Identification of Downregulated Exosome-Associated Gene ENPP1 as a Novel Lipid Metabolism and Immune-Associated Biomarker for Hepatocellular Carcinoma.

Exosome plays an important role in the occurrence and development of tumors, such as hepatocellular carcinoma (LIHC). However, the functions and mechanisms of exosome-associated molecules in LIHC are still underexplored. Here, we investigated the role of the exosome-related gene ENPP1 in LIHC. Comprehensive bioinformatics from multiple databases revealed that ENPP1 was significantly downregulated in LIHC tissues. The patients with downregulated ENPP1 displayed a poor prognosis. Immunohistochemistry (IHC) was used to further confirm the downregulated ENPP1 in LIHC tissues. In addition, the coexpression network of ENPP1 was also explored to understand its roles in the underlying signaling pathways, including fatty acid degradation and the PPAR signaling pathway. Simultaneously, GSEA analysis indicated the potential roles of ENPP1 in the lipid metabolism-associated signaling pathways in the pathogenesis of LIHC, including fatty acid metabolism, fatty acid synthesis, and so on. Finally, immunological analysis indicated that ENPP1 might also be involved in multiple immune-related features, including immunoinhibitors, immunostimulators, and chemokines. Taken together, these findings could enhance our understanding of ENPP1 in LIHC pathogenesis and immune response and provide a new target for ENPP1-related immunotherapy in clinical treatment.

Pan-cancer analysis of the prognosis and immunological role of AKAP12: A potential biomarker for resistance to anti-VEGF inhibitors.

The primary or acquired resistance to anti-VEGF inhibitors remains a common problem in cancer treatment. Therefore, identifying potential biomarkers enables a better understanding of the precise mechanism. Through the GEO database, three profiles associated with bevacizumab (BV) resistance to ovarian cancer, glioma, and non-small-cell lung carcinoma, respectively, were collected for the screening process, and two genes were found. A-kinase anchor protein 12 (AKAP12), one of these two genes, correlates with tumorigenesis of some cancers. However, the role of AKAP12 in pan-cancer remains poorly defined. The present study first systematically analyzed the association of AKAP12 with anti-VEGF inhibitors' sensitivity, clinical prognosis, DNA methylation, protein phosphorylation, and immune cell infiltration across various cancers via bioinformatic tools. We found that AKAP12 was upregulated in anti-VEGF therapy-resistant cancers, including ovarian cancer (OV), glioblastoma (GBM), lung cancer, and colorectal cancer (CRC). A high AKAP12 expression revealed dismal prognoses in OV, GBM, and CRC patients receiving anti-VEGF inhibitors. Moreover, AKAP12 expression was negatively correlated with cancer sensitivity towards anti-VEGF therapy. Clinical prognosis analysis showed that AKAP12 expression predicted worse prognoses of various cancer types encompassing colon adenocarcinoma (COAD), OV, GBM, and lung squamous cell carcinoma (LUSC). Gene mutation status may be a critical cause for the involvement of AKAP12 in resistance. Furthermore, lower expression of AKAP12 was detected in nearly all cancer types, and hypermethylation may explain its decreased expression. A decreased phosphorylation of T1760 was observed in breast cancer, clear-cell renal cell carcinoma, and lung adenocarcinoma. For the immunologic significance, AKAP12 was positively related to the abundance of pro-tumor cancer-associated fibroblasts (CAFs) in various types of cancer. The results of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that "cell junction organization" and "MAPK pathway" participated in the effect of AKAP12. Importantly, we discovered that AKAP12 expression was greatly associated with metastasis of lung adenocarcinoma as well as differential and angiogenesis of retinoblastoma through investigating the single-cell sequencing data. Our study showed that the dual role of AKAP12 in various cancers and AKAP12 could serve as a biomarker of anti-VEGF resistance in OV, GBM, LUSC, and COAD.

The RIPK family: expression profile and prognostic value in lung adenocarcinoma.

Receptor interacting protein kinases (RIPKs) are a family of serine/threonine kinases which are supposed to regulate tumor generation and progression. Rare study illustrates the roles and functions of RIPKs family in lung adenocarcinoma (LUAD) comprehensively. Our results indicated that the expression of RIPK2 higher in LUAD patients while RIPK5 (encoded by gene DSTYK) expression was lower. Only RIPK2 had a strong correlation with pathological stage in LUAD patients. Kaplan-Meier plotter revealed that LUAD patients with low RIPK2 or RIPK3 level showed better overall survival (OS), but worse when LUAD patients with high RIPK5. Further, lower expression of RIPK2 and higher expression of RIPK1, RIPK4 and RIPK5 prompted a longer disease free survival (DFS). Genetic alterations based on cBioPortal revealing 16% alteration rates of RIPK2, as well as RIPK5. We also found that the functions of RIPKs family were linked to cellular senescence, protein serine/threonine kinase activity, apoptosis process et al. TIMER database indicated that the RIPKs family members had distinct relationships with the infiltration of six types of immune cells (macrophages, neutrophils, CD8+ T-cells, B-cells, CD4+ T-cells and dendritic cells). Moreover, RIPK2 could be observed as an independent prognostic factor with Cox proportional hazard model analysis. DiseaseMeth databases revealed that the global methylation levels of RIPK2 increased in LUAD patients. Thus, the findings above will enhance the understanding of RIPKs family in LUAD pathology and progression, providing novel insights into RIPKs-core therapy for LUAD patients.

A Prognostic Signature Consisting of Pyroptosis-Related Genes and SCAF11 for Predicting Immune Response in Breast Cancer.

Pyroptosis, characterized as an inflammasome-mediated cell death pathway, may be participated in tumorigenesis and progression. However, the underlying molecular function and mechanism of pyroptosis in BRCA remain unclear. In our study, we aimed to develop a prognostic signature in BRCA based on pyroptosis-associated genes. Data was downloaded from TCGA database, and then we screened 760 female BRCA samples and 104 normal breast tissues as the training set. Seven pyroptosis-related genes (CASP9, GPX4, IL18, NLRC4, SCAF11, TIRAP, and TNF) were identified as the pyroptosis-related prognostic model for BRCA using LASSO Cox regression. We subsequently tested the prognostic value of pyroptosis-associated gene signature in a validation set, GSE 20685. Time-dependent receiver operating characteristic analysis demonstrated the credible predictive capacity of this pyroptosis-associated gene signature. The area under the curves were 0.806 at 3 years, 0.787 at 5 years, 0.775 at 8 years, and 0.793 at 10 years in the training set, and 0.824 at 5 years, 0.808 at 8 years, and 0.790 at 10 years in the validation set. Furthermore, there are currently few data on SCAF11 regulating pyroptosis. To clarify this issue, we performed integrative bioinformatics and experimental analysis. Knocking down SCAF11 possessed an anti-cancer effect in terms of inhibiting cell viability and suppressing colony-formation in in-vitro functional assays. Meanwhile, the biological functions of SCAF11 in BRCA were further validated with several algorithms, such as Xiantao tool, LinkedOmics, GEPIA2, and TISIDB. These findings indicated that the expression of SCAF11 was significantly correlated with diverse tumor-infiltrating lymphocytes (TILs), including T central memory cell (Tcm), and type 2 T helper cell (Th2), etc. Functional enrichment analysis suggested that co-expression genes of SCAF11 primarily participated in inflammation and immune-related signaling pathways, such as oxidative phosphorylation, antimicrobial humoral response, and immunoglobulin complex. Moreover, SCAF11 expression was positively correlated with several immune checkpoints, including PD-L1, B7H3, and PDCD1LG2. Taken together, this study uncovered that pyroptosis-associated gene signature might be applied as an effective independent predictor in patients with BRCA. The pyroptosis-related gene SCAF11 might play potential roles in the regulation of immune microenvironment in BRCA.

Potential Biological Roles of Exosomal Long Non-Coding RNAs in Gastrointestinal Cancer.

Exosomes, a type of extracellular vesicles (EVs), are secreted by almost all cells and contain many cellular constituents, such as nucleic acids, lipids, and metabolites. In addition, they play a crucial role in intercellular communication and have been proved to be involved in the development and treatment of gastrointestinal cancer. It has been confirmed that long non-coding RNAs (lncRNAs) exert a range of biological functions, such as cell metastasis, tumorigenesis, and therapeutic responses. This review mainly focused on the emerging roles and underlying molecular mechanisms of exosome-derived lncRNAs in gastrointestinal cancer in recent years. The biological roles of exosomal lncRNAs in the pathogenesis and therapeutic responses of gastrointestinal cancers were also investigated.

Tropane Skeleta from the Intramolecular Photocycloaddition of (4+3) Cycloadducts of Oxidopyridinium Ions and Dienes.

Easily prepared cycloadducts derived from the (4+3) cycloaddition of oxidopyridinium ions with dienes reacted intramolecularly in a [2+2] cycloaddition process to afford complex polycyclic species in which the tropane skeleton was embedded.

Endo Selectivity in the (4 + 3) Cycloaddition of Oxidopyridinium Ions.

The (4 + 3) cycloaddition of 2-trialkylsilyl-4-alkylbutadienes with an N-methyloxidopyridinium ion affords cycloadducts with high regioselectivity and excellent endo selectivity.

Generation of the 7-Azabicyclo[4.3.1]decane Ring System via (4 + 3) Cycloaddition of Oxidopyridinium Ions.

Oxidopyridinium ions bearing an ester group at the 5-position undergo (4 + 3) cycloaddition reaction to afford congeners of 7-azabicyclo[4.3.1]decane. The reaction generally proceeds in high yield, although an excess of diene is often required to achieve such yields. The reaction is highly regioselective, but not endo/exo selective. It appears the cycloaddition process can be either kinetically or thermodynamically controlled, depending on the nature of the diene used and the reaction time. An intramolecular Heck reaction was used to demonstrate that some chemistry is possible with the cycloadducts.

Synthesis of 3-(Arylsulfonyl)-3-pyrrolines from Allenyl Sulfonamides by Silver Ion Catalysis.

Treatment of allenyl sulfonamides with catalytic amounts of silver fluoride in acetonitrile at reflux afforded the corresponding 3-sulfonyl-3-pyrrolines in excellent yields by intramolecular hydroamination via a 5- endo-trig cyclization. The starting allenyl sulfonamides were prepared by lithiation of allenic sulfones and trapping with various N-sulfonylimines.

(4+3) Cycloaddition Reactions of N-Alkyl Oxidopyridinium Ions.

N-Methylation of methyl 5-hydroxynicotinate followed by reaction with a diene in the presence of triethylamine afforded (4+3) cycloadducts in good to excellent yields. High regioselectivity was observed with 1-substituted and 1,2-disubstituted butadienes. Density functional theory calculations indicate that the cycloaddition involves concerted addition of the diene onto the oxidopyridinium ion. The process provides rapid access to bicyclic nitrogenous structures resembling natural alkaloids.