Cancer-related Biological Processes Research Articles

Redox proteomics of PANC-1 cells reveals the significance of HIF-1 signaling protein oxidation in pancreatic ductal adenocarcinoma pathogenesis

BackgroundProtein cysteine oxidation is substantially involved in various biological and pathogenic processes, but its implications in pancreatic cancer development remains poorly understood.Methods and resultsIn this study, we performed a global characterization of protein oxidation targets in PDAC cells through iodoTMT-based quantitative proteomics, which identified over 4300 oxidized cysteine sites in more than 2100 proteins in HPDE6c7 and PANC-1 cells. Among them, 1715 cysteine residues were shown to be differentially oxidized between HPDE6c7 and PANC-1 cells. Also, charged amino acids including aspartate, glutamate and lysine were significantly overrepresented in flanking sequences of oxidized cysteines. Differentially oxidized proteins in PANC-1 cells were enriched in multiple cancer-related biological processes and signaling pathways. Specifically, the HIF-1 signaling proteins exhibited significant oxidation alterations in PANC-1 cells, and the reduced PHD2 oxidation in human PDAC tissues was correlated with lower survival time in pancreatic cancer patients.ConclusionThese investigations provided new insights into protein oxidation-regulated signaling and biological processes during PDAC pathogenesis, which might be further explored for pancreatic cancer diagnosis and treatment.

Natural Compound Dioscin Targeting Multiple Cancer Pathways through its High Affinity Binding to B Cell Lymphoma-2.

The study aimed to explore the crucial genes involved in cancer-related biological processes, including EMT, autophagy, apoptosis, anoikis, and metastasis. It also sought to identify common genes among the pathways linked to these biological processes, determine the level of Bcl-2 expression in various types of cancers, and find a potent inhibitor of Bcl-2 among natural compounds. Common genes involved in the pathways related to EMT, autophagy, apoptosis, anoikis, and metastasis were explored, and the level of the most frequently overexpressed gene that was Bcl-2, in various types of cancers was analyzed by gene expression analysis. A set of 102 natural compounds was sorted according to their docking scores using molecular docking and filtering. The top-ranked molecule was chosen for additional molecular dynamics (MD) simulation for 100 ns. Differential gene expression analysis was performed for Dioscin using GEO2R. The study identified four common genes, Bcl-2, Bax, BIRC3, and CHUK, among the pathways linked to EMT, autophagy, apoptosis, anoikis, and metastasis. Bcl-2 was highly overexpressed in many cancers, including Acute Myeloid Leukemia, Diffuse large B cell lymphoma, and Thymoma. The Dioscin structure in the Bcl-2 binding site received the highest docking score and the most relevant interactions. Dioscin's determined binding free energy by MM/GBSA was -52.21 kcal/mol, while the same calculated by MM/PBSA was -9.18 kcal/mol. A p-value of less than 0.05 was used to determine the statistical significance of the analysis performed using GEO2R. It was observed that Dioscin downregulates Bcl-2, BIRC3, and CHUK and upregulates the pro-apoptotic protein Bax. The study concluded that Dioscin has the potential to act as a protein inhibitor, with a noteworthy value of binding free energy and relevant interactions with the Bcl-2 binding site. Dioscin might be a good alternative for targeting multiple cancer pathways through a single target.

Alteration of genome-wide DNA methylation in non-uranium miners induced by high level radon exposure.

In China, according to statistics about underground non-uranium mine radon levels, 15% exceed the national standard intervention level of 1000Bq/m3, and some mines may exceed 10,000Bq/m3. The relationship between radon exposure in underground miners and lung cancer has already been established, but the mechanisms and biological processes underlying it are poorly understood. In order to identify the genome-wide DNA methylation profile associated with long-term radon exposure, we performed the Infinium Human Methylation 850K BeadChip measurement in whole blood samples obtained from 15 underground non-uranium miners and 10 matched aboveground control workers. Radon concentrations in the air of workplaces and living environments were measured by CR-39 radon detectors, and annual effective doses were calculated using the detection data. Under the high radon concentration with an average value of 12,700Bq·m-3, a total of 165 significant differentially methylated positions (127 hypermethylated sites and 38 hypomethylated sites) annotated to 71 genes were identified in underground miners (|Δβ| ≥ 0.10, p<0.05), and the average DNA methylation level of 165 DMPs was significantly higher than that of the control workers. Most DMPs were found on chromosome 1, and approximately one-quarter of them were located in genomic promoter regions. Through bioinformatics analysis and pyrosequencing validation, five candidate genes differentially methylated by radon, including TIMP2, EMP2, CPT1B, AMD1 and SLC43A2 were identified. GO and KEGG analysis implicated that long term radon exposure could induce the lung cancer related biological processes such as cell adhesion and cellular polarity maintenance. Our study provides evidence for the alterations of genome-wide DNA methylation profiles induced by long-term high level radon exposure, and new insights into searching for carcinogenic biomarkers of high radon exposure in future studies.

RNAseq Analysis of Novel 1,3,4-Oxadiazole Chalcogen Analogues Reveals Anti-Tubulin Properties on Cancer Cell Lines.

1,3,4-Oxadiazole derivatives are among the most studied anticancer drugs. Previous studies have analyzed the action of different 1,3,4-oxadiazole derivatives and their effects on cancer cells. This study investigated the characterization of two new compounds named 6 and 14 on HeLa and PC-3 cancer cell lines. Based on the previously obtained IC50, cell cycle effects were monitored by flow cytometry. RNA sequencing (RNAseq) was performed to identify differentially expressed genes, followed by functional annotation using gene ontology (GO), KEGG signaling pathway enrichment, and protein-protein interaction (PPI) network analyses. The tubulin polymerization assay was used to analyze the interaction of both compounds with tubulin. The results showed that 6 and 14 strongly inhibited the proliferation of cancer cells by arresting them in the G2/M phase of the cell cycle. Transcriptome analysis showed that exposure of HeLa and PC-3 cells to the compounds caused a marked reprograming of gene expression. Functional enrichment analysis indicated that differentially expressed genes were significantly enriched throughout the cell cycle and cancer-related biological processes. Furthermore, PPI network, hub gene, and CMap analyses revealed that compounds 14 and 6 shared target genes with established microtubule inhibitors, indicating points of similarity between the two molecules and microtubule inhibitors in terms of the mechanism of action. They were also able to influence the polymerization process of tubulin, suggesting the potential of these new compounds to be used as efficient chemotherapeutic agents.

Androgen receptor variant 7 exacerbates hepatocarcinogenesis in a c-MYC-driven mouse HCC model

Androgen receptor variant 7 (AR-V7), an AR isoform with a truncated ligand-binding domain, functions as a transcription factor in an androgen-independent manner. AR-V7 is expressed in a subpopulation of hepatocellular carcinoma (HCC), however, its role(s) in this cancer is undefined. In this study, we investigated the potential roles of AR-V7 in hepatocarcinogenesis in vivo in a c-MYC-driven mouse HCC model generated by the hydrodynamic tail-vein injection system. The impacts of AR-V7 on gene expression in mouse HCC were elucidated by RNA-seq transcriptome and ontology analyses. The results showed that AR-V7 significantly exacerbated the c-MYC-mediated oncogenesis in the livers of both sexes. The transcriptome and bioinformatics analyses revealed that AR-V7 and c-MYC synergistically altered the gene sets involved in various cancer-related biological processes, particularly in lipid and steroid/sterol metabolisms. Importantly, AR-V7 suppressed a tumor suppressor Claudin 7 expression, upregulated by c-MYC overexpression via the p53 signaling pathway. Claudin 7 overexpression significantly suppressed the c-MYC-driven HCC development under p53-deficient conditions. Our results suggest that the AR-V7 exacerbates the c-MYC-driven hepatocarcinogenesis by potentiating the oncogenic roles and minimizing the anti-oncogenic functions of c-MYC. Since AR-V7 is expressed in a subpopulation of HCC cases, it could contribute to the inter- and intra-heterogeneity of HCC.

GAPDH: A common housekeeping gene with an oncogenic role in pan-cancer

Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is one of the most prominent housekeeping proteins and is widely used as an internal control in some semi-quantitative assays. In addition to glycolysis, GAPDH is involved in several cancer-related biological processes and has been reported to be commonly dysregulated in multiple cancer types. Therefore, its role in the physiological process of cancer needs to be urgently elucidated. Pan-cancer analysis indicated that GAPDH is ubiquitously highly expressed in most cancer types, and that patients with a high GAPDH expression of in tumor tissues have a poor prognosis. The concordance of GAPDH expression in tumors with the infiltration of immune cells and immune checkpoints implies a certain association between GAPDH and the tumor microenvironment as well as tumor development. Gene Set Enrichment Analysis revealed that GAPDH may contribute to multiple important cancer-related pathways and biological processes. Multi-omics analysis and in vitro cell experiments revealed that GAPDH overexpression is regulated by DNA copy number amplification and promoter methylation modification. Importantly, a transcription factor, forkhead box M1 (FOXM1), which is capable of regulating GAPDH expression, was also identified and was confirmed to be an oncogene and ubiquitously highly expressed in multiple cancer types. Semi-quantitative chromatin immunoprecipitation, quantitative PCR, and dual-luciferase assays showed that FOXM1 mainly binds to the promoter region of GAPDH in two cancer cell lines. The present findings revealed the implication of GAPDH in tumor development, thus bringing attention to this important molecule and casting doubts on its role as an internal reference gene in cancer studies.

The prognostic value and immunological role of angiogenesis-related patterns in colon adenocarcinoma

Colon adenocarcinoma (COAD) is a malignant tumor with a high mortality rate. Angiogenesis plays a key role in the development and progression of cancer. However, in COAD, studies between angiogenesis and prognosis, immune cell infiltration, and personalized treatment guidance are currently lacking. In the present study, we comprehensively assessed 35 angiogenesis-related genes (ARG) and identified key ARGs affecting OS in COAD patients. The ARG Prognostic Index (ARGPI) was constructed based on a univariate Cox regression model and its prognostic value was evaluated in TCGA-COAD, GSE39582, GSE161158 and TRSJTUSM Cohort. We constructed ARGPI as an independent risk factor for OS in COAD patients and combined with clinical parameters to further construct an ARGPI-based nomogram, which showed a strong ability to predict overall survival in COAD patients. High ARGPI is associated with cancer-related and immune-related biological processes and signaling pathways; high TP53 mutation rate; high infiltration of MSC, pericytes, and stromal cells; and more CMS4 subtype. And low ARGPI benefited more from immune checkpoint inhibitor treatment. In addition, we also predicted the sensitivity of different ARGPI groups to common chemotherapeutic and targeted agents. In conclusion, this study constructed an ARGPI based on ARG, which robustly predicted the OS of COAD patients and provided a possible personalized treatment regime for COAD patients.

Prioritizing Cancer lncRNA Modulators via Integrated lncRNA-mRNA Network and Somatic Mutation Data

Abstract: Background: Long noncoding RNAs (LncRNAs) represent a large category of functional RNA molecules that play a significant role in human cancers. lncRNAs can be genes modulators to affect the biological process of multiple cancers. Methods: Here, we developed a computational framework that uses lncRNA-mRNA network and mutations in individual genes of 9 cancers from TCGA to prioritize cancer lncRNA modulators. Our method screened risky cancer lncRNA regulators based on integrated multiple lncRNA functional networks and 3 calculation methods in network. Results: Validation analyses revealed that our method was more effective than prioritization based on a single lncRNA network. This method showed high predictive performance and the highest ROC score was 0.836 in breast cancer. It’s worth noting that we found that 5 lncRNAs scores were abnormally high and these lncRNAs appeared in 9 cancers. By consulting the literatures, these 5 lncRNAs were experimentally supported lncRNAs. Analyses of prioritizing lncRNAs reveal that these lncRNAs are enriched in various cancer-related biological processes and pathways. Conclusions: Together, these results demonstrated the ability of this method identifying candidate lncRNA molecules and improved insights into the pathogenesis of cancer.

Development and Validation of a Liquid-Liquid Phase Separation-Related Gene Signature as Prognostic Biomarker for Low-Grade Gliomas.

Aim To explore whether the liquid-liquid phase separation- (LLPS-) related genes were potential prognostic markers that could contribute to the further classification of low-grade gliomas (LGGs). Methods The LLPS-related genes were subjected to functional enrichment analysis. The univariable, least absolute shrinkage and selection operator, and multivariable stepwise Cox regression analyses were performed to develop an LLPS-related gene signature (GS) in the discovery data set. The biological characteristics of the high-risk LGG were explored using gene set enrichment analysis. Two independent external data sets were used to validate the LLPS-related GS. Results LLPS-related genes are involved in multiple important cancer-related biological processes and pathways in LGG. Nine LLPS-related genes were identified to construct the LLPS-related GS, which was significantly associated with the prognosis of LGG patients. The LLPS-related GS could successfully divide patients with LGG into high- and low-risk groups, and the high-risk group showed a poorer prognosis than the low-risk group. Furthermore, the LLPS-related GS was independent of IDH and 1p19q status. Several cancer-related pathways may be more active in high-risk LGGs, such as IL6 JAK STAT3 signaling pathway. The LLPS-related GS was successfully validated with two independent external data sets. Conclusion We developed and validated a novel LLPS-related GS for risk stratification of LGG. Our findings may provide more precise management for LGGs and a useful reference for LLPS mechanism to link LGG studies.

Integration of TE Induces Cancer Specific Alternative Splicing Events.

Alternative splicing of messenger RNA (mRNA) precursors contributes to genetic diversity by generating structurally and functionally distinct transcripts. In a disease state, alternative splicing promotes incidence and development of several cancer types through regulation of cancer-related biological processes. Transposable elements (TEs), having the genetic ability to jump to other regions of the genome, can bring about alternative splicing events in cancer. TEs can integrate into the genome, mostly in the intronic regions, and induce cancer-specific alternative splicing by adjusting various mechanisms, such as exonization, providing splicing donor/acceptor sites, alternative regulatory sequences or stop codons, and driving exon disruption or epigenetic regulation. Moreover, TEs can produce microRNAs (miRNAs) that control the proportion of transcripts by repressing translation or stimulating the degradation of transcripts at the post-transcriptional level. Notably, TE insertion creates a cancer-friendly environment by controlling the overall process of gene expression before and after transcription in cancer cells. This review emphasizes the correlative interaction between alternative splicing by TE integration and cancer-associated biological processes, suggesting a macroscopic mechanism controlling alternative splicing by TE insertion in cancer.

Overexpression of hsa_circ_0061817 Can Inhibit the Proliferation and Invasion of Lung Cancer Cells Based on Active Compounds

Objective. This study was aimed at investigating the expression level of hsa_circ_0061817 in lung adenocarcinoma cells and its effect on cell proliferation and invasion and the possible mechanism of hsa_circ_0061817 in lung adenocarcinoma. Methods. The overexpression plasmids of hsa_circ_0061817 (OE-hsacirc_0061817) were transfected into human lung A549 cells and mouse LLC-LUC cells, respectively. The cell viability was detected by CCK-8, and the cell proliferation was detected by cell clone formation assay and EdU assay. Transwell test was used to detect the ability of cell invasion, and apoptosis was detected by flow cytometry. WB was applied to determine the expression of apoptosis and epithelial mesenchymal transition- (EMT-) related proteins and also target proteins for observation the effect of OE-hsa_circ_0061817 on the growth of A549 cells in nude mice. Bioinformatics method was used to predict the binding microRNA (miRNA) of hsa_circ_0061817 and construct the regulatory network of competitive endogenous RNA (ceRNA) and functional analysis of miRNA target genes. Results. Compared with PLO-ciR group, the cell viability, proliferation, and invasive ability of A549 and LLC-LUC were significantly reduced in OE-hsa_circ_00061817 group, while the apoptosis increased in OE-hsa_circ_00061817 group compared to PLO-ciR group. WB results showed that the expression of caspase 3, caspase 7, caspase 9, and E-cadherin increased significantly, while the expression levels of vimentin and N-cadherin decreased severely. Most importantly, OE-hsa_circ_00061817 inhibited the growth of A549 tumor-bearing nude mice. According to TargetScan and mirBase databases, hsa_circ_0061817 may competitively bind hsa_mir-181b-3p, hsa-mir-337-3p, hsa-mir-421, and hsa-mir-548d-3p. The results of functional enrichment showed that miRNA target genes were involved in many cancer-related biological processes, including negative regulation of apoptosis, gene expression, transcriptional imbalance in cancer, transforming growth factor-β, and P53 signal pathway. Conclusions. Over expression of hsa_circ_0061817 inhibits the proliferation of lung adenocarcinoma A549 and LLC-LUC cells and may reduce the invasive ability of lung adenocarcinoma cells by weakening the process of EMT, which provides a new target for the prevention and treatment of lung adenocarcinoma.

A novel necroptosis-related gene signature associated with immune landscape for predicting the prognosis of papillary thyroid cancer.

Background: Necroptosis, a type of programmed cell death, has been implicated in a variety of cancer-related biological processes. However, the roles of necroptosis-related genes in thyroid cancer yet remain unknown. Methods: A necroptosis-related gene signature was constructed using the least absolute shrinkage and selection operator (LASSO) regression analysis and Cox regression analysis. The predictive value of the prognostic signature was validated in an internal cohort. Additionally, the single-sample gene set enrichment analysis (ssGSEA) was used to examine the relationships between necroptosis and immune cells, immunological functions, and immune checkpoints. Next, the modeled genes expressions were validated in 96 pairs of clinical tumor and normal tissue samples. Finally, the effects of modeled genes on PTC cells were studied by RNA interference approaches in vitro. Results: In this study, the risk signature of seven necroptosis-related genes was created to predict the prognosis of papillary thyroid cancer (PTC) patients, and all patients were divided into high- and low-risk groups. Patients in the high-risk group fared worse in terms of overall survival than those in the low-risk group. The area under the curve (AUC) of the receiving operating characteristic (ROC) curves proved the predictive capability of created signature. The risk score was found to be an independent risk factor for prognosis in multivariate Cox analysis. The low-risk group showed increased immune cell infiltration and immunological activity, implying that they might respond better to immune checkpoint inhibitor medication. Next, GEO database and qRT-PCR in 96 pairs of matched tumorous and non-tumorous tissues were used to validate the expression of the seven modeled genes in PTCs, and the results were compatible with TCGA database. Finally, overexpression of IPMK, KLF9, SPATA2 could significantly inhibit the proliferation, invasion and migration of PTC cells. Conclusion: The created necroptosis associated risk signature has the potential to have prognostic capability in PTC for patient outcome. The findings of this study could pave the way for further research into the link between necroptosis and tumor immunotherapy.

PANoptosis-based molecular clustering and prognostic signature predicts patient survival and immune landscape in colon cancer.

PANoptosis is a newly-discovered cell death pathway that involves crosstalk and co-ordination between pyroptosis, apoptosis, and necroptosis processes. However, the roles of PANoptosis-related genes (PRGs) in prognosis and immune landscape of colon cancer remain widely unknown. Here, we performed a bioinformatics analysis of expression data of nineteen PRGs identified from previous studies and clinical data of colon cancer patients obtained from TCGA and GEO databases. Colon cancer cases were divided into two PRG clusters, and prognosis-related differentially expressed genes (PRDEGs) were identified. The patient data were then separated into two corresponding distinct gene clusters, and the relationship between the risk score, patient prognosis, and immune landscape was analyzed. The identified PRGs and gene clusters correlated with patient survival and immune system and cancer-related biological processes and pathways. A prognosis signature based on seven genes was identified, and patients were divided into high-risk and low-risk groups based on the calculated risk score. A nomogram model for prediction of patient survival was also developed based on the risk score and other clinical features. Accordingly, the high-risk group showed worse prognosis, and the risk score was related to immune cell abundance, cancer stem cell (CSC) index, checkpoint expression, and response to immunotherapy and chemotherapeutic drugs. Results of quantitative real-time polymerase chain reaction (qRT-PCR) showed that LGR5 and VSIG4 were differentially expressed between normal and colon cancer samples. In conclusion, we demonstrated the potential of PANoptosis-based molecular clustering and prognostic signatures for prediction of patient survival and tumor microenvironment (TME) in colon cancer. Our findings may improve our understanding of the role of PANoptosis in colon cancer, and enable the development of more effective treatment strategies.

MicroRNAs as Potential Biomarkers in the Differential Diagnosis of Lipomatous Tumors and Their Mimics.

Adipocytic tumors are the most common subtype of soft tissue tumors. In current clinical practice, distinguishing benign lipomas from well-differentiated liposarcomas (WDLPS), as well as dedifferentiated liposarcomas (DDLPS) from their morphologic mimics, remains a significant diagnostic challenge. This is especially so when examining small biopsy samples and without the aid of additional ancillary tests. Recognizing the important role that microRNAs (miRNAs) play in tumorigenesis and their potential utility in tumor classification, we analyzed routine clinical tissue samples of benign and malignant lipomatous tumors, as well as other sarcoma mimics, to identify distinguishing miRNA-based signatures that can aid in the differential diagnosis of these entities. We discovered a 6-miRNA signature that separated lipomas from WDLPS with high confidence (AUC of 0.963), as well as a separate 6-miRNA signature that distinguished DDLPS from their more aggressive histologic mimics (AUC of 0.740). Functional enrichment analysis unveiled possible mechanistic involvement of these predictive miRNAs in adipocytic cancer-related biological processes and pathways such as PI3K/AKT/mTOR and MAPK signaling, further supporting the relevance of these miRNAs as biomarkers for adipocytic tumors. Our results demonstrate that miRNA expression profiling may potentially be used as an adjunctive tool for the diagnosis of benign and malignant adipocytic tumors. Further validation studies are warranted.

Computational epigenetic landscape analysis reveals association of CACNA1G-AS1, F11-AS1, NNT-AS1, and MSC-AS1 lncRNAs in prostate cancer progression through aberrant methylation

Aberrant expression of long non-coding RNAs (lncRNAs), caused by alterations in DNA methylation, is a driving factor in several cancers. Interplay between lncRNAs’ aberrant methylation and expression in prostate cancer (PC) progression still remains largely elusive. Therefore, this study characterized the genome-wide epigenetic landscape and expression profiles of lncRNAs and their clinical impact by integrating multi-omics data implementing bioinformatics approaches. We identified 62 differentially methylated CpG-sites (DMCs) and 199 differentially expressed lncRNAs (DElncRNAs), where 32 DElncRNAs contain 32 corresponding DMCs within promoter regions. Significant negative correlation was observed between 8 DElncRNAs-DMCs pairs. 3 (cg23614229, cg23957912, and cg11052780) DMCs and 4 (CACNA1G-AS1, F11-AS1, NNT-AS1, and MSC-AS1) DElncRNAs were identified as high-risk factors for poor prognosis of PC patients. Overexpression of hypo-methylated CACNA1G-AS1, F11-AS1, and NNT-AS1 and down-regulation of hyper-methylated MSC-AS1 significantly lower the survival of PC patients and could be a potential prognostic and therapeutic biomarker. These DElncRNAs were found to be associated with several molecular functions whose deregulation can lead to cancer. Involvement of these epigenetically deregulated DElncRNAs in cancer-related biological processes was also noticed. These findings provide new insights into the understanding of lncRNA regulation by aberrant DNA methylation which will help to clarify the epigenetic mechanisms underlying PC.

Comprehensive analysis of the expression, prognostic significance, and function of FAM83 family members in breast cancer

BackgroundThe FAM83 family plays a key role in tumorigenesis and cancer progression. However, the role of the FAM83 family in the development of breast tumors is unclear to date. This report explores the expression, prognostic significance, and function of the FAM83 family members in breast cancer using public databases.MethodsUALCAN database was used to explore the expression of FAM83 family members in breast cancer. Furthermore, we validated the expression of FAM83 family members in twenty pairs of breast cancer and normal tissues by RT-PCR. Kaplan–Meier plotter database was used to explore the prognostic significance of FAM83 family members in breast cancer. GeneMANIA and DAVID databases were used for functional and pathway enrichment analysis of genes co-expressed with FAM83A, FAM83D, FAM83F, and FAM83G. MEXPRESS and UALCAN databases were used to analyze the level of DNA promoter methylation of FAM83A, FAM83D, FAM83F, and FAM83G in breast cancer. TIMER database was utilized to explore the relationships between immune cell infiltration and FAM83A, FAM83D, FAM83F, and FAM83G expression.ResultsAmong FAM83 family members, FAM83A, FAM83D, FAM83F, and FAM83G were higher expressed in breast cancer than in normal tissues. We also validated the significant high expression of FAM83A, FAM83D, FAM83F, and FAM83G mRNA in breast cancer than in normal samples. Their increased expression has an adverse prognostic effect on breast cancer patients. These genes co-expressed with FAM83A, FAM83D, FAM83F, and FAM83G might take part in cell proliferation, G2/M transition of the mitotic cell cycle, regulation of apoptosis process and other cancer-related biological processes. In addition, they were mainly enriched in the Hippo signaling pathway, Hedgehog signaling pathway, PI3K/AKT signaling pathway, and other cancer-related pathways. We also found that promoter DNA methylation might regulate the expression of FAM83A, FAM83D, FAM83F, and FAM83G mRNA in most CpG islands. At last, we found the expression of FAM83A, FAM83D, FAM83F, and FAM83G mRNA was significantly related to immune cell infiltration.ConclusionsFAM83A, FAM83D, FAM83F, and FAM83G were highly expressed in breast cancer tissues and had an adverse effect on the survival outcomes of breast cancer patients. Also, they were involved in breast cancer-related signal pathways. Therefore, they might serve as potential therapeutic targets for breast cancer clinical treatment.

Nano-sized polystyrene plastic particles affect many cancer-related biological processes even in the next generations; zebrafish modeling

With the ever-increasing plastic pollution, the nano-sized plastic particles that are constantly released from the main materials have a greater potential threat. Studies continue on how to eliminate plastic waste, which has become a global problem, from nature. We are aware that complete elimination is not easy at all, but it is not known clearly that even if it is successful, its effects on organisms will also disappear completely. In this study, zebrafish injected with 20 nm-sized polystyrene particles (PS) only during the embryonic period were grown in an environment without plastic exposure. The effects of PS on their offspring embryo/larvae were examined at morphological, molecular and metabolomic levels. Results showed that parental PNP exposure caused significant malformations, decreased survival rate, increased heart rate and blood flow rate, as well as decreased eye size, height and locomotor activity, which were attributed to growth retardation in the offspring. According to the results of whole-mount immunofluorescence larval staining, cell death and reactive oxygen species were significantly increased, while lipid accumulation was decreased in new generation larvae from zebrafish injected with PNP. In order to elucidate the mechanisms underlying these morphological, physiological and molecular damages, the metabolome analyses were performed by evaluating the Q-TOF MS/MS spectra with chemometric analyses in the offspring larvae. According to the metabolomics results, 28 annotated metabolomes suggested by the OPLS-DA analysis that may vary significantly through a variable in projection scores were detected. In addition, it was detected that the significantly increased histopathological findings and immunopositivity of JNK, H2A.X, PI3 and NOP10 in new generation larvae. In conclusion, it has been shown that exposure to PS, even only during the embryonic period, may affect many cancer-related biological processes in the next generation.

Peroxiredoxin, Senescence, and Cancer.

Peroxiredoxins are multifunctional enzymes that play a key role in protecting cells from stresses and maintaining the homeostasis of many cellular processes. Peroxiredoxins were firstly identified as antioxidant enzymes that can be found in all living organisms. Later studies demonstrated that peroxiredoxins also act as redox signaling regulators, chaperones, and proinflammatory factors and play important roles in oxidative defense, redox signaling, protein folding, cycle cell progression, DNA integrity, inflammation, and carcinogenesis. The versatility of peroxiredoxins is mainly based on their unique active center cysteine with a wide range of redox states and the ability to switch between low- and high-molecular-weight species for regulating their peroxidase and chaperone activities. Understanding the molecular mechanisms of peroxiredoxin in these processes will allow the development of new approaches to enhance longevity and to treat various cancers. In this article, we briefly review the history of peroxiredoxins, summarize recent advances in our understanding of peroxiredoxins in aging- and cancer-related biological processes, and discuss the future perspectives of using peroxiredoxins in disease diagnostics and treatments.

Expression Profile and Molecular Basis of Cyclin-Dependent Kinases Regulatory Subunit 2 in Endometrial Carcinoma Detected by Diversified Methods.

Purpose: Our purpose was to systematically appraise the clinicopathological significance and explore the molecular bases of CKS2 in endometrial carcinoma. Patients and Methods: We measured the clinicopathological significance of CKS2 using diverse methods of public RNA-seq, microarrays, and in-house tissue microarrays to investigate the molecular basis of CKS2 in endometrial carcinoma through upstream transcriptional analysis, immune infiltration correlation analysis, and co-expression analysis. Results: Both the analysis for public RNA-seq plus the microarray data and in-house tissue microarray confirmed the significant overexpression of CKS2 in a total of 1,021 endometrial carcinoma samples compared with 279 non-cancer endometrium samples (SMD = 2.10, 95% CI = 0.72–3.48). The upregulated CKS2 was significantly related to the lymph node metastasis and advanced clinical grade of endometrial carcinoma patients (p < 0.001). Mutation types such as amplification and mRNA occurred with high frequency in the CKS2 gene in endometrial carcinoma patients. A series of miRNAs and transcription factors, such as hsa-miR-26a, hsa-miR-130a, hsa-miR-30, E2F4, MAX, and GABPA, were predicted to regulate the transcription and expression of CKS2. Significant links were found between CKS2 expression and the infiltration level of B cells, CD4+ T cells, and neutrophils in endometrial carcinoma. CKS2-coexpressed genes were actively involved in pathways such as the mitotic cell cycle process, PID aurora B pathway, and prolactin signaling pathway. Conclusion: The overexpressed CKS2 showed positive correlations with the clinical progression of endometrial carcinoma and was associated with various cancer-related biological processes and pathways, showing potential as a promising clinical biomarker for endometrial carcinoma.

A novel four-gene signature for predicting the prognosis of hepatocellular carcinoma

Objective To identify and utilize gene signatures for the prognostic evaluation of postoperative patients with hepatocellular carcinoma (HCC). Methods The gene mRNA expression profiles and corresponding clinicopathological data of postoperative patients with HCC were downloaded from The Cancer Genome Atlas (TCGA) database. Highly differentially expressed genes (DEGs) in tumor tissues compared to adjacent tissues were identified, and their associations with the overall survival (OS) of HCC patients were analyzed. The strongly associated genes were used to develop a prognostic score for the survival stratification of HCC, and the underlying mechanisms were analyzed using bioinformatics. Results A total of 376 DEGs were identified and four DEGs (ADH4, COL15A1, RET and KCNJ16) were independently associated with OS. A prognostic score derived from the four genes could effectively stratify HCC patients with different OS outcomes, independent of clinical parameters. Patients with high scores exhibited poorer OS than patients with low scores (HR 5.526, 95% CI: 2.451–12.461, p < .001). The four genes were involved in cancer-related biological processes and were independent of each other in bioinformatics analyses. Conclusion Four genes strongly associated with the prognosis of postoperative patients with HCC were identified, and the derived prognostic score was simple and valuable for overall survival prediction.