) represents a significant clinical challenge and is the leading cause of cancer-related death worldwide. Immune checkpoint inhibitors (ICIs), particularly those targeting the programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) pathway, have transformed the treatment of advanced-stage NSCLC; however, their efficacy varies, and optimal strategies following initial ICI failure remain undefined. Envafolimab, a novel humanized single-domain anti-PD-L1 antibody fragment fused to an Fc domain, is the first globally approved subcutaneous PD-L1 inhibitor. Its unique structure confers advantages in terms of tissue penetration and distribution compared to conventional monoclonal antibodies.

Case description: This report details the case of a 66-year-old male diagnosed with stage IVB (cT4N2M1c) squamous cell carcinoma of the left upper lung with confirmed hepatic metastasis. Initial immunohistochemistry revealed a tumor proportion score for PD-L1 ≥1%, prompting the following standard first-line therapy as per the guidelines: three cycles of albumin-bound paclitaxel [470 mg, day (d)1], carboplatin (568 mg, d1), and pembrolizumab (200 mg, d1). This regimen yielded inadequate disease control. Subsequently, second-line therapy comprising two cycles of gemcitabine (1.6 g, d1; 1.4 g, d8), cisplatin (40 mg, d1-3), endostar (30 mg, d1-4), and subcutaneous envafolimab (200 mg, d1) was initiated. Follow-up computed tomography (CT) imaging revealed a notable reduction in the left hilar mass and significant alleviation of the bronchial obstruction. This therapeutic response was sustained for over 6 months during envafolimab monotherapy maintenance without recurrence.

Conclusions: This case shows the potential efficacy of envafolimab-based combination therapy in achieving a clinically significant and durable response for a patient with metastatic squamous NSCLC (sq-NSCLC) who showed disease progression on first-line pembrolizumab-containing chemotherapy. It suggests that envafolimab warrants consideration as a viable treatment option in this setting, particularly following the failure of PD-1 inhibitors. Further larger clinical trials need to be conducted to confirm these findings and define its optimal role in the NSCLC treatment sequence.

Background: Uterine corpus endometrial carcinoma (UCEC) which is originated from endometrial epithelium, ranks the second among frequent malignant tumors in female reproductive system. The discovery of novel therapeutic targets is urgently needed to address unmet clinical demands. In this study, we conducted a comprehensive bioinformatic analysis to identify key drivers of UCEC.

Methods: The prognostic factors for UCEC were analyzed by Human Protein Atlas (HPA), The University of ALabama at Birmingham CANcer data analysis Portal (UALCAN), and Encyclopedia of RNA Interactomes (ENCORI). The expression levels of the overlapped prognostic factors were analyzed by UALCAN, and ENCORI. The heatmap of the potential 12 prognostic factors was exhibited by UALCAN. The online databases including BioGrid, BioPlex and OpenCell were utilized to predict the molecules which could interact with SNX24. Cell proliferation was assessed by Cell Counting Kit 8 (CCK-8) assay. Cell invasion was detected by transwell assay.

Results: Of note, higher SNX24 predicted a worse prognosis of patients with UCEC, and SNX24 was overexpressed in patients with UCEC, as revealed by HPA, UALCAN and ENCORI. There were two molecules which could interact with SNX24, i.e., the casein kinase 1 (CSNK1A1 and CSNK1E). Silencing of SNX24 significantly inhibited proliferation and invasion of endometrial carcinoma (EC) cells by downregulating the expression of CSNK1A1 and CSNK1E.

Conclusions: Taken together, our data demonstrated the prognostic significance and tumor-promoting role of SNX24 in UCEC.

Background: The early diagnostic rate of gastric cancer (GC) is relatively low. Transfer RNA-derived fragments (tRFs), as a class of non-coding RNAs with tumor-specific expression and stability in body fluids, have emerged as highly promising diagnostic candidate biomarkers. However, their application value in GC still requires systematic validation. Therefore, this study aims to systematically evaluate the value of specific tsRNA molecules as novel diagnostic biomarkers for GC by identifying and validating them.

Methods: After identifying differentially expressed tsRNAs through the OncotRF database, the expression levels of tRF-28-P4R8YP9LOND5 were measured in serum samples from 117 GC patients, 89 healthy controls, and 51 gastritis patients using reverse transcription quantitative polymerase chain reaction (RT-qPCR) technology. The study evaluated the correlation between this biomarker and clinicopathological features, and the diagnostic efficacy of the single biomarker as well as its combination with carcinoembryonic antigen (CEA), cancer antigen 199 (CA199), and CA724 was analyzed using receiver operating characteristic (ROC) curves. Bioinformatics methods were employed to predict potential target genes and enriched signaling pathways.

Results: tRF-28-P4R8YP9LOND5, a 5' tRNA-derived fragment originating from tRNA-Gly-GCC, was significantly upregulated in GC sera (P<0.001), with expression levels positively correlated with tumor invasion depth (T3-T4 stage), advanced tumor, node, and metastasis staging (III-IV), and neurovascular invasion (all P<0.05). The single-biomarker ROC analysis yielded an area under the curve (AUC) of 0.737, while combination with CEA and CA199 improved AUC to 0.821 (GC vs. healthy controls) and 0.883 (GC vs. gastritis patients), with optimal sensitivity of 80.3%. Bioinformatics revealed that several target genes were enriched in key pathways, such as cancer pathways and p53 signaling, which are critical to GC progression. Specifically, genes involved in cell migration, such as claudin-1, and p53 signaling-related genes like TP53 and MDM2, are known to play pivotal roles in GC pathogenesis. These genes have been implicated in the regulation of tumor invasion, metastasis, and response to DNA damage, which are central to the malignant behavior of GC cells.

Conclusions: This study reveals that tRF-28-P4R8YP9LOND5 has the potential to serve as a novel serum diagnostic marker for GC. It demonstrates significant promise in distinguishing GC from benign conditions such as gastritis and provides a new strategy for early detection. Further studies are needed to explore its biological functions and its potential for therapeutic applications.

Background: Hepatocellular carcinoma (HCC) is one of the most common types of primary liver cancer worldwide. It is characterized by high heterogeneity and poor prognosis, and current treatment outcomes remain limited. Studies have shown that propofol possesses certain anticancer properties. However, the combined effects of albiflorin and the underlying mechanisms remain unclear. This study aimed to evaluate the anticancer activity of albiflorin in HCC, further investigate the combined effects and underlying mechanism of albiflorin and propofol.

Methods: Huh-7 cells were treated with different concentrations of albiflorin (0, 25, 50, and 100 μg/mL) and propofol (0, 30, 60, and 120 μM), either alone or in combination. The effects on cell proliferation, apoptosis, migration, and invasion were evaluated. Cell proliferation was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis and epithelial-mesenchymal transition (EMT) were measured by flow cytometry and western blotting, and cell migration and invasion were evaluated using Transwell assays. Additionally, the expression of key Wnt/β-catenin signaling molecules was analyzed by western blotting and reverse transcription-quantitative polymerase chain reaction to explore potential mechanisms.

Results: Both albiflorin and propofol alone inhibited the proliferation, migration, invasion, and EMT of Huh-7 cells in a dose-dependent manner and promoted apoptosis. The combination of albiflorin and propofol effectively enhanced the inhibitory effects of propofol on HCC cells. Mechanistic studies revealed that the combined treatment significantly downregulated the expression of Wnt3a and β-catenin, suggesting that the antitumor effects may be mediated through the suppression of the Wnt/β-catenin signaling pathway.

Conclusions: Albiflorin and propofol exert synergistic inhibitory effects on HCC cell proliferation, migration, invasion, and EMT while promoting apoptosis. These effects are likely associated with suppression of Wnt/β-catenin signaling. This study provides new experimental evidence supporting the development of multitargeted combination therapies and identifies potential molecular targets for comprehensive HCC treatment.