Journal of Experimental & Clinical Cancer Research最新文献

Background: Cancer resistance is one of the major challenges in oncology, often resulting in disease relapse and poor patient outcomes. Within the RNA family, microRNAs (miRNAs) regulate core biological processes and have been recognized also as critical contributors of tumor resistance and therapy failure. Being pivotal, they are increasingly exploited as biomarkers in various settings. Although in silico analyses facilitate miRNAs identification, PCR-based approaches remain essential to validate their expression. Currently, a plethora of well-established, single-target methods exist but multiplex detection from the same input have been only rarely explored.

Methods: We present miRquad, the first-in-class digital PCR (dPCR) TaqMan™ multiplex clinical research assay for miRNA detection in head and neck (HNC) cancers. Based on a patented prognostic signature including miR-21-5p, miR-96-5p, miR-21-3p and miR-429, the assay would enable simultaneous miRNA analysis via qPCR and dPCR on multiple clinically relevant sample types.

Results: We designed and optimized miRquad using both synthetic controls and retrospective patient-derived tissues, sera and saliva. A multicentre ring study was conducted to evaluate assay reliability across different platforms, demonstrating strong correlation with commercial singleplexes, broad applicability, reduced turnaround time (TAT) and cost-effectiveness. Finally, we provide evidence for its potential clinical application to predict disease outcome in HNC, testing miRquad on tumoral and peritumoral tissues, sera and saliva samples collected throughout patient follow up.

Conclusions: The assay overcomes common challenges associated with multiple miRNAs detection, particularly in liquid biopsy samples (e.g., multiple pipetting issues, increased consumption of sample for multiple assessment, extended TAT for complete profiling) and provides robust and accurate detection, demonstrating potential for real-time patient monitoring and prognostication in HNC.

Hepatocellular carcinoma (HCC), often arising from liver fibrosis in nonalcoholic fatty liver disease (NAFLD), remains a leading cause of cancer-related death. Targeting the gut-liver axis offers new therapeutic opportunities to prevent this progression. In this study, colon-targeted chitosan/pectin-based nanoparticles loaded with Astragalus polysaccharide (APs-CS/PT-NPs) were developed to modulate gut microbiota and inhibit liver tumorigenesis. The nanoparticles exhibited robust physicochemical stability and pH-responsive release. In vivo, oral administration of APs-CS/PT-NPs attenuated hepatic steatosis, reduced inflammatory cytokines, and suppressed NAFLD-induced HCC development. 16 S rRNA sequencing revealed restoration of microbial diversity and enhanced production of short-chain fatty acids, especially acetate. Mechanistically, transcriptomic profiling and functional analysis identified acetate as a key mediator, acting via G-protein-coupled receptor 43 (GPR43) to inhibit the NF-κB pathway. These results highlight the therapeutic potential of APs-CS/PT-NPs in modulating the gut-liver axis, rebalancing intestinal microbiota, and suppressing pro-inflammatory signaling. This nanoparticle-based strategy offers a promising food-derived preventive intervention for liver fibrosis-HCC transition.

Radiotherapy remains a cornerstone in cancer treatment, used in over 50% of cases. It employs ionizing radiation, primarily X-rays, to target and destroy tumors through direct DNA damage and indirect effects via reactive oxygen species. Despite technological advancements improving precision of the delivered dose to the tumor, radiotherapy faces critical challenges, particularly damage to healthy tissues, which limits the maximum safe dose. Recent years have seen significant improvements in radiation delivery, including advanced imaging for real-time tumor tracking and combinations with immunotherapy. However, the need for innovative strategies to enhance radiotherapy's therapeutic index remains essential. The radioenhancer NBTXR3 could represent a solution in addressing these limitations. This nanotechnology has been designed to amplify radiotherapy's effects within tumors without increasing toxicity in non-injected adjacent healthy tissues. Beyond better cancer cell destruction and tumor control, radiotherapy-activated NBTXR3 nanoparticles can also stimulate systemic antitumor immune responses in preclinical models. This review aims to provide a comprehensive analysis of preclinical research on NBTXR3, focusing on its mechanism of action and role in initiating and enhancing antitumor immune responses.

Background: The pathogenesis of bladder cancer (BCa) is driven in part by aberrant epigenetic regulation, most notably the dysregulated expression of histone deacetylases (HDACs). As a class I HDAC, HDAC2 is often overexpressed in cancers and promotes malignancy through diverse mechanisms. Given its broad oncogenic role, an in-depth investigation of its specific functions in epigenetic and post-translational regulation within BCa holds significant promise for developing novel precision therapies.

Methods: In vitro functional assays, including CCK-8, colony formation, transwell and apoptotic assays, as well as in vivo assays in a nude mouse subcutaneous tumor model, were performed to assess the oncogenic and drug-resistant effects of HDAC2. RNA-seq and ATAC-seq were employed to analyze the epigenetic regulatory mechanisms of HDAC2. Combined proteome, lactylome and acetylome analysis of control and HDAC2-overexpressing BCa cells were conducted to map the global profiling of protein lysine acetylation (Kac) and lactylation (Kla).

Results: In vitro and in vivo experiments confirmed that HDAC2 overexpression significantly promoted proliferation, metastasis and chemoresistance of BCa. Integrated RNA-seq and ATAC-seq analysis revealed that HDAC2 overexpression led to significant epigenetic alternations, and knockdown of its downstream GRIK2 significantly reversed the oncogenic effects of HDAC2. We screened class I HDACs for their impact on Kac and Kla in BCa cells and found that HDAC2 most significantly reduced global Kla levels. Subsequent proteomic analysis of HDAC2-overexpressing cells identified 528 differentially regulated Kla proteins (encompassing 683 sites) and 1,129 differentially regulated Kac proteins (encompassing 1,458 sites). Notably, DHX15 in the splicesome pathway emerged as the most prominent HDAC2-regulated lactylated protein in the absence of concurrent Kac alterations. Moreover, HDAC2 promoted BCa malignancy through the downregulation of DHX15 Kla and the subsequent modulation of RPL9 splicing.

Conclusion: Collectively, these findings suggest the pivotal role of HDAC2 in epigenetic modulation and lysine lactylation, and underscore HDAC2 as a promising therapeutic target in BCa.