Translational cancer research最新文献

Background: Ovarian cancer is the fourth leading cause of death among neoplastic diseases in women. The Ovarian-Adnexal Reporting Data System (O-RADS) magnetic resonance imaging (MRI) scoring is a five-point risk stratification system that combines morphological features with diffusion and perfusion features, which allows categorization of adnexal masses. This study aimed to evaluate the value of apparent diffusion coefficient (ADC) histogram analysis and serum carbohydrate antigen 125 (CA-125) levels to improve the performance of the O-RADS MRI score in classification of adnexal lesions.

Methods: The retrospective study included 196 patients with 235 adnexal lesions. Exclusion criteria included lack of histopathological results, prior treatment for adnexal lesions, poor image quality, and absence of ADC maps or contrast-enhanced (CE) magnetic resonance (MR) images. The MRI protocol included T1-weighted imaging (T1WI), T2-weighted imaging (T2WI), diffusion weighted imaging (DWI), and CE sequences, with ADC histogram parameters extracted using FireVoxel software. Histological results of surgically excised specimens served as the reference standard. Clinical information, ADC histogram parameters and O-RADS MRI scores were compared between benign and malignant lesions. Predictive factors for malignancy were identified through univariate and multivariate analyses, while diagnostic performance of the multivariate model, O-RADS score, and their combination was assessed using receiver operating characteristic (ROC) curve analysis.

Results: Significant differences in ADC histogram parameters were observed between benign and malignant lesions, except for the ADC maximum value (ADC_Max) (P=0.97). The O-RADS MRI score demonstrated strong diagnostic performance for malignancy with an area under the curve (AUC) of 0.915, a sensitivity of 84.25%, a specificity of 90.74%, and an accuracy of 87.23%. Incorporating ADC mean value (ADC_Mean), ADC Kurtosis (ADC_Kurtosis), and the serum CA-125 levels further improved differentiation, achieving a higher AUC (0.956), with a sensitivity of 92.91%, a specificity of 89.81%, and accuracy of 90.64%.

Conclusions: The ADC histogram analysis may improve the diagnostic performance of the O-RADS MRI score in preoperative classification of adnexal lesions.

Background: Gastric cancer (GC) is a highly prevalent malignancy associated with extremely poor prognosis. METTL17, a mitochondrial protein belonging to the methyltransferase-like (METTL) family, has been shown to drive the progression of several cancers including colorectal and oral cancers, yet its role in GC remains unexplored. This study sought to characterize the expression profile, biological functions, and underlying regulatory mechanisms of METTL17 in GC.

Methods: In this study, bioinformatics analysis, tissue microarray (TMA) immunohistochemistry (IHC), and Western blot were performed to determine the expression levels of METTL17 in GC cells and tissues and to assess its clinical relevance. In vitro and in vivo (BALB/c immunodeficient nude mice) functional assays were conducted to investigate the effects of METTL17 on the proliferation, migration, invasion, and tumorigenic potential of GC cells. Quantitative proteomics and Western blot were further applied to screen and validate the downstream signaling pathways regulated by METTL17.

Results: METTL17 was significantly upregulated in GC and correlated with poor prognosis in affected patients. Functional assays demonstrated that knockdown of METTL17 suppressed the proliferation, migration, invasion, and in vivo tumorigenic capacity of GC cells, whereas overexpression of METTL17 yielded the opposite effects. Mechanistically, quantitative proteomic profiling and Western blot analysis showed that METTL17 negatively regulated glycogen synthase kinase-3β (GSK-3β) expression, thereby activating the Wnt/β-catenin signaling pathway.

Conclusions: METTL17 activates the Wnt/β-catenin signaling pathway by inhibiting GSK-3β expression, thereby promoting the malignant progression of cancer. This suggests that METTL17 is a promising potential therapeutic target for GC.

Background: Osteosarcoma (OS) is the most common primary bone malignancy in adolescents, but its pathogenesis remains poorly understood. Creatine kinase mitochondrial 2 (CKMT2) has been associated with tumor progression and prognosis in several cancers. This study aimed to elucidate the role and underlying mechanisms of CKMT2 in OS.

Methods: Bioinformatics analyses were conducted using Gene Expression Omnibus (GEO) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) databases. Western blotting evaluated CKMT2 expression in OS cell lines. Cox regression analyses determined its prognostic significance. Functional assays including Cell Counting Kit-8 (CCK-8), flow cytometry, 5-ethynyl-2'-deoxyuridine (EdU), wound-healing, and Transwell were performed in CKMT2-silenced MG63 cells. Gene Set Enrichment Analysis (GSEA) identified relevant pathways. Potential interacting genes, chemical compounds targeting CKMT2, and its relationship with immune cell infiltration were also investigated.

Results: CKMT2 was significantly overexpressed in OS tissues and associated with poor patient prognosis. It was confirmed as an independent prognostic factor. A predictive nomogram integrating CKMT2 with clinical features was developed. CKMT2 knockdown inhibited OS cell proliferation, migration, and invasion. GSEA revealed enrichment in metabolic pathways, especially pyruvate metabolism. Silencing CKMT2 reduced PKM2 and LDHA protein levels, along with pyruvate and lactate content. CKMT2 expression also showed a positive correlation with immune cell infiltration, notably resting mast cells (MCs).

Conclusions: CKMT2 serves as a promising prognostic biomarker and potential therapeutic target in OS. It promotes malignant phenotypes by regulating metabolic pathways and influencing the tumor immune microenvironment.

Background: Glioma is the most common primary intracranial tumor, with a high degree of malignancy. If the tumor can be completely removed during surgery, better treatment results will be achieved. However, it is often difficult to determine the tumor boundary during surgery, so the total tumor resection rate is not high. Raman spectroscopy (RS) is an analytical technique that utilizes the principle of light scattering, RS is an analytical technique, based on the loss of laser energy when the incident laser interacts with the vibrations of molecular chemical bonds. This energy difference corresponds to the frequency of chemical bond vibration, which is also called the fingerprint information of molecular vibration. Therefore, RS can reflect the chemical composition of the sample. This study aims to utilize the characteristic of RS to explore the feasibility of RS in rapid diagnosis of gliomas.

Methods: We first conducted RS studies on three glioblastoma cell lines U87, LN229, T98G, and one normal human astrocyte cell line HA1800. Then, we screened out RS bands with significant differences, and validated the selected bands in clinical specimens (three patients with glioblastoma and one contused brain tissue from a patient with severe traumatic brain injury) to verify whether there were similar band intensity differences between cell lines and clinical specimens.

Results: The linear discriminant analysis (LDA) method can completely distinguish the four cell lines. The support vector machine (SVM) algorithm for machine learning was used to build a library model, and it was found that there were significant intensity differences between astrocyte HA1800 and the three glioblastoma cell lines. Subsequently, the same different intensity of RS bands between three clinical glioblastoma specimens and one brain tissue specimen were validated at the same positions using the same algorithm and computational model.

Conclusions: Data collected by Raman microscopy scanning and modeling using SVM algorithm can accurately identify glioma cell lines and ordinary glial cells; and significant differences in RS band intensity between benign and malignant cells can be determined. These differences also exist in clinical specimens of glioblastoma and brain tissue specimens.

Background: Glutathione (GSH) has been increasingly implicated in tumor progression. This study aimed to investigate the role of GSH in oral squamous cell carcinoma (OSCC) and to characterize how its metabolism is modulated.

Methods: Following treatment with osteoblast-specific factor 2 (OSF-2, POSTN), HN6 cells were subjected to RNA sequencing, metabolomics analysis and protein mass spectrometry. Then the levels of GSH, glutathione disulfide (GSSG) and reactive oxygen species (ROS) were measured. Western blot analysis was employed to determine the expression of PRKRA in recombinant human POSTN (rhPOSTN)-treated HN6 cells. Statistical analysis was performed using SPSS 19.0 and P<0.05 was considered to be statistically significant.

Results: Following rhPOSTN treatment, the GSH expression levels were significantly reduced, while the GSSG and ROS levels were significantly increased. Similarly, PRKRA expression was also significantly decreased. Overexpression of PRKRA markedly elevated the GSH levels and reduced the GSSG and ROS levels in OSCC cells. However, this effect was reversed by rhPOSTN. Finally, multiple pathways were implicated in POSTN-induced GSH reduction, of which the first three were apoptotic signaling, Wnt signaling and I-kappaB kinase/NF-kappaB signaling pathways.

Conclusions: Collectively, these findings indicate that POSTN reduced GSH levels through downregulating PRKRA, suggesting that GSH may serve as a potential therapeutic target in OSCC, thereby informing novel strategies for cancer intervention.

Background: Nasopharyngeal carcinoma (NPC) is a malignant tumor of the nasopharyngeal mucosal epithelium. The aryl hydrocarbon receptor (AhR)-a widely distributed nuclear receptor regulating adaptive adverse responses-is confirmed carcinogenic upon activation. Thus, this study aims to identify novel biomarkers for NPC treatment.

Methods: Relevant data were obtained from public databases. Biomarkers were developed through the application of differential expression analysis, univariate Cox regression, and machine learning algorithms. Molecular mechanisms were then explored through immune infiltration and molecular regulatory networks. Additionally, the drug sensitivity analysis revealed potential differences in sensitivity to chemotherapy drugs. The experimental verification was conducted using reverse transcription quantitative polymerase chain reaction (RT-qPCR).

Results: Cholinergic receptor nicotinic beta 2 subunit (CHRNB2), adenylate cyclase 4 (ADCY4), and cell division cycle 6 (CDC6) were identified as biomarkers. CHRNB2 and CDC6 were highly expressed, while ADCY4 was lowly expressed in NPC. ADCY4 showed a significant positive correlation with plasmacytoid dendritic cells [correlation coefficient (cor) =0.48, P<0.001]. In contrast, CDC6 exhibited a strong negative correlation with central memory CD4 T cells (cor =-0.75, P<0.001), while CHRNB2 was significantly negatively correlated with activated B cells (cor =-0.50, P<0.001). A total of 9 microRNAs (hsa-miR-26a-5p) and 31 long non-coding RNAs (lncRNAs) (GAS5) associated with biomarkers were predicted. Patients with high ADCY4 expression demonstrated a higher half-maximal inhibitory concentration (IC₅₀) value for gemcitabine compared to those with low expression. However, the opposite trend was observed for CDC6 and CHRNB2.

Conclusions: This study identified CHRNB2, ADCY4, and CDC6 as candidate biomarkers and provided preliminary clues for further exploration of potential therapeutic strategies for NPC.

Background: Head and neck squamous cell carcinoma (HNSCC) poses a significant global health challenge, accounting for approximately 4.5% of all malignancies, with approximately 890,000 new cases and 450,000 related deaths annually. Research indicates that partial epithelial-mesenchymal transition (p-EMT) figures prominently in the progression and metastasis of HNSCC. This study was conducted to determine whether the differentially expressed genes (DEGs) in HNSCC are key regulators of p-EMT.

Methods: Twelve DEGs were screened out from the Gene Expression Omnibus, and the clinical characteristics were obtained from The Cancer Genome Atlas. Subsequently, PLAU was confirmed as a gene related to p-EMT. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were applied to predict the potential functions of PLAU. Subsequently, immunohistochemistry was performed to examine the expression of PLAU and p-EMT markers in 75 samples of HNSCC tissue. To clarify the relationship between PLAU and p-EMT, PLAU was knocked down with small interfering RNA (siRNA), and wound healing, Transwell, and Western blot assays were conducted.

Results: The results of univariate and multivariate Cox regression analyses based on microarray data indicated that PLAU is involved in HNSCC. Consistent with this, PLAU expression was strongly correlated with p-EMT marker expression, and inducible knockdown of PLAU in HNSCC cell lines inhibited cell proliferation, cell invasion, and migration. Moreover, the PLAU-knockdown group had significantly higher and lower ITGA5 and PDPN expression, respectively.

Conclusions: These findings confirm PLAU to be an independent predictor of prognosis in HNSCC and involved in p-EMT-related metastasis.

Background: Locally advanced pancreatic cancer (LAPC) is mostly unresectable at initial diagnosis. Conversion therapy has become core treatment to downstage tumors for radical resection, yet consensus on optimal first-line regimen remains lacking. This real-world study compared three mainstream conversion regimens and identified independent survival predictors to guide individualized treatment.

Methods: A single-center retrospective cohort of 172 unresectable LAPC patients receiving gemcitabine plus nab-paclitaxel (AG), modified FOLFIRINOX (mFOLFIRINOX), or AG sequential chemoradiotherapy (CRT) from 2019 to 2023 was enrolled. Tumor conversion, surgical, survival and safety outcomes were analyzed. Cox regression was adopted to screen independent prognostic factors, with P<0.05 defined as statistical significance.

Results: The overall conversion rate reached 38.4%. mFOLFIRINOX yielded the highest conversion rate (52.8%) versus AG (32.6%) and AG + CRT (33.3%). Among 66 converted patients, 87.9% achieved R0 resection, with 34.8% major pathological response (MPR). Median overall survival (OS) of converted patients reached 32.5 months, far superior to non-converted cases (12.3 months). Multivariate analysis confirmed preoperative carbohydrate antigen 19-9 (CA19-9) normalization and prognostic nutritional index (PNI) ≥41.7 as two independent favorable prognostic markers. Grade 3-4 adverse events were most frequent in the mFOLFIRINOX group (56.6%).

Conclusions: For physically fit unresectable LAPC patients, mFOLFIRINOX provides superior conversion efficacy despite higher toxicity. Normalized CA19-9 and well-maintained nutritional status are reliable prognostic biomarkers. This real-world evidence supports mFOLFIRINOX as preferred first-line conversion regimen and routine monitoring of CA19-9 and nutrition during therapy.

Background: Glioma remains a challenging malignancy with limited therapeutic options, and the underlying molecular mechanisms driving its progression are not fully understood. Although miR-506-5p has been implicated in various tumors, its role in glioma progression and the associated mechanisms warrant further investigation. This study aims to explore whether miR-506-5p suppresses glioma growth and invasion by targeting MAPK7, thereby regulating matrix metalloproteinases (MMPs) and epithelial-mesenchymal transition (EMT).

Methods: Expression levels of miR-506-5p and MAPK7 in glioma tissues and cell lines were examined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The direct interaction between miR-506-5p and MAPK7 was validated using dual-luciferase reporter assays. Gain- and loss-of-function approaches were employed in U87 glioma cells, followed by 5-ethynyl-2'-deoxyuridine (EdU), wound healing, and Transwell assays to assess proliferation, migration, and invasion. Western blotting was performed to evaluate MAPK7, MMPs, and EMT-related markers. Rescue experiments were conducted to confirm the involvement of MAPK7 in miR-506-5p-mediated effects. Additionally, a xenograft model was established to evaluate the anti-tumor activity of miR-506-5p in vivo.

Results: MiR-506-5p expression was significantly downregulated, while MAPK7 expression was markedly upregulated, in glioma tissues and cell lines compared with controls. Dual-luciferase reporter assays confirmed that miR-506-5p directly targeted the 3'-UTR of MAPK7. Overexpression of miR-506-5p suppressed cell proliferation, migration, invasion, and EMT, accompanied by decreased expression of MAPK7, MMP9, MMP12, N-cadherin, and vimentin, and increased E-cadherin expression. Conversely, miR-506-5p knockdown produced opposite effects. Rescue experiments demonstrated that MAPK7 overexpression reversed the suppressive effects induced by miR-506-5p, whereas MAPK7 knockdown reversed the pro-tumorigenic effects of miR-506-5p inhibition. In vivo, miR-506-5p overexpression significantly inhibited xenograft tumor growth, reduced Ki-67 positivity, and recapitulated the molecular changes observed in vitro.

Conclusions: MiR-506-5p functions as a tumor suppressor in glioma by directly targeting MAPK7, thereby inhibiting MMP expression and EMT to suppress tumor growth, migration, and invasion. The miR-506-5p/MAPK7 axis represents a potential therapeutic target for glioma intervention.