The mechanism of RGS5 regulating gastric cancer mismatch repair protein.

The incidence and mortality rates of gastric cancer (GC) remain alarmingly high worldwide, imposing a substantial healthcare burden. In this study, we utilized data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. A 4-gene prognostic model was developed to predict patient prognosis, and its accuracy was validated across multiple datasets. Patients with a low-risk score exhibited improved prognosis, elevated tumor mutation burden, heightened sensitivity to both immunotherapy and conventional chemotherapy. Notably, our investigation revealed that the key gene RGS5 positively modulates the expression of mismatch repair proteins via c-Myc. Furthermore, co-immunoprecipitation (COIP) assays demonstrated the interaction between RGS5 and c-Myc. Additionally, we confirmed that RGS5 regulates c-Myc through the ubiquitin-proteasome pathway. Moreover, RGS5 was identified as a positive regulator of PD-L1 expression and exhibited a negative correlation with the majority of immune cells. These findings underscore the potential of RGS5 as a novel biomarker and therapeutic target in the context of GC.

pH/ROS dual stimuli-responsive anionic flexible supramolecular organic frameworks for synergistic therapy.

Supramolecular organic frameworks (SOFs) have emerged as a promising class of organic porous materials with vast potential as nanocarriers for combination therapy. Here, we successfully construct an anionic flexible supramolecular organic framework (TPP-SOF) by leveraging multiple host-guest interactions. TPP-SOF is fabricated by the hierarchical orthogonal assembly between anionic water-soluble dimacrocyclic host (P5CD), porphyrin photosensitizers (TPP), and ROS-sensitive thioketal linked adamantane dimer (Ada-S-Ada). TPP-SOF exhibits pH-dependent activation of 1O2 production, which further facilitates the cleavage of Ada-S-Ada linker and promotes the disintegration of the framework. Moreover, leveraging electrostatic and hydrophobic interactions, the anionic TPP-SOF serves as an effective platform for loading cationic photosensitizer IR780 and chemotherapeutic prodrug PhenPt(IV), leading to the formation of supramolecular nanoparticles (IR780/Pt@TPP-SOF) for synergistic therapy. The obtained nanoparticles exhibit good stability, efficient generation of 1O2, and photothermal performance. In vitro and in vivo studies indicate that IR780/Pt@TPP-SOF exhibits remarkable synergistic chemo/PDT/PTT effects under 808 and 660 nm light irradiation. This study showcases a deep insight for the development of SOFs and a new approach for delivering cationic drugs and constructing synergistic combination therapy systems. STATEMENT OF SIGNIFICANCE: In this work, a pH/ROS-responsive anionic flexible supramolecular organic framework, TPP-SOF, was innovatively designed by the hierarchical orthogonal assembly, to co-deliver cationic photosensitizer IR780 and prodrug PhenPt(IV) for synergistic cancer therapy. The drug-loaded TPP-SOF is termed IR780/Pt@TPP-SOF, in which the photoactivity of porphyrin within TPP-SOF could be activated under acidic conditions, the 1O2 generated by the photosensitizers could break the thioketal bonds in Ada-S-Ada, leading to the disassembly of the framework and releasing the drugs. This supramolecular drug delivery system displays good biocompatibility and exhibits remarkable synergistic chemo/PDT/PTT effects.

RIG-I promotes cell proliferation in esophageal squamous cell carcinoma by facilitating p21 degradation.

Retinoic acid-inducible gene-I (RIG-I) is considered a key sensor for host recognition of RNA virus infections. Recent studies have shown that RIG-I also regulates carcinogenesis. However, the role of RIG-I in esophageal squamous cell carcinoma (ESCC) remains unclear. We investigated the RIG-I expression in ESCC cells using a public database, immunohistochemistry, and Western blotting. We evaluated the proliferative activity of ESCC cells using CCK-8, colony formation, and EdU staining assays. Further, we determined the ESCC cell-cycle changes using flow cytometry and the ubiquitination of p21 in the cells using cycloheximide chase and ubiquitination assays. Finally, we verified the in vivo effects of RIG-I on ESCC cells by constructing xenograft models. RIG-I was highly expressed in ESCC cells and significantly promoted their proliferation and cell-cycle. Moreover, RIG-I knockdown inhibited xenograft growth in nude mice. Furthermore, RIG-I accelerated the cell-cycle by promoting the ubiquitination and degradation of p21. Overall, this study revealed that the increased expression of RIG-I due to ESCC accelerated the progression of esophageal cancer by promoting the ubiquitination and degradation of p21, which is related to the prognosis of ESCC. Thus, RIG-I may be a novel therapeutic target for ESCC treatment.

NAT10 mediated mRNA acetylation modification patterns associated with colon cancer progression and microsatellite status.

N4-acetylcytidine (ac4C) is one type of RNA modification found in eukaryotes. RNA acetylation modifications are gradually expanding in oncology. However, the role of RNA acetylation modifications in colorectal cancer and its association with colorectal cancer microsatellite status remain unclear. Using public databases and in vitro experiments, we verified the expression and biological function of NAT10, as the key RNA acetylation modification enzyme, in colorectal cancer. The results showed that NAT10 was highly expressed in colorectal cancer, and significantly promoted colorectal cancer cell proliferation. NAT10 was also involved in several aspects of cell homoeostasis such as ion transport, calcium-dependent phospholipid binding, and RNA stability. NAT10 expression positively correlated with immune infiltration in colorectal cancer. We further constructed a risk regression model for mRNA acetylation in colorectal cancer using acetylation-related differential genes. We found that tumour immune infiltration, microsatellite instability (MSI) proportion, tumour immune mutation burden, and patient response to immunotherapy were positively correlated with risk scores. For the first time, our study showed that the level of mRNA acetylation modification level is elevated in colorectal cancer and positively correlates with immune infiltration and microsatellite status of patients. Based on our findings, NAT10 may be a new target for colorectal cancer treatment.

RIG-I promotes immune evasion of colon cancer by modulating PD-L1 ubiquitination.

Colon cancer is one of the most prevalent cancers and exhibits high mortality worldwide. Despite the certain success in the immunotherapy of many tumor types, the limited response of colon cancer to immunotherapy remains a difficult problem. Retinoic acid-inducible gene-I (RIG-I) is a crucial component in innate antiviral immunity, but its role in antitumor immunity remains unclear. Here, in this report, we found that silencing RIG-I decreased resistance to tumor cells killed by T cells and attenuated colon tumor growth in immunocompetent mice. Meanwhile, overexpressing RIG-I promoted tumor progression, and high expression of RIG-I sensitized cells to anti-programmed cell death protein-1 (PD-1) therapy in vivo. Interestingly, we found that RIG-I influenced programmed cell death ligand 1 (PD-L1) expression to promote colon cancer immune evasion without relying on type I interferon stimulation. Mechanistically, RIG-I could compete with Speckle Type POZ protein (SPOP) to bind PD-L1, leading to attenuation of the polyubiquitination and proteasomal degradation of PD-L1. Collectively, our work reveals new insights into the contribution of RIG-I to driving immune evasion by maintaining the stability of PD-L1 through post-translational modification and provides a promising biomarker of the efficacy of immunotherapy in colon cancer.

Identification and Validation of a Potential Stemness-Associated Biomarker in Hepatocellular Carcinoma.

Background: Cancer stem cells (CSCs) are typically related to metastasis, recurrence, and drug resistance in malignant tumors. However, the biomarker and mechanism of CSCs need further exploration. This study is aimed at comprehensively depicting the stemness characteristics and identify a potential stemness-associated biomarker in hepatocellular carcinoma (HCC). Methods: The data of HCC patients from The Cancer Genome Atlas (TCGA) were collected and divided based on the mRNA expression-based stemness index (mRNAsi) in this study. Weighted gene coexpression network analysis (WGCNA) and the protein-protein interaction (PPI) network were performed, and the genes were screened through the Cytoscape software. Then, we constructed a prognostic expression signature using the multivariable Cox analysis and verified using the GEO and ICGC databases. Even more importantly, we used the three-dimensional (3D) fibrin gel to enrich the tumor-repopulating cells (TRCs) to validate the expression of the signature in CSCs by quantitative RT-PCR. Results: mRNAsi was significantly elevated in tumor and high-mRNAsi score was associated with poor overall survival in HCC. The positive stemness-associated (blue) module with 737 genes were screened based on WGCNA, and Budding uninhibited by benzimidazoles 1 (BUB1) was identified as the hub gene highly related to stemness in HCC. Then, the prognostic value and stemness characteristics were well validated in the ICGC and GSE14520 cohorts. Further analysis showed the expression of BUB1 was elevated in TRCs. Conclusion: BUB1, as a potential stemness-associated biomarker, could serve as a therapeutic CSCs-target and predicted the clinical outcomes of patients with HCC.