Identification of ferroptosis related genes and pathways in prostate cancer cells under erastin exposure.

BACKGROUND: Few studies are focusing on the mechanism of erastin acts on prostate cancer (PCa) cells, and essential ferroptosis-related genes (FRGs) that can be PCa therapeutic targets are rarely known. METHODS: In this study, in vitro assays were performed and RNA-sequencing was used to measure the expression of differentially expressed genes (DEGs) in erastin-induced PCa cells. A series of bioinformatic analyses were applied to analyze the pathways and DEGs. RESULTS: Erastin inhibited the expression of SLC7A11 and cell survivability in LNCaP and PC3 cells. After treatment with erastin, the concentrations of malondialdehyde (MDA) and Fe2+ significantly increased, whereas the glutathione (GSH) and the oxidized glutathione (GSSG) significantly decreased in both cells. A total of 295 overlapping DEGs were identified under erastin exposure and significantly enriched in several pathways, including DNA replication and cell cycle. The percentage of LNCaP and PC3 cells in G1 phase was markedly increased in response to erastin treatment. For four hub FRGs, TMEFF2 was higher in PCa tissue and the expression levels of NRXN3, CLU, and UNC5B were lower in PCa tissue. The expression levels of SLC7A11 and cell survivability were inhibited after the knockdown of TMEFF2 in androgen-dependent cell lines (LNCaP and VCaP) but not in androgen-independent cell lines (PC3 and C4-2). The concentration of Fe2+ only significantly increased in TMEFF2 downregulated LNCaP and VCaP cells. CONCLUSION: TMEFF2 might be likely to develop into a potential ferroptosis target in PCa and this study extends our understanding of the molecular mechanism involved in erastin-affected PCa cells.

[Research progress of non-coding RNA involved in glycolysis regulation of hepatocellular carcinoma].

Liver cancer is a common tumor of digestive system. Hepatocellular carcinoma (HCC) is a common type of liver cancer, which has a high degree of malignancy and ranks among the top causes of cancer-related death in the world. Metabolic reprogramming is considered to be an important marker of carcinogenesis. Glucose metabolism is one of the main ways for cells to produce energy. Glycolysis, as the basic reaction of glucose metabolism, plays an important role in cell metabolism. Therefore, the regulation of glycolysis is of great significance to the proliferation and evolution of tumors. More and more non-coding RNAs (ncRNA) have been proved to play an important role in the regulation of tumor glycolysis. This article reviews the role of ncRNA in the regulation of HCC glycolysis and its related mechanisms. At the same time, the prospect of targeted therapy for HCC based on the related mechanisms of glycolysis regulation is put forward.

P14.5 functions to inhibit cell migration and can be used as a prognostic marker in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with a high mortality rate. P14.5 is a member of the highly conserved YER057c/YIL051c/YjgF subfamily and is highly expressed in the liver. However, its low expression is associated with carcinogenesis in HCC. OBJECTIVE: This study aimed to investigate the role and prognostic significance of P14.5 in HCC. METHODS: The clinical significance of P14.5 in HCC was examined using ONCOMINE, UALCAN, Human Protein Atlas, and Kaplan-Meier plotter. The DNA methylation profile of the P14.5 promoter was examined in 103 HCC and paired precancerous tissues; the HCC cell lines HepG2, MHCC-97L, SMMC-7721, SK-Hep-1, and Huh7; and the normal hepatic cell line HL-7702 via MALDI-TOF mass spectrometry. In addition, in vitro experiments were performed to examine the effects of P14.5 overexpression on the proliferation and migration of SMMC-7721 cells. RESULTS: Low expression of P14.5 was correlated with shorter overall survival (OS) and disease-free survival (DFS) in HCC. Based on the results of MALDI-TOF mass spectrometry, no difference was observed in the methylation level between HCC cells and normal human hepatic cells and between HCC and paired precancerous tissues. Additionally, P14.5 overexpression promoted the proliferation and inhibited the migration of SMMC7721 cells in vitro. CONCLUSIONS: P14.5 may serve as a prognostic biomarker in HCC and plays a role in the migration and proliferation of HCC cells. Low expression of P14.5 during hepatocarcinogenesis is not attributed to DNA methylation.

Emerging Severe Acute Respiratory Syndrome Coronavirus 2 Mutation Hotspots Associated With Clinical Outcomes and Transmission.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Understanding the influence of mutations in the SARS-CoV-2 gene on clinical outcomes is critical for treatment and prevention. Here, we analyzed all high-coverage complete SARS-CoV-2 sequences from GISAID database from January 1, 2020, to January 1, 2021, to mine the mutation hotspots associated with clinical outcome and developed a model to predict the clinical outcome in different epidemic strains. Exploring the cause of mutation based on RNA-dependent RNA polymerase (RdRp) and RNA-editing enzyme, mutation was more likely to occur in severe and mild cases than in asymptomatic cases, especially A > G, C > T, and G > A mutations. The mutations associated with asymptomatic outcome were mainly in open reading frame 1ab (ORF1ab) and N genes; especially R6997P and V30L mutations occurred together and were correlated with asymptomatic outcome with high prevalence. D614G, Q57H, and S194L mutations were correlated with mild and severe outcome with high prevalence. Interestingly, the single-nucleotide variant (SNV) frequency was higher with high percentage of nt14408 mutation in RdRp in severe cases. The expression of ADAR and APOBEC was associated with clinical outcome. The model has shown that the asymptomatic percentage has increased over time, while there is high symptomatic percentage in Alpha, Beta, and Gamma. These findings suggest that mutation in the SARS-CoV-2 genome may have a direct association with clinical outcomes and pandemic. Our result and model are helpful to predict the prevalence of epidemic strains and to further study the mechanism of mutation causing severe disease.

The reference genome and transcriptome of the limestone langur, Trachypithecus leucocephalus, reveal expansion of genes related to alkali tolerance.

BACKGROUND: Trachypithecus leucocephalus, the white-headed langur, is a critically endangered primate that is endemic to the karst mountains in the southern Guangxi province of China. Studying the genomic and transcriptomic mechanisms underlying its local adaptation could help explain its persistence within a highly specialized ecological niche. RESULTS: In this study, we used PacBio sequencing and optical assembly and Hi-C analysis to create a high-quality de novo assembly of the T. leucocephalus genome. Annotation and functional enrichment revealed many genes involved in metabolism, transport, and homeostasis, and almost all of the positively selected genes were related to mineral ion binding. The transcriptomes of 12 tissues from three T. leucocephalus individuals showed that the great majority of genes involved in mineral absorption and calcium signaling were expressed, and their gene families were significantly expanded. For example, FTH1 primarily functions in iron storage and had 20 expanded copies. CONCLUSIONS: These results increase our understanding of the evolution of alkali tolerance and other traits necessary for the persistence of T. leucocephalus within an ecologically unique limestone karst environment.

[Corrigendum] Two prostate cancer­associated polymorphisms in the 3'UTR of IGF1R influences prostate cancer susceptibility by affecting miRNA binding.

Following the publication of the above article, the authors have realized that the way in which the western blotting results were presented in Fig. 6 was not optimal, and that original data should have been included in this figure in order that readers could have understood the content of this paper better. The authors regret that these errors were not picked up upon before the article went to print, and apologize to the readership for any confusion these errors may have caused. [the original article was published in Oncology Reports 41: 512-524, 2019; DOI: 10.3892/or.2018.6810].

MitoQ Modulates Lipopolysaccharide-Induced Intestinal Barrier Dysfunction via Regulating Nrf2 Signaling.

BACKGROUND: Gut barrier dysfunction with alterant mucosal permeability during sepsis is a challenge problem in clinical practice. Intestinal epithelial cells (IECs) are strongly involved in mucosal oxidative stress and inflammatory response. The current study aimed at investigating the effect of MitoQ, a mitochondrial targeted antioxidant, in the treatment of intestinal injury and its potential mechanism during sepsis. METHODS: 30 minutes before sepsis induction by lipopolysaccharide (LPS) treatment, mice were treated with MitoQ. Intestinal histopathology, mucosal permeability, inflammatory cytokines, and mucosal barrier proteins were evaluated in the present study. RESULTS: MitoQ pretreatment significantly decreased the levels of plasma diamine oxidase, D-lactate, and intestinal histological damage and markedly restored the levels of tight junction proteins (ZO-1 and occludin) following LPS challenge. Furthermore, MitoQ inhibited the LPS-induced intestinal oxidative stress and inflammatory response, evidenced by increased levels of intestinal superoxide dismutase and glutathione, and decreased levels of intestinal IL-1, IL-6, TNF-α, and nitric oxide levels. Mechanically, we found that MitoQ inhibited the oxidative stress via activating nuclear factor E2-related factor 2 (Nrf2) signaling pathway and its downstream antioxidant genes, including HO-1, NQO-1, and GCLM. CONCLUSIONS: MitoQ exerts antioxidative and anti-inflammatory effects against sepsis-associated gut barrier injury by promoting Nrf2 signaling pathway.

A phenomics-based approach for the detection and interpretation of shared genetic influences on 29 biochemical indices in southern Chinese men.

BACKGROUND: Phenomics provides new technologies and platforms as a systematic phenome-genome approach. However, few studies have reported on the systematic mining of shared genetics among clinical biochemical indices based on phenomics methods, especially in China. This study aimed to apply phenomics to systematically explore shared genetics among 29 biochemical indices based on the Fangchenggang Area Male Health and Examination Survey cohort. RESULT: A total of 1999 subjects with 29 biochemical indices and 709,211 single nucleotide polymorphisms (SNPs) were subjected to phenomics analysis. Three bioinformatics methods, namely, Pearson's test, Jaccard's index, and linkage disequilibrium score regression, were used. The results showed that 29 biochemical indices were from a network. IgA, IgG, IgE, IgM, HCY, AFP and B12 were in the central community of 29 biochemical indices. Key genes and loci associated with metabolism traits were further identified, and shared genetics analysis showed that 29 SNPs (P < 10- 4) were associated with three or more traits. After integrating the SNPs related to two or more traits with the GWAS catalogue, 31 SNPs were found to be associated with several diseases (P < 10- 8). Using ALDH2 as an example to preliminarily explore its biological function, we also confirmed that the rs671 (ALDH2) polymorphism affected multiple traits of osteogenesis and adipogenesis differentiation in 3 T3-L1 preadipocytes. CONCLUSION: All these findings indicated a network of shared genetics and 29 biochemical indices, which will help fully understand the genetics participating in biochemical metabolism.

Key Genes And Pathways Controlled By E2F1 In Human Castration-Resistant Prostate Cancer Cells.

BACKGROUND: Treatment of castration-resistant prostate cancer (CRPC) is an enormous challenge. As E2F transcription factor 1 (E2F1) is an essential factor in CRPC, this study investigated the genes and pathways controlled by E2F1 and their effects on cellular behavior in CRPC. METHODS: In vitro assays were used to evaluate cellular proliferation, apoptosis, and behavior. Cellular expression was quantified by RNA sequencing (RNA-seq). Gene co-expression was assessed using the GeneMANIA database, and correlations were analyzed with the GEPIA server. Altered pathways of differentially expressed genes (DEGs) were revealed by functional annotation. Module analysis was performed using the STRING database and hub genes were filtered with the Cytoscape software. Some DEGs were validated by real-time quantitative PCR (RT-qPCR). RESULTS: Knockdown of E2F1 significantly inhibited proliferation and accelerated apoptosis in PC3 cells but not in DU145 cells. Invasion and migration were reduced for both cell lines. A total of 1811 DEGs were identified in PC3 cells and 27 DEGs in DU145 cells exhibiting E2F1 knockdown. Ten overlapping DEGs, including TMOD2 and AIF1L, were identified in both knockdown cell lines and were significantly enriched for association with actin filament organization pathways. TMOD2 and KREMEN2 were genes co-expressed with E2F1; six overlapping DEGs were positively correlated with transcription factor E2F1. DEGs of the PC3 and DU145 groups were associated with multiple pathways. Five DEGs that overlapped between the two cell lines and three hub DEGs from PC3 cells were validated by RT-qPCR. CONCLUSION: The results of this study suggest that E2F1 has a critical role in regulating actin filaments, as indicated by the change in expression level of several genes, including TMOD2 and AIF1L, in CRPC. This extends our understanding of the cellular responses affected by E2F1 in CRPC.

Two prostate cancer­associated polymorphisms in the 3'UTR of IGF1R influences prostate cancer susceptibility by affecting miRNA binding.

Prostate cancer (PCa) is a common malignant cancer in men worldwide. Numerous genetic variations have been associated with PCa, but their biological function remains unclear. Single nucleotide polymorphisms (SNPs) inside 3' untranslated region (UTR) affect gene expression, with one essential mechanism being regulation by micro (mi)RNAs. Based on data from genome­wide association study of the Consortium for Chinese Consortium for Prostate Cancer Genetics, rs1815009 and rs2684788 inside 3'UTR of insulin­like growth factor 1 receptor (IGF1R) presented significant genotype distribution between PCa and control samples. In the current study, targeting miRNAs were predicted using TargetScan and miRanda. The prediction was confirmed using a thermodynamic model for miRNA­target interaction and luciferase reporter assays for miRNA binding inside IGF1R 3'UTR. Furthermore, data from public databases and miRNA overexpression further supported miRNAs function. The results suggested that miR­133a and miR­133b may bind near rs1815009, and miR­455 near rs2684788, within IGF1R 3'UTR. Compared with normal tissues, miR­133a, miR­133b and miR­455 exhibited significantly lower expression in PCa tissues in the public datasets analyzed. The results of the present study revealed an association between rs1815009, rs2684788 and PCa risk, which involves altered miRNA regulation and contributes to cancer susceptibility.

eQTL analysis from co-localization of 2739 GWAS loci detects associated genes across 14 human cancers.

Genetic variants can predict other "linked" diseases because alterations in one or more genes in vivo may affect relevant phenotype properties. Our study systematically explored the pan-cancer common gene and cancer type-specific genes based on GWAS loci and TCGA data of multiple cancers. It was found that there were 17 SNPs were significantly associated with the expression of 18 genes. Associations between the 18 cis-regulatory genes and the pathologic stage of each cancer showed that MYL2 and PTGFR in HNSC, 4 genes (F8, SATB2, G6PD and UGT1A6) in KIRP, 3 genes (CHMP4C, MAP3K1 and MECP2) in LUAD were all strongly associated with cancer stage levels. Additionally, the survival association analysis showed that SATB2 was correlated with HNSC survival, and MPP1 was strongly associated with the survival of SARC. This study will shed light on the biological pathways involved in cancer-genetic associations, and has the potential to be applied to the predictions of the risk of cancers developing in healthy individuals.