RRP8, associated with immune infiltration, is a prospective therapeutic target in hepatocellular carcinoma.

BACKGROUND: Ribosomal RNA Processing 8 (RRP8) is a nucleolar Rossman fold-like methyltransferase that exhibits increased expression in many malignant tumours. However, the role of RRP8 in hepatocellular carcinoma (HCC) is still uncertain. We explored the relationships between RRP8 and prognosis and immune infiltration, as well as the putative pathological function and mechanism of RRP8 in HCC. METHODS: Analysis of RRP8 expression across cancers was performed by using multiple databases. Associations between RRP8 expression and clinicopathological factors were further examined. Gene enrichment analysis was used to identify various putative biological activities and regulatory networks of RRP8 in HCC. The relationship between RRP8 expression and immune infiltration was confirmed by single-sample gene set enrichment analysis (ssGSEA). Univariate and multivariate Cox regression analyses were conducted to assess the impact of clinical variables on patient outcomes. Furthermore, a nomogram was constructed to estimate survival probability based on multivariate Cox regression analysis. Functional validation of RRP8 in HCC was performed with two different systems: doxycycline-inducible shRNA knockdown and CRISPR-Cas9 knockout. RESULTS: RRP8 was markedly overexpressed in HCC clinical specimens compared to adjacent normal tissues. Further analysis demonstrated that RRP8 was directly connected to multiple clinical characteristics and strongly associated with various immune markers in HCC. Moreover, elevated RRP8 expression indicated an unfavourable prognosis. Our functional studies revealed that both knockdown and knockout of RRP8 dramatically attenuated liver cancer cells to proliferate and migrate. Knockout of RRP8 decreased the phosphorylation of MEK1/2 and ß-catenin-(Y654) signalling pathway components; downregulated downstream signalling effectors, including Cyclin D1 and N-cadherin; and upregulated E-cadherin. CONCLUSIONS: RRP8 is strongly implicated in immune infiltration and could be a potential therapeutic target in HCC.

Donor-Acceptor Interactions Enhanced Colorimetric Sensors for Both Acid and Base Vapor Based on Two-Dimensional Covalent Organic Frameworks.

Due to the high surface area and uniform porosity of covalent organic frameworks (COFs), they exhibit superior properties in capturing and detecting even trace amounts of gases in the air. However, the COFs materials that possess dual detected functionality are still less reported. Here, an imine-based COF containing thiophene as a donor and triazine as an acceptor to form spatial-distribution-defined D-A structures was prepared. D-A system between thiophene and triazine facilitates the charge transfer process during the protonation process of the imine and the triazine units. The obtained COF exhibits simultaneous sensing ability toward both acidic and alkaline vapors with obvious colorimetric sensing functionality.

Single-cell dissection of the multicellular ecosystem and molecular features underlying microvascular invasion in HCC.

BACKGROUND AND AIMS: Microvascular invasion (MVI) is a crucial pathological hallmark of HCC that is closely associated with poor outcomes, early recurrence, and intrahepatic metastasis following surgical resection and transplantation. However, the intricate tumor microenvironment and transcriptional programs underlying MVI in HCC remain poorly understood. APPROACH AND RESULTS: We performed single-cell RNA sequencing of 46,789 individual cells from 10 samples of MVI+ (MVI present) and MVI- (MVI absent) patients with HCC. We conducted comprehensive and comparative analyses to characterize cellular and molecular features associated with MVI and validated key findings using external bulk, single-cell, and spatial transcriptomic datasets coupled with multiplex immunofluorescence assays. The comparison identified specific subtypes of immune and stromal cells critical to the formation of the immunosuppressive and pro-metastatic microenvironment in MVI+ tumors, including cycling T cells, lysosomal associated membrane protein 3+ dendritic cells, triggering receptor expressed on myeloid cells 2+ macrophages, myofibroblasts, and arterial i endothelial cells. MVI+ malignant cells are characterized by high proliferation rates, whereas MVI- malignant cells exhibit an inflammatory milieu. Additionally, we identified the midkine-dominated interaction between triggering receptor expressed on myeloid cells 2+ macrophages and malignant cells as a contributor to MVI formation and tumor progression. Notably, we unveiled a spatially co-located multicellular community exerting a dominant role in shaping the immunosuppressive microenvironment of MVI and correlating with unfavorable prognosis. CONCLUSIONS: This study provides a comprehensive single-cell atlas of MVI in HCC, shedding light on the complex multicellular ecosystem and molecular features associated with MVI. These findings deepen our understanding of the underlying mechanisms driving MVI and provide valuable insights for improving clinical diagnosis and developing more effective treatment strategies.

Characterization of prognostic value and immunological roles of RAB22A in hepatocellular carcinoma.

Background: The protein-coding gene RAB22A, a member of the RAS oncogene family, is amplified or overexpressed in certain cancers. However, its action mechanism in hepatocellular carcinoma (HCC) remains unclear. Here, we aimed to examine the connection between RAB22A and survival prognosis in HCC and explore the biological significance of RAB22A. Methods: A database-based pan-cancer expression analysis of RAB22A was performed. Kaplan-Meier analysis and Cox regression were performed to evaluate the association between RAB22A expression and survival prognosis in HCC. Using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), various potential biological functions and regulatory pathways of RAB22A in HCC were discovered. Tumor immune infiltration was studied using the single sample gene set enrichment analysis (ssGSEA) method. N6-methyladenosine modifications and the regulatory network of competitive endogenous RNA (ceRNA) were verified in the TCGA cohort. Results: RAB22A was upregulated in HCC samples and cell lines. A high RAB22A expression in HCC was strongly correlated with sex, race, age, weight, TNM stage, pathological stage, tumor status, histologic grade, TP53 mutation status, and alpha fetal protein (AFP) levels. Overexpression of RAB22A indicated a poor prognosis was related to overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). GO and KEGG analyses revealed that the differentially expressed genes related to RAB22A might be involved in the proteasomal protein catabolic process, ncRNA processing, ribosome ribosomal subunit, protein serine/threonine kinase activity, protein serine kinase activity, Endocytosis, and non-alcoholic fatty liver disease. GSEA analyses revealed that the differentially expressed genes related to RAB22A might be involved in the T cell receptor, a co-translational protein, that binds to the membrane, axon guidance, ribosome, phagocytosis, and Eukaryotic translation initiation. RAB22A was correlated with N6-methyladenosine expression in HCC and established RAB22A-related ceRNA regulatory networks. Finally,RAB22A expression was positively connected the levels of infiltrating with T helper cells, Tcm cells, and Th2 cells,In contrast, we observed negatively correlations with cytotoxic cells, DCs, and pDCs cells.Moreover,RAB22A expression showed a strong correlation with various immunomarkergroups in HCC. Conclusions: RAB22A is a potential therapeutic target for improving HCC prognosis and is closely related to immune cell infiltration.

A Novel Score Combining Magnetic Resonance Spectroscopy Parameters and Systemic Immune-Inflammation Index Improves Prognosis Prediction in Non-Small Cell Lung Cancer Patients With Brain Metastases After Stereotactic Radiotherapy.

Objective: The aim of this study was to evaluate the prognostic significance of the combination of the magnetic resonance spectroscopy (MRS) parameters and systemic immune-inflammation index (SII) in patients with brain metastases (BMs) from non-small cell lung cancer (NSCLC) treated with stereotactic radiotherapy. Methods: A total of 118 NSCLC patients with BM who were treated with stereotactic radiotherapy were retrospectively enrolled in this study. All patients underwent MRS and blood samples test for SII analysis before the initiation of stereotactic radiotherapy. The correlation between the parameters of MRS and SII level was assessed using Spearman's correlation coefficient. The cutoff values for the parameters of MRS, SII, and clinical laboratory variables were defined by the receiver operating characteristic (ROC) curve analysis to quantify these predictive values. The prognostic factors of overall survival (OS) and progression-free survival (PFS) curves were assessed using the Kaplan-Meier and Cox proportional hazards models. Results: The median follow-up time was 25 months (range, 12-49 months). The optimal cutoff point for the choline/creatine (Cho/Cr) ratio and SII were 1.50 and 480, respectively. The Cho/Cr ratio was negatively correlated with SII (rs = 0.164, p = 0.075), but there was a trend. The C-SII score was established by combining the Cho/Cr ratio and SII. Patients with both an elevated Cho/Cr ratio (>1.50) and an elevated SII (>480) were given a C-SII score of 2, and patients with one or neither were given a C-SII score of 1 or 0, respectively. The Kaplan-Meier analysis showed that a C-SII score of 2 was significantly linked with poor OS and PFS (p < 0.001 and p < 0.001, respectively). In the Cox proportional hazards model, the C-SII score independently predicted OS [hazard ratio (HR), 1.749; 95% CI, 1.176-2.601; p = 0.006] and PFS (HR, 2.472; 95% CI, 1.624-3.763; p < 0.001). Conclusion: The C-SII score was more accurate for predicting the clinical outcomes of NSCLC patients with BM who underwent stereotactic radiotherapy. The C-SII score, which was superior to either score alone, could be used to identify BM in NSCLC patients with poor outcomes.

Systemic immune-inflammation index changes predict outcome in stage III non-small-cell lung cancer patients treated with concurrent chemoradiotherapy.

Background: Although the systemic immune-inflammation index (SII) has been used to predict recurrence and survival in non-small-cell lung cancer (NSCLC) patients, the prognostic significance of change in SII (ΔSII) is unclear for stage III NSCLC patients treated with concurrent chemoradiotherapy (CCRT). In the present study we aimed to explore the association between ΔSII and the clinical outcomes of 142 patients with stage III NSCLC treated with CCRT. Methods: A total of 142 patients were included in this retrospective study. The SII values were calculated based on laboratory data regarding platelet, neutrophil and lymphocyte counts, and ΔSII was calculated using data acquired before and approximately 2 weeks after CCRT. The receiver operating characteristic curve was used to determine the optimal cut-off value for the peripheral blood inflammation index. Kaplan-Meier analysis and Cox proportional regression were used to analyze the prognostic value of ΔSII for overall survival (OS) and progression-free survival (PFS). Results: The area under the receiver operating characteristic curve for ΔSII (0.708) was larger than those for pre-CCRT SII (0.578) and post-CCRT SII (0.610). The optimal cut-off point for ΔSII was defined as 43. OS and PFS were better in patients with low ΔSII and in multivariate analysis, the ΔSII was an independent predictor of OS and PFS (p = 0.006 and p = 0.017, respectively). Conclusions: ΔSII is related to progression and death in patients with stage III NSCLC. The ΔSII can provide a detailed prognostic prediction for stage III NSCLC.

ABCA8 is regulated by miR-374b-5p and inhibits proliferation and metastasis of hepatocellular carcinoma through the ERK/ZEB1 pathway.

BACKGROUND: ATP binding cassette subfamily A member 8 (ABCA8) belongs to the ATP binding cassette (ABC) transporter superfamily. ABCA8 is a transmembrane transporter responsible for the transport of organics, such as cholesterol, and drug efflux. Some members of the ABC subfamily, such as ABCA1, may inhibit cancer development. However, the mechanism of ABCA8 in the process of cancer activation is still ambiguous. METHODS: The expression of ABCA8 in human hepatocellular carcinoma (HCC) tissues and cell lines was examined using qPCR, immunoblotting, and immunohistochemical staining. The effects of ABCA8 on the proliferation and metastasis of HCC were examined using in vitro and in vivo functional tests. A luciferase reporter assay was performed to explore the binding between microRNA-374b-5p (miR-374b-5p) and the ABCA8 3'-untranslated region (UTR). RESULTS: ABCA8 was frequently down-regulated in HCC and this down-regulation was negatively correlated with prognosis. The overexpression of ABCA8 inhibited growth and metastasis in HCC, whereas the knockdown of ABCA8 exerted the antithetical effects both in vivo and in vitro. ABCA8 was down-regulated by miR-374b-5p; this down-regulation can induce epithelial transformation to mesenchyme via the ERK/ZEB1 signaling pathway and promote HCC progression. CONCLUSION: We exposed the prognostic value of ABCA8 in HCC, and illuminated a novel pathway in ABCA8-regulated inhibition of HCC tumorigenesis and metastasis. These findings may lead to a new targeted therapy for HCC through the regulation of ABCA8, and miR-374b-5p.