Protease nexin 1 (PN1) is an endogenous serine protease inhibitor (SERPIN), expressed at high levels in the prostate, and capable of inhibiting the proliferation of prostate cancer cells. We previously showed that PN1-uPA complexes inhibited Sonic Hedgehog (SHH) signalling through engagement of the LRP receptor. Here, we describe an alternative anti-proliferative mechanism through which PN1 expression leads to apoptosis. In prostate cancer cells, increased expression of PN1 led to substantial reduction of XIAP levels and apoptosis mediated through the uPAR, but not the LRP receptor. The alterations in XIAP were effected in two ways 1) via alteration in the NF-κB pathway, a pathway known to signal XIAP transcription and 2) by promoting XIAP instability. The AKT pathway is known to phosphorylate XIAP at serine 87 leading to protein stability and PN1 expression is shown to interfere with this process. As a result of both mechanisms, programmed cell death is substantially increased. Consistent with these observations, reduced PN1 protein correlated with elevated p65/XIAP expression and with higher Gleason scores in human prostate tissue arrays. Thus, PN1 expression appears to differentially down-regulate distinct oncogenic pathways depending upon the cell surface receptor engaged by its complexes and demonstrates a novel molecular mechanism by which the protein can promote tumor cell apoptosis.
Accumulating evidence supports the concept that DNA damage response targeted therapies can improve antitumor immune response by increasing the immunogenicity of tumor cells and improving the tumor immune microenvironment. Ataxia telangiectasia mutated (ATM) is a core component of the DNA repair system. Although the ATM gene has a significant mutation rate in many human cancers, including colorectal, prostate, lung, and breast, it remains understudied compared with other DDR-involved molecules such as PARP and ATR. Here, we found that either gene knockout or drug intervention, ATM inhibition activated the cGAS/STING pathway and augmented MHC class I in CRC cells, and these effects could be amplified by radiation. Furthermore, we found that MHC class I upregulation induced by ATM inhibition is dependent on the activation of the NFκB/IRF1/NLRC5 pathway and independent of STING. Animal experiments have shown increasing infiltration and cytotoxic function of T cells and better survival in ATM-deficient tumors. This work indicated that ATM nonsense mutation predicted the clinical benefits of radiotherapy combined with immune checkpoint blockade for patients with CRC. It also provides a molecular mechanism rationale for ATM-targeted agents for patients with CRC.
Deciphering the composition of the tumor microenvironment (TME) is critical for understanding tumorigenesis and to design immunotherapies. In the present study, we mapped genetic effects on cell-type proportions using single-cell and bulk RNA sequencing data, identifying 3,494 immunity quantitative trait loci (immunQTLs) across 23 cancer types from The Cancer Genome Atlas. Functional annotation revealed regulatory potential and we further assigned 1,668 genes that regulate TME composition. We constructed a combined immunQTL map by integrating data from European and Chinese colorectal cancer (CRC) samples. A polygenic risk score that incorporates these immunQTLs and hits on a genome-wide association study outperformed in CRC risk stratification within 447,495 multiethnic individuals. Using large-scale population cohorts, we identified that the immunQTL rs1360948 is associated with CRC risk and prognosis. Mechanistically, the rs1360948-G-allele increases CCL2 expression, recruiting regulatory T cells that can exert immunosuppressive effects on CRC progression. Blocking the CCL2-CCR2 axis enhanced anti-programmed cell death protein 1 ligand therapy. Finally, we have established a database (CancerlmmunityQTL2) to serve the research community and advance our understanding of immunogenomic interactions in cancer pathogenesis.
BACKGROUND:The stent type may be associated with adverse events in carotid artery stenting (CAS). This study aimed to compare the clinical outcomes (stroke/myocardial infarction (MI)/death) of CAS with open- and closed-cell stents for patients with carotid artery stenosis. METHODS:Between April 2012 and May 2024, the clinical data of 223 patients who underwent CAS in our center were retrospectively analyzed. In terms of the stent type used, patients were divided into a closed-cell stent group and an open-cell stent group. Clinical outcomes between the two groups were compared. Univariate and multivariate analyses were performed to identify the independent risk factors. Subgroup analyses in terms of carotid plaque types and smoking history were conducted in carotid artery stenosis patients receiving CAS with open- and closed-cell stents. RESULTS:The combined in-hospital stroke/MI/death rate was significantly lower in the closed-cell stent group than in the open-cell stent group (p=0.026). Open-cell stents, smoking, and unstable plaques were the independent risk factors associated with a higher in-hospital stroke/MI/death rate. Subgroup analyses showed that for patients with unstable plaques, the combined in-hospital stroke/MI/death rate was significantly higher in the open-cell stent group than in the closed-cell stent group (p=0.016). For patients who smoked, the combined in-hospital stroke/MI/death rate was significantly higher in the open-cell stent group than in the closed-cell stent group (p=0.038). CONCLUSION:For carotid artery stenosis patients with unstable carotid plaques or smoking history, using closed-cell stents in CAS may help reduce the combined in-hospital stroke/MI/death rate.
To address environmental and health risks from antibiotic abuse, this study develops a highly sensitive detection probe using a Y 3+ heavy‐doping strategy in Eu‐MOF. The approach achieves triple optimization: structural stabilization, energy transfer enhancement, and pore polarization. Y 3+ doping creates single‐ion dispersed Eu 3 ⁺ nodes, suppressing concentration quenching and improving charge transfer. The dipole moment increases to 8.7239 debye , strengthening norfloxacin (NOR) adsorption (−157.65 kcal mol −1 binding energy). The resulting 334.8 nm particles show reduced cytotoxicity (IC 50 : 76.66 µM). The Eu 0.2 Y 0.8 ‐BTB probe achieves a 0.4058 µM NOR detection limit (10.8× more sensitive than undoped systems) with high selectivity. Theoretical simulations reveal synergistic weak interactions and coordination bonding activate dual‐path energy transfer: the NOR → Eu 3+ antenna effect extends fluorescence lifetime (189.68 → 460.76 µs), while coordination reduces the LMCT barrier by 64% (1.553 → 0.556 eV). The probe enables specific “Turn‐On” NOR imaging in cells, leveraging Eu 3+ 's large Stokes shift (270 nm) to avoid background interference. This work provides a new paradigm for developing ultra‐sensitive, biocompatible lanthanide MOF‐based diagnostic platforms.
