In silico analysis of small molecule compounds based on pharmacophore- and backbone-leaping peroxiredoxin 1 (PRDX1) inhibitors.

Abnormal expression of PRDX has been found to play a significant role in the growth of colorectal cancer and other types of tumors. Despite the identification of several PRDX1 inhibitory compounds in recent years, none of them have been utilized in clinical treatments. Therefore, we conducted a virtual screening of 210,331 small molecules from the SPECS library using PRDX1 and multiple methods. From this screening, we identified 13 compounds with the highest scores from the molecular docking analysis. To further validate the accuracy of our pharmacophore model, we constructed a structure-based pharmacophore model and analyzed the receiver operating characteristic curve (ROC curve). Through this process, we selected nine compounds using skeleton jumping and virtual screening based on the highest pharmacophore model scores. Subsequently, we examined the ADMET properties of these nine compounds to assess their drug-forming potential, resulting in three compounds with the best drug properties. Finally, we assessed the binding stability of these three candidate molecules to proteins using molecular dynamics and MM-PBSA calculations. After a comprehensive evaluation, we found that compounds 6 and 9 formed stable complexes with PRDX1 proteins and could potentially serve as competitive inhibitors of PRDX1 substrates.Communicated by Ramaswamy H. Sarma.

Construction of an Immune-Related Prognostic Signature and lncRNA‒miRNA-mRNA ceRNA Network in Acute Myeloid Leukaemia.

The progression of acute myeloid leukaemia (AML) is influenced by the immune microenvironment in the bone marrow and dysregulated intracellular competing endogenous RNA (ceRNA) networks. Our study utilized data from UCSC Xena, Cancer Genome Atlas Program, Gene Expression Omnibus, Immunology Database and Analysis Portal. Using Cox regression analysis, we identified an immune-related prognostic signature. Genomic analysis of prognostic mRNA was conducted through Gene Set Cancer Analysis (GSCA), and a prognostic ceRNA network was constructed using the Encyclopedia of RNA Interactomes. Correlations between signature mRNAs and immune cell infiltration, checkpoints, and drug sensitivity were assessed using R software, GEPIA, and CellMiner, respectively. Adhering to the ceRNA hypothesis, we established a potential lncRNA/miRNA/mRNA regulatory axis. Our findings pinpointed nine immune-related prognostic mRNAs (KIR2DL1, CSRP1, APOBEC3G, CKLF, PLXNC1, PNOC, ANGPT1, IL1R2, and IL3RA). GSCA analysis revealed the impact of copy number variations and methylation on AML. The ceRNA network comprised 14 differentially expressed prognostic lncRNAs (DE-lncRNAs), six prognostic DE-miRNAs, and three prognostic immune-related IR-DEmRNAs. Correlation analyses linked these mRNA's expression to 22 immune cell types, six immune checkpoints, and potential sensitivity to 27 antitumor drugs. Finally, we identified a potential LINC00963/hsa-miR-431-5p/CSRP1 axis. This study offers innovative insights for AML diagnosis and treatment through a novel immune-related signature and ceRNA axis. Identified novel biomarkers, including two mRNAs (CKLF, PNOC), one miRNA (hsa-miR-323a-3p), and ten lncRNAs (SNHG25, LINC01857, AL390728.6, AC127024.5, Z83843.1, AP002884.1, AC007038.1, AC112512, AC020659.1, AC005921.3) present promising candidates as potential targets for precision medicine, contributing to the ongoing advancements in the field.

Identification and validation of an immunotherapeutic signature for colon cancer based on the regulatory patterns of ferroptosis and their association with the tumor microenvironment.

The integrated landscape of ferroptosis regulatory patterns and their association with colon microenvironment have been demonstrated in recent studies. However, the ferroptosis-related immunotherapeutic signature for colon cancer (CC) remains unclear. We comprehensively evaluated 1623 CC samples, identified patterns of ferroptosis modification based on ferroptosis-associated genes, and systematically correlated these patterns with tumor microenvironment (TME) cell infiltration characteristics. In addition, the ferroptosis-regulated gene score (FRG-score) was constructed to quantify the pattern of ferroptosis alterations in individual tumors. Three distinct patterns of ferroptosis modification were identified, including antioxidant defense, iron toxicity, and lipid peroxidation. The characteristics of TME cell infiltration under these three patterns were highly consistent with the three immune phenotypes of tumors, including immune-inflamed, immune-excluded and immune-desert phenotypes. We also demonstrated that evaluation of ferroptosis regulatory patterns within individual tumors can predict tumor inflammatory status, tumor subtype, TME stromal activity, genetic variation, and clinical outcome. Immunotherapy cohorts confirmed that patients with low FRG-scores showed remarkable therapeutic and clinical benefits. Furthermore, the hub gene apolipoprotein L6 (APOL6), a drug-sensitive target associated with cancer cell ferroptosis, was identified through our proposed novel key gene screening process and validated in CC cell lines and scRNA-seq.

Ethyl 2,2-difluoro-2-(2-oxo-2H-chromen-3-yl) acetate attenuates the malignant biological behaviors of non-small cell lung cancer via suppressing EGFR/PI3K/AKT/mTOR signaling pathway.

OBJECTIVE: The goal of the study is to examine the impact on the malignant biological behaviors of non-small cell lung cancer (NSCLC) of a novel coumarin derivative, ethyl 2,2-difluoro-2-(2-oxo-2H-chromen-3-yl) acetate (C2F). It also aims to define its underlying mechanism. METHODS: NSCLC cell lines and xenograft nude mice model were conducted to explore the anti-NSCLC effects of C2F in vitro and in vivo. Then, network pharmacology analysis and molecular docking were applied to estimate the possible targets of C2F in NSCLC. Finally, the underlying mechanism of C2F against NSCLC cellular proliferation and tumor development was confirmed using inhibitors or activators of the PI3K/AKT signaling pathway. RESULTS: Our results showed that C2F was able to inhibit proliferation, migration, and invasion of NSCLC cell lines, induce cell cycle arrest and apoptosis in vitro, and prevent tumor growth in vivo. In addition, the estimated glomerular filtration rate and its downstream pathway (PI3K/AKT/mTOR) were found to be critical for the anti-NSCLC activity of C2F. CONCLUSIONS: C2F inhibits malignant biological behaviors of NSCLC by suppressing EGFR/PI3K/AKT/mTOR signaling pathway.

Lysosome-targeted ruthenium(II) complex encapsulated with pluronic® F-127 induces oncosis in A549 cells.

Transition metal complexes with characteristics of unique packaging in nanoparticles and remarkable cancer cell cytotoxicity have emerged as potential alternatives to platinum-based antitumor drugs. Here we report the synthesis, characterization, and antitumor activities of three new Ruthenium complexes that introduce 5-fluorouracil-derived ligands. Notably, encapsulation of one such metal complex, Ru3, within pluronic® F-127 micelles (Ru3-M) significantly enhanced Ru3 cytotoxicity toward A549 cells by a factor of four. To determine the mechanisms underlying Ru3-M cytotoxicity, additional in vitro experiments were conducted that revealed A549 cell treatment with lysosome-targeting Ru3-M triggered oxidative stress, induced mitochondrial membrane potential depolarization, and drastically reduced intracellular ATP levels. Taken together, these results demonstrated that Ru3-M killed cells mainly via a non-apoptotic pathway known as oncosis, as evidenced by observed Ru3-M-induced cellular morphological changes including cytosolic flushing, cell swelling, and cytoplasmic vacuolation. In turn, these changes together caused cytoskeletal collapse and activation of porimin and calpain1 proteins with known oncotic functions that distinguished this oncotic process from other cell death processes. In summary, Ru3-M is a potential anticancer agent that kills A549 cells via a novel mechanism involving Ru(II) complex triggering of cell death via oncosis.

Cyclometalated ruthenium complexes overcome cisplatin resistance through PI3K/mTOR/Nrf2 signaling pathway.

Currently, cisplatin resistance remains a primary clinical obstacle in the successful treatment of non-small cell lung cancer. Here, we designed, synthesized, and characterized two novel cyclometalated Ru(II) complexes, [Ru(bpy)2(1-Ph-7-OCH3-IQ)] (PF6) (bpy = 2,2'-bipyridine, IQ = isoquinoline, RuIQ7)and [Ru(bpy)2(1-Ph-6,7-(OCH3)2-IQ)] (PF6) (RuIQ8). As experimental controls, we prepared complex [Ru(bpy)2(1-Ph-IQ)](PF6) (RuIQ6) lacking a methoxy group in the main ligand. Significantly, complexes RuIQ6-8 displayed higher in vitro cytotoxicity when compared to ligands, precursor cis-[Ru(bpy)2Cl2], and clinical cisplatin. Mechanistic investigations revealed that RuIQ6-8 could inhibit cell proliferation by downregulating the phosphorylation levels of Akt and mTOR proteins, consequently affecting the rapid growth of human lung adenocarcinoma cisplatin-resistant cells A549/DDP. Moreover, the results from qRT-PCR demonstrated that these complexes could directly suppress the transcription of the NF-E2-related factor 2 gene, leading to the inhibition of downstream multidrug resistance-associated protein 1 expression and effectively overcoming cisplatin resistance. Furthermore, the relationship between the chemical structures of these three complexes and their anticancer activity, ability to induce cell apoptosis, and their efficacy in overcoming cisplatin resistance has been thoroughly examined and discussed. Notably, the toxicity test conducted on zebrafish embryos indicated that the three Ru-IQ complexes displayed favorable safety profiles. Consequently, the potential of these developed compounds as innovative therapeutic agents for the efficient and low-toxic treatment of NSCLC appears highly promising.

Mitochondria-targeted cyclometalated iridium (III) complexes: Dual induction of A549 cells apoptosis and autophagy.

In this study, we synthesized 4 cyclometalated iridium complexes using N-(1,10-phenanthrolin-5-yl)picolinamide (PPA) as the main ligand, denoted as [Ir(ppy)2PPA]PF6 (ppy = 2-phenylpyridine, Ir1), [Ir(bzq)2PPA]PF6 (bzq = benzo[h]quinoline, Ir2), [Ir(dfppy)2PPA]PF6 (dfppy = 2-(3,5-difluorophenyl)pyridine, Ir3), and [Ir(thpy)2PPA]PF6 (thpy = 2-(thiophene-2-yl)pyridine, Ir4). Compared to cisplatin and oxaliplatin, all four complexes exhibited significant anti-tumor activity. Among them, Ir2 demonstrated higher cytotoxicity against A549 cells, with an IC50 value of 1.6 ± 0.2 µM. The experimental results indicated that Ir2 primarily localized in the mitochondria, inducing a large amount of reactive oxygen species (ROS) generation, that decreased in mitochondrial membrane potential (MMP), reduced ATP production, and further impaired mitochondrial function, leading to cytochrome c release. Additionally, Ir2 caused cell cycle arrest at the S phase and induced apoptosis through the AKT-mediated signaling pathway. Further investigations revealed that Ir2 could simultaneously induce both apoptosis and autophagy in A549 cells, with the latter acting as a non-protective mechanism that promoted cell death. More importantly, Ir2 exhibited low toxicity to both normal LO2 cells in vitro and zebrafish embryos in vivo. Consequently, these newly developed Ir(III) complexes show great potential in the development of novel and low-toxicity anticancer agents.

Exploring the potential mechanisms of Yi-Yi-Fu-Zi-Bai-Jiang-San therapy on the immune-inflamed phenotype of colorectal cancer via combined network pharmacology and bioinformatics analyses.

BACKGROUND: The development and progression of colorectal cancer (CRC) is closely associated with its complex tumor microenvironment (TME). Assessment of the modified pattern of immune cell infiltration (ICI) will help increase knowledge regarding the characteristics of TME infiltration. Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS) has been shown to have positive effects on the regulation of the immune microenvironment of CRC. However, its pharmacological targets and molecular mechanisms remain to be elucidated. METHODS: Network pharmacological analysis was used to identify the target of YYFZBJS in the TME of CRC. Patients with the immune-inflamed phenotype (IIP) were identified using CRC samples from The Cancer Genome Atlas (TCGA) database. Consensus genes were identified by intersecting YYFZBJS targets, CRC disease targets and differentially expressed genes in the CRC microenvironment. Then, least absolute shrinkage and selection operator (LASSO) Cox analyses were used to identify a prognostic signature from the consensus genes. Cytoscape software was further used to build a unique herb-compound-target network diagram of the important components of YYFZBJS and prognostic gene targets. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed using the prognostic gene sets to explore the molecular mechanism of the prognostic genes in drug therapy for CRC IIP patients. Finally, single-cell analysis was performed to validate the expression of the prognostic genes in the TME of CRC using the TISCH2 database. RESULTS: A total of 284 IIP patients were identified from 480 patients with CRC. A total of 35 consensus genes were identified as targets of YYFZBJS in the TME of CRC patients. An eleven-gene prognostic signature, including PIK3CG, C5AR1, PRF1, CAV1, HPGDS, PTGS2, SERPINE1, IDO1, TGFB1, CXCR2 and MMP9, was identified from the consensus genes, with areas under the receiver operating characteristic (ROC) curve (AUCs) values of 0.84 and 0.793 for the training and test cohorts, respectively. In the herb-compound-target network, twenty-four compounds were shown to interact with the 11 prognostic genes, which were significantly enriched in the IL-17 signaling, arachidonic acid metabolism and metabolic pathways. Single-cell analysis of the prognostic genes confirmed that their abnormal expression was associated with the TME of CRC. CONCLUSION: This study organically integrated network pharmacology and bioinformatics analyses to identify prognostic genes in CRC IIP patients from the targets of YYFZBJS. Although this data mining work was limited to the study of mechanisms related to prognosis based on the immune microenvironment, the methodology provides new perspectives in the search for novel therapeutic targets of traditional Chinese medicines (TCMs) and accurate diagnostic indicators of cancers targeted by TCMs.

Cyclometalated iridium(III) complexes induce immunogenic cell death in HepG2 cells via paraptosis.

Immunotherapy has been shown to provide superior antitumor efficacy by activating the innate immune system to recognize, attack and eliminate tumor cells without seriously harming normal cells. Herein, we designed and synthesized three new cyclometalated iridium(III) complexes (Ir1, Ir2, Ir3) then evaluated their antitumor activity. When co-incubated with HepG2 cells, the complex Ir1 localized in the lysosome, where it induced paraptosis and endoplasmic reticulum stress (ER stress). Notably, Ir1 also induced immunogenic cell death (ICD), promoted dendritic cell maturation that enhanced effector T cell chemotaxis to tumor tissues, down-regulated proportions of immunosuppressive regulatory T cells within tumor tissues and triggered activation of antitumor immunity throughout the body. To date, Ir1 is the first reported iridium(III) complex-based paraptosis inducer to successfully induce tumor cell ICD. Furthermore, Ir1 induced ICD of HepG2 cells without affecting cell cycle or reactive oxygen species levels.

8-Hydroxyquinoline ruthenium(II) complexes induce ferroptosis in HeLa cells by down-regulating GPX4 and ferritin.

Ruthenium complexes are one of the most promising anticancer drugs triggered extensive research. Here, the synthesis and characterization of two ruthenium(II) polypyridine complexes containing 8-hydroxylquinoline as ligand, [Ru(dip)2(8HQ)]PF6 (Ru1), [Ru(dpq)2(8HQ)]PF6 (Ru2) (8HQ = 8-hydroxylquinoline; dip = 4,7-diphenyl-1,10-phenanthroline; dpq = pyrazino[2,3-f][1,10]phenanthroline) were reported. On the basis of cytotoxicity tests, Ru1 (IC50 = 1.98 ± 0.02 µM) and Ru2 (IC50 = 10.02 ± 0.19 µM) both showed good anticancer activity in a panel of cell lines, especially in HeLa cells. Researches on mechanism indicated that Ru1 and Ru2 acted on mitochondria and nuclei and induced reactive oxygen species (ROS) accumulation, while the morphology of nuclei and cell cycle had no significant change. Western blot assay further proved that GPX4 and Ferritin were down-regulated, which eventually triggered ferroptosis in HeLa cells. In addition, the toxicity test of zebrafish embryos showed that the concentrations of Ru1 and Ru2 below 120 µM and 60 µM were safe and did not have obvious effect on the normal development of zebrafish embryos.

Asymmetric total synthesis and anti-hepatocellular carcinoma profile of enantiopure euphopilolide and jolkinolide E.

A flexible asymmetric synthesis of both enantiomers of euphopilolide (1) and jolkinolide E (2) [(+)-and (-)-1, (+)-and (-)-2] has been accomplished. This synthesis features an intramolecular oxa-Pauson-Khand reaction (o-PKR) to expeditiously construct the challenging tetracyclic [6.6.6.5] abietane-type diterpene framework, elegantly showcasing the complexity-generating features of o-PKR synthetic methodology leveraging on a judiciously chosen suitable chiral pool scaffold. Furthermore, the anti-hepatocellular carcinoma (HCC) activity of synthetic (-)-euphopilolide (1), (-)-jolkinolide E (2) and their analogues was evaluated. We found that (-)-euphopilolide (1) and (-)-jolkinolide E (2) inhibited the proliferation and induced apoptosis in HCC cells. These findings lay a good foundation for further pharmacology studies of abietane lactone derivatives and provide valuable insight for the development of anti-HCC small molecule drug of natural product origin.

Cyclometalated ruthenium (II) complexes induced HeLa cell apoptosis through intracellular reductive injury.

The main challenge of cancer chemotherapy is the resistance of tumor cells to oxidative damage. Herein, we proposed a novel antitumor strategy: cyclic metal­ruthenium (Ru) complexes mediate reductive damage to kill tumor cells. We designed and synthesized Ru(II) complexes with ß-carboline as ligands: [Ru (phen)2(NO2-Ph-ßC)](PF6) (RußC-7) and [Ru(phen)2(1-Ph-ßC)](PF6) (RußC-8). In vitro experimental results showed that RußC-7 and RußC-8 can inhibit cell proliferation, promote mitochondrial abnormalities, and induce DNA damage. Interestingly, RußC-7 with SOD activity could reduce intracellular reactive oxygen species (ROS) levels, while RußC-8 has the opposite effect. Accordingly, this study identified the reductive damage mechanism of tumor apoptosis, and may provide a new ideas for the design of novel metal complexes.

Ruthenium(II) complexes as mitochondrial inhibitors of topoisomerase induced A549 cell apoptosis.

Two new ruthenium(II) complexes [Ru(dip)2(PPßC)]PF6 (Ru1, dip = 4,7-diphenyl-1,10-phenanthroline, PPßC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide) and [Ru(phen)2(PPßC)]PF6 (Ru2, phen = 1, 10-phenanthroline) with ß-carboline derivative PPßC as the primary ligand, were designed and synthesized. Ru1 and Ru2 displayed higher antiproliferative activity than cisplatin against the test cancer cells, with IC50 values ranging from 0.5 to 3.6 µM. Moreover, Ru1 and Ru2 preferentially accumulated in mitochondria and caused a series of changes in mitochondrial events, including the depolarization of mitochondrial membrane potential, the damage of mitochondrial DNA, the depletion of cellular ATP, and the elevation of intracellular reactive oxygen species levels. Then, it induced caspase-3/7-mediated A549 cell apoptosis. More importantly, both complexes could act as topoisomerase I catalytic inhibitors to inhibit mitochondrial DNA synthesis. Accordingly, the developed Ru(II) complexes hold great potential to be developed as novel therapeutics for cancer treatment.

Mitochondria-targeted cyclometalated iridium-ß-carboline complexes as potent non-small cell lung cancer therapeutic agents.

Natural products and metals play a crucial role in cancer research and the development of antitumor drugs. We designed and synthesized three new carboline-based cyclometalated iridium complexes [Ir(C-N)2(PPßC)](PF6), where PPßC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide, C-N = 2-phenylpyridine (ppy, Ir1), 2-(2,4-difluorophenyl) pyridine (dfppy, Ir2), 7,8-benzoquinoline (bzq, Ir3), by combining iridium with ß-carboline derivative. These iridium complexes exhibited high potential antitumor effects after being promptly taken up by A549 cells. Accumulating in mitochondria rapidly and preferentially, Ir1-3 caused a series of changes in mitochondrial events, including the loss of mitochondrial membrane potential, the depletion of cellular ATP, and the elevation of reactive oxygen species, leading to significant death of A549 cells. Moreover, the activation of intracellular caspase pathway and apoptosis was further validated to contribute to iridium complexes-induced cytotoxicity. These novel iridium complexes exerted a prominent inhibitory effect on tumor growth in a three-dimensional multicellular tumor spheroid model.

Dimeric oxyberberine CT4-1 targets LINC02331 to induce cytotoxicity and inhibit chemoresistance via suppressing Wnt/ß-catenin signaling in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a type of cancer characterized by high recurrence rates. Overcoming chemoresistance can reduce HCC recurrence and improve patients' prognosis. This work aimed to identify HCC chemoresistance-associated long non-coding RNA (lncRNA) and find an effective drug targeting the identified lncRNA for ameliorating the chemoresistance. In this investigation, bioinformatics analysis based on The Cancer Genome Atlas revealed a new chemoresistance index and suggested LINC02331 as an HCC chemoresistance and patients' prognosis-associated lncRNA that served as an independent prognostic indicator. Moreover, LINC02331 promoted DNA damage repair, DNA replication, and epithelial-mesenchymal transition as well as attenuated cell cycle arrest and apoptosis through regulating Wnt/ß-catenin signaling, thus stimulating HCC resistance to cisplatin cytotoxicity, proliferation, and metastasis. Interestingly, we developed a novel oxidative coupling approach to synthesize a dimeric oxyberberine CT4-1, which exerted superior anti-HCC activities without obvious side effects measured by in vivo mice model and could downregulate LINC02331 mice model and could downregulate LINC02331 to mitigate LINC02331-induced HCC progression by suppressing Wnt/ß-catenin signaling. RNA sequencing analyses verified the involvement of CT4-1-affected differential expression genes in dysregulated pathways and processes, including Wnt, DNA damage repair, cell cycle, DNA replication, apoptosis, and cell adhesion molecules. Furthermore, CT4-1 was demonstrated to be an effective cytotoxic drug in ameliorating HCC patients' prognosis with a prediction model constructed based on RNA-sequencing data from CT4-1-treated cancer cells and public cancer database. In summary, HCC chemoresistance-associated LINC02331 independently predicted poor patients' prognosis and enhanced HCC progression by promoting resistance to cisplatin cytotoxicity, proliferation, and metastasis. Targeting LINC02331 by the dimeric oxyberberine CT4-1 that exhibited synergistic cytotoxicity with cisplatin could alleviate HCC progression and improve patients' prognosis. Our study identified LINC02331 as an alternative target and suggested CT4-1 as an effective cytotoxic drug in HCC treatment.

Multi-omics analysis reveals genomic, clinical and immunological features of SARS-CoV-2 virus target genes in pan-cancer.

The SARS-CoV-2 virus, also known as the severe acute respiratory syndrome coronavirus 2, has raised great threats to humans. The connection between the SARS-CoV-2 virus and cancer is currently unclear. In this study, we thus evaluated the multi-omics data from the Cancer Genome Atlas (TCGA) database utilizing genomic and transcriptomic techniques to fully identify the SARS-CoV-2 target genes (STGs) in tumor samples from 33 types of cancers. The expression of STGs was substantially linked with the immune infiltration and may be used to predict survival in cancer patients. STGs were also substantially associated with immunological infiltration, immune cells, and associated immune pathways. At the molecular level, the genomic changes of STGs were frequently related with carcinogenesis and patient survival. In addition, pathway analysis revealed that STGs were involved in the control of signaling pathways associated with cancer. The prognostic features and nomogram of clinical factors of STGs in cancers have been developed. Lastly, by mining the cancer drug sensitivity genomics database, a list of potential STG-targeting medicines was compiled. Collectively, this work demonstrated comprehensively the genomic alterations and clinical characteristics of STGs, which may offer new clues to explore the mechanisms on a molecular level between SARS-CoV-2 virus and cancers as well as provide new clinical guidance for cancer patients who are threatened by the COVID-19 epidemic.

Ferroptosis and triple-negative breast cancer: Potential therapeutic targets.

Purpose: Triple-negative breast cancer (TNBC) is an aggressive tumor with poor prognosis, it has higher recurrence and metastatic rates than other breast cancer subtypes. This study aims to investigate biomarkers and potential targets for TNBC related to ferroptosis through data mining and bioinformatics analysis. The findings may provide new insights for treating TNBC. Methods: The TNBC patients' data from the Cancer Genome Atlas (TCGA) database were extracted for differential expression and prognosis analysis. Consensus genes obtained by intersecting differential expressed and ferroptosis-related genes was used to establish the prognostic model by the univariate and multivariate Cox analyses. Besides, TNBC data from the Gene Expression Omnibus (GEO) database was used to confirm the reliability of the prognosis model. Moreover, clinical information was analyzed by multifactorial independent analysis to identify independent prognostic factors. The expression of genes constituting the prognostic model was further validated using the Human Protein Atlas (HPA) database. Finally, the Comparative Toxicogenomic Data (CTD) database was used to explore possible treatment drugs for TNBC. Results: We obtained 13,245 differential expressed genes, and 177 consensus genes. 98 genes with prognostic implication were obtained by univariable Cox. Then, a prognostic model including 12 ferroptosis-related genes was constructed by multivariable Cox. The area under curve (AUC) value of the prognostic model for TNBC was 0.82. The GEO database validated that the model (AUC = 0.77) could predict the patient outcomes. The staining results of 10 out of 12 prognostic model genes in HPA database showed that their expression was consistent with our predictions. Clinical risk analysis indicated that risk score of patients could act as an independent prognostic factor. Finally, six drugs that may have interaction with 12 ferroptosis-related genes were obtained using the CTD database. Conclusion: The prognostic model composed of 12 ferroptosis-related genes could predict the prognosis of TNBC patients, and seven genes (ASNS, LAMP2, CAV1, DPP4, HELLS, TF, ZFP69B) could be potential new therapeutic targets for TNBC, and two drugs (1-methyl-3-isobutylxanthine, rosiglitazone) could act as potential therapeutic drugs for the treatment of TNBC.

Exploring the Characteristics of Monkeypox-Related Genes in Pan-Cancer.

Monkeypox, an infectious virus that is a member of the Poxviridae family, has raised great threats to humans. Compared to the known oncoviruses, the relationship between monkeypox and cancer still remains obscure. Hence, in this study, we analyzed the multi-omics data from the Cancer Genome Atlas (TCGA) database by using genomic and transcriptomic approaches to comprehensively assess the monkeypox-related genes (MRGs) in tumor samples from 33 types of cancers. Based on the results, the expression of MRGs was highly correlated with the immune infiltration and could be further utilized to predict survival in cancer patients. Furthermore, it was shown that tumorigenesis and patient survival were frequently associated with the genomic alterations of MRGs. Moreover, pathway analysis showed that MRGs participated in the regulation of apoptosis, cell cycle, Epithelial to Mesenchymal Transition (EMT), DNA damage, and hormone androgen receptor (AR), as well as RAS/MAPK and RTK signaling pathways. Besides, we also developed the prognostic features and consensus clustering clusters of MRGs in cancers. Lastly, by mining the cancer drug sensitivity genomics database, we further identified a series of candidate drugs that may target MRGs. Collectively, this study revealed genomic alterations and clinical features of MRGs, which may provide new hints to explore the potential molecular mechanisms between viruses and cancers as well as to provide new clinical guidance of cancer patients who also face the threats during the monkeypox epidemic.

Identification of Hypoxia-Related Prognostic Signature and Competing Endogenous RNA Regulatory Axes in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a common type of liver cancer and one of the highly lethal diseases worldwide. Hypoxia plays an important role in the development and prognosis of HCC. This study aimed to construct a new hypoxia-related prognosis signature and investigate its potential ceRNA axes in HCC. RNA profiles and hypoxia genes were downloaded, respectively, from the Cancer Genome Atlas hepatocellular carcinoma database and Gene Set Enrichment Analysis website. Cox regression analyses were performed to select the prognostic genes and construct the risk model. The ENCORI database was applied to build the lncRNA-miRNA-mRNA prognosis-related network. The TIMER and CellMiner databases were employed to analyze the association of gene expression in ceRNA with immune infiltration and drug sensitivity, respectively. Finally, the co-expression analysis was carried out to construct the potential lncRNA/miRNA/mRNA regulatory axes. We obtained a prognostic signature including eight hypoxia genes (ENO2, KDELR3, PFKP, SLC2A1, PGF, PPFIA4, SAP30, and TKTL1) and further established a hypoxia-related prognostic ceRNA network including 17 lncRNAs, six miRNAs, and seven mRNAs for hepatocellular carcinoma. Then, the analysis of immune infiltration and drug sensitivity showed that gene expression in the ceRNA network was significantly correlated with the infiltration abundance of multiple immune cells, the expression level of immune checkpoints, and drug sensitivity. Finally, we identified three ceRNA regulatory axes (SNHG1/miR-101-3p/PPFIA4, SNHG1/miR-101-3p/SAP30, and SNHG1/miR-101-3p/TKTL1) associated with the progression of HCC under hypoxia. Here, we constructed a prognosis gene signature and a ceRNA network related to hypoxia for hepatocellular carcinoma. Among the ceRNA network, six highly expressed lncRNAs (AC005540.1, AC012146.1, AC073529.1, AC090772.3, AC138150.2, AL390728.6) and one highly expressed mRNA (PPFIA4) were the potential biomarkers of hepatocellular carcinoma which we firstly reported. The three predicted hypoxia-related regulatory axes may play a vital role in the progression of hepatocellular carcinoma.