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Sequence variants identified from transcriptome data. (A) An overview of sequence variants identified from transcriptome NGS. (B) Single nucleotide variants in TP53 and GSTP1 detected in NPC and NP cell lines. Height of sequence logos represents the frequency of nucleotides detected at each position.
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Nasopharyngeal carcinoma (NPC) is a prevalent malignancy in Southeast Asia among the Chinese population. Aberrant regulation of transcripts has been implicated in many types of cancers including NPC. Herein, we characterized mRNA and miRNA transcriptomes by RNA sequencing (RNASeq) of NPC model systems. Matched total mRNA and small RNA of undifferen...
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... variants analysis detecting SNP and short INDELS was carried out using VarScan [ 41 ]. The 17,389 SNP / INDELS were de- tected from NP460, HK1, and C666 and the results are summarized in Fig. 5 A and Supplement 5 . Sequence variants, which are not solely from X666, are also listed in Supplement 5 , while variants solely from X666 were removed due to possible contamination of mouse sequences. A total of 62% (10,929 / 17,389) of variants are from non- protein coding regions, while around 37% (6460 / 17,389) are from the exonic ...Context 2
... variants, which are not solely from X666, are also listed in Supplement 5 , while variants solely from X666 were removed due to possible contamination of mouse sequences. A total of 62% (10,929 / 17,389) of variants are from non- protein coding regions, while around 37% (6460 / 17,389) are from the exonic regions of the genome ( Fig. 5 A). Of the exonic variants, note, we discovered a novel TP53 mutation at Chr17:7,579,335T > G in NP460, HK1, and C666 cell lines. ...Context 3
... the exonic variants, note, we discovered a novel TP53 mutation at Chr17:7,579,335T > G in NP460, HK1, and C666 cell lines. Differences in polymorphism of GSTP1 (Chr11:67,352,689A > G) across NP460, HK1, and C666-1 were also found from the NGS data ( Fig. 5 B). ...Context 4
... from expression analysis, we have analyzed the sequence variants and their relationship to expression. Besides proteins en- coding SNV / INDEL, a large portion of sequence variants are located in UTRs of the mRNA transcript whose function still remains un- known ( Fig. 5 A). The analysis of SNV, short INDEL, and UTR sequence may provide a possible opportunity for further mechanistic studies ( Supplements 5 and 6 ). From the TP53 mutant database [ 76 ], we dis- covered a novel TP53 mutation at the HCDII binding domain. From the RNASeq data of NP460, HK1, and C666 cell lines ( Fig. 5 B), this T-to-G ...Context 5
... the TP53 mutant database [ 76 ], we dis- covered a novel TP53 mutation at the HCDII binding domain. From the RNASeq data of NP460, HK1, and C666 cell lines ( Fig. 5 B), this T-to-G variation occurs in the range of 30% to 50% of the total tran- scripts ( Supplement 5 ). The mutation causes an amino acid change (Thr118 > Pro) at the DNA binding domain, reducing transactivation activity in various promoters (14-3-3-σ, AIP, BAX, GADD45, MDM2, NOXA, p53R2, WAF1) from 50% to 90% in a TP53 yeast mutant library [ 77 , 78 ]. ...Context 6
... also identified a differential variation of GSTP1 SNV in NP and NPC cell lines. All of the transcripts from RNASeq were in T-to-C variant (rs1695 / rs947894) form in C666, whilst only wild- type GSTP1 was found in NP460, and around 65% of the variants are found in HK1 ( Fig. 5 B). This polymorphism is reported to lower en- zyme activity of GSTP1 [ 81 ] and has been reported in NPC and the Han Chinese population [ 82 ]. ...Similar publications
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Citations
... For example, upregulated levels of EBV-miRNAs BART2-5p and 6-5p, 17-5p were found in the serum of NPC patients compared to healthy controls [196]. Furthermore, the PTEN tumor-suppressor and the Wnt signaling pathway were shown to be targeted by these EBV v-miRNAs [197]. This study revealed a significant correlation of these BART miRNA between NPC tumor and serum samples, hence their proposed use as diagnostic and prognostic biomarkers. ...
About 15% of all human cancers have a viral etiology. Although progress has been made, understanding the viral oncogenesis and associated molecular mechanisms remain complex. The discovery of cellular miRNAs has led to major breakthroughs. Interestingly, viruses have also been discovered to encode their own miRNAs. These viral, small, non-coding miRNAs are also known as viral-miRNAs (v-miRNAs). Although the function of v-miRNAs largely remains to be elucidated, their role in tumorigenesis cannot be ignored. V-miRNAs have also been shown to exploit the cellular machinery to benefit viral replication and survival. Although the discovery of Hepatitis C virus (HCV), and its viral miRNAs, is a work in progress, the existence of HPV-, EBV-, HBV-, MCPyV-and KSHV-encoded miRNA has been documented. V-miRNAs have been shown to target host factors to advance tumorigenesis, evade and suppress the immune system, and deregulate both the cell cycle and the apoptotic machinery. Although the exact mechanisms of v-miRNAs-induced tu-morigenesis are still unclear, v-miRNAs are active role-players in tumorigenesis, viral latency and cell transformation. Furthermore, v-miRNAs can function as posttranscriptional gene regulators of both viral and host genes. Thus, it has been proposed that v-miRNAs may serve as diagnostic bi-omarkers and therapeutic targets for cancers with a viral etiology. Although significant challenges exist in their clinical application, emerging reports demonstrate their potent role in precision medicine. This review will focus on the roles of HPV-, HCV-, EBV-, HBV-, MCPyV-, and KSHV-produced v-miRNAs in tumorigenesis, as effectors in immune evasion, as diagnostic biomarkers and as novel anti-cancer therapeutic targets. Finally, it will discuss the challenges and opportunities associated with v-miRNAs theranostics in precision oncology.
... The RNA sequencing data of NPC and GC cell lines and tumor tissues were obtained from the Gene Expression Omnibus (GEO) database. The RNA sequencing datasets, including GSE60873 [26], GSE147512, GSE54174 [27], GSE51575 [26] GSE102349 [28], GSE68799, GSE74956 [29], and GSE118719 [30], were downloaded and analyzed in this study. The raw RNA sequencing reads were first aligned to a reference human genome (hg38) using Spliced Transcript Alignment to a Reference aligner v2.7.3a. ...
Simple Summary
Nasopharyngeal carcinoma (NPC), Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC), and oral squamous cell carcinoma (OSCC) are epithelial cancers that are associated with EBV infection. However, the gene signatures and common hallmarks associated with EBV infection in EBV-associated epithelial cancers (EBVaCAs) have not been fully elucidated. Here, we performed a panel of transcriptome analyses to identify the gene signatures and common hallmarks of these EBVaCAs. Based on the changes in the expression levels of genes in EBV-infected cell lines and tumor tissues, we identified two upregulated genes, SLC26A9 and TMC8, as gene signatures for EBVaCAs. In addition, SLC26A9 and TMC8 are differentially expressed genes (DEGs) in EBV-infected cells, and their expression is highly correlated with the stimulation of genes involved in numerous biological processes and pathways, such as IL6/JAK/STAT3 and TNF-α/NF-κB signaling pathways. Here, we propose SLC26A9 and TMC8 as novel gene signatures. In addition, we propose IL6/JAK/STAT3 and TNF-α/NF-κB signaling pathways as common hallmarks of EBVaCAs.
Abstract
Epstein-Barr virus (EBV) is associated with various types of human malignancies, including nasopharyngeal carcinoma (NPC), EBV-associated gastric carcinoma (EBVaGC), and oral squamous cell carcinoma (OSCC). The present study aimed to identify gene signatures and common signaling pathways that can be used to predict the prognosis of EBV-associated epithelial cancers (EBVaCAs) by performing an integrated bioinformatics analysis of cell lines and tumor tissues. We identified 12 differentially expressed genes (DEGs) in the EBVaCA cell lines. Among them, only four DEGs, including BAMBI, SLC26A9, SGPP2, and TMC8, were significantly upregulated. However, SLC26A9 and TMC8, but not BAMBI and SGPP2, were significantly upregulated in EBV-positive tumor tissues compared to EBV-negative tumor tissues. Next, we identified IL6/JAK/STAT3 and TNF-α/NF-κB signaling pathways as common hallmarks of EBVaCAs. The expression of key genes related to the two hallmarks was upregulated in both EBV-infected cell lines and EBV-positive tumor tissues. These results suggest that SLC26A9 and TMC8 might be gene signatures that can effectively predict the prognosis of EBVaCAs and provide new insights into the molecular mechanisms of EBV-driven epithelial cancers.
... Mechanistically, circCRIM1 competitively binds to miR-422a and prevents the suppressive effects of miR-422a on its target gene FOXQ1, which finally leads to NPC metastasis, EMT, and docetaxel chemoresistance. 290 The combination of miRNA and transcriptome sequencing Szeto et al. 291 characterized mRNA and miRNA transcriptomes by RNA sequencing (RNA-Seq) of NPC model systems. They found 2812 genes and 149 miRNAs (human and EBV) to be differentially expressed in NP460, HK1, C666, and X666 with RNASeq and 533 miRNA-mRNA target pairs were inversely regulated in the three NPC cell lines compared to NP460 cells. ...
Epstein–Barr virus-associated diseases are important global health concerns. As a group I carcinogen, EBV accounts for 1.5% of human malignances, including both epithelial- and lymphatic-originated tumors. Moreover, EBV plays an etiological and pathogenic role in a number of non-neoplastic diseases, and is even involved in multiple autoimmune diseases (SADs). In this review, we summarize and discuss some recent exciting discoveries in EBV research area, which including DNA methylation alterations, metabolic reprogramming, the changes of mitochondria and ubiquitin-proteasome system (UPS), oxidative stress and EBV lytic reactivation, variations in non-coding RNA (ncRNA), radiochemotherapy and immunotherapy. Understanding and learning from this advancement will further confirm the far-reaching and future value of therapeutic strategies in EBV-associated diseases.
... However, the regulatory mechanism by which HCSCs acquire the ability to resist drugs and be efficiently transplanted remains unclear. Therefore, high-throughput transcriptomic sequencing is essential for better understanding the cellular characteristics and signaling pathways of HCSCs involved in tumor initiation or progression (12). ...
Cancer stem cells are considered to be tumor-initiating cells. To explain the initiation or progression of hepatocellular carcinoma (HCC), we previously established a culture system that may enrich hepatic cancer stem-like cells (HCSCs). However, the regulatory mechanisms by which HCSCs acquire stem cell properties remain unclear. In the present study, three pairs of HCSCs and case-matched human HCC cells were analyzed by high-throughput screening, and novel biomarkers and pathways for the regulation of HCSCs were identified. The results led to the identification and stratification of 406 differentially expressed genes (DEGs), among which 73 GO terms were found to be significantly associated with DEGs in HCSCs, and only complement and coagulation cascade pathways were identified during the development of HCSCs. By combining the results of the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, it was revealed that 7 genes were downregulated in the complement and coagulation cascade pathways, and 7 miRNAs were predicted to target several downregulated genes involved in these pathways. The results may contribute toward hepatic cancer stem cell studies and novel drug research for HCC treatment.
... However, both the host cell and EBV viral factor-mediated inhibition of expression or silencing of the Wnt-negative regulators appear to contribute to the dysregulation of Wnt signaling in NPC. These include (i) epigenetic silencing of some major negative Wnt regulators (e.g., methylation of WNT Inhibitory Factor 1 (WIF-1) and APC genes) [29,30]; (ii) phosphorylated inactivation of Glycogen Synthase Kinase 3 Beta (GSK3β) [31]; (iii) dysregulation of the expression of miRNA for the Wnt pathway [16,17]; (iv) targeting of the negative Wnt regulators (e.g., WIF1, APC, Nemo Like Kinase (NLK)) by the EBV-encoded miRNAs [32]; ...
... These include self-renewal, cell growth and differentiation, and cell migration [36,37]. In NPC, dysregulation of miRNA for the Wnt pathway has been well documented [16,17]. Especially the expression of miR-449a was found to be downregulated from stages I to IV and also metastatic NPC [18]. ...
The Wnt signaling pathway is one of the major signaling pathways used by cancer stem cells (CSC). Ecotropic Viral Integration Site 1 (EVI1) has recently been shown to regulate oncogenic development of tumor cells by interacting with multiple signaling pathways, including the Wnt signaling. In the present study, we found that the Wnt modulator ICG-001 could inhibit the expression of EVI1 in nasopharyngeal carcinoma (NPC) cells. Results from loss-of-function and gain-of-function studies revealed that EVI1 expression positively regulated both NPC cell migration and growth of CSC-enriched tumor spheres. Subsequent studies indicated ICG-001 inhibited EVI1 expression via upregulated expression of miR-96. Results from EVI1 3′UTR luciferase reporter assay confirmed that EVI1 is a direct target of miR-96. Further mechanistic studies revealed that ICG-001, overexpression of miR-96, or knockdown of EVI1 expression could restore the expression of miR-449a. The suppressive effect of miR-449a on the cell migration and tumor sphere formation was confirmed in NPC cells. Taken together, the miR-96/EVI1/miR-449a axis is a novel pathway involved in ICG-001-mediated inhibition of NPC cell migration and growth of the tumor spheres.
... In addition, an extensive body of researches have demonstrated miRNAs could regulate gene expressions by binding to the 3′-untranslated regions (3′-UTR) of the targeted mRNAs to exhibit their posttranscriptional regulatory effects [46,47]. Current researches also suggested that a number of circRNAs included miRNA response elements (MREs), indicating that circRNAs may serve as miRNAs sponge to reduce the miRNAs levels and releases the targeted genes of miRNAs [48,49]. ...
Background:
Thyroid cancer is an endocrine malignancy that is growing in incidence worldwide. Despite progress in diagnostics and treatment of thyroid cancer, prognosis remains poor. Emerging research has shown that circular RNAs (circRNAs) have crucial regulatory roles in cancers. However, the possible functions and mechanisms of hsa_circ_0011385 remain undetermined.
Materials and methods:
Expression levels of hsa_circ_0011385 and miR-361-3p were evaluated by qRT-PCR assay. The interaction between hsa_circ_0011385 and miR-361-3p was verified by dual-luciferase reporter assay. Effects of hsa_circ_0011385 or miR-361-3p on cell viability, proliferation, cell cycle, apoptosis, migration and invasion were confirmed by cell counting kit-8 (CCK-8), carboxyfluoresceinsuccinimidyl ester (CFSE), flow cytometry, and Transwell assays in vitro. The effect of hsa_circ_0011385 on thyroid cancer progression was also determined by in vivo tumor formation assay. Target genes of miR-361-3p were predicted by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and the expression of apoptosis- and metastasis-related proteins were assessed by Western blot assay.
Results:
Hsa_circ_0011385 upregulated in thyroid cancer; hsa_circ_0011385 knockdown inhibited thyroid cancer cell proliferation, migration and invasion, and promoted cell cycle arrest and apoptosis. In addition, hsa_circ_0011385 could negatively regulate miR-361-3p by functioning as a sponge. Hsa_circ_0011385 promoted thyroid cancer cell proliferation, migration and invasion and suppressed cell cycle arrest and apoptosis by targeting miR-361-3p in vitro. We also found that hsa_circ_0011385 knockdown dramatically inhibited thyroid cancer growth in vivo. Furthermore, hsa_circ_0011385 regulated expression of apoptosis and metastasis-related proteins in thyroid cancer.
Conclusions:
Hsa_circ_0011385facilitated thyroid cancer cell proliferation, invasion and migration, and inhibited thyroid cancer cell cycle arrest and apoptosis by targeting miR-361-3p, suggesting that the hsa_circ_0011385/miR-361-3p axis might be a promising therapeutic target for thyroid cancer.
... Advances in next generation sequencing have contributed to an explosion of knowledge regarding the EBV genome and transcriptome, as well as the effects of EBV on the human genome: discovery of novel small non-coding RNAs expressed by EBV [9], EBV encoded circular RNAs (circRNAs) [13,14], EBV and host miRNA expression in patient and cultured cell samples [15][16][17][18][19][20][21][22][23][24], differential expression of host and EBV mRNAs, long non-coding RNAs (lncRNAs) as well as sequence variations in EBV genomes [9,[25][26][27][28][29]. However, the effect of infection on host non-micro small non-coding (nc)RNA has not been extensively studied. ...
Epstein–Barr virus (EBV) is a ubiquitous human herpes virus, which is implicated in cancer and various autoimmune diseases. This study profiles non-micro small non-coding RNA expression changes induced by latent EBV infection. Using small RNA-Seq, 346 non-micro small RNAs were identified as being significantly differentially expressed between EBV(+) BJAB-B1 and EBV(−) BJAB cell lines. Select small RNA expression changes were experimentally validated in the BJAB-B1 cell line as well as the EBV-infected Raji and Jijoye cell lines. This latter analysis recapitulated the previously identified induction of vault RNA1, while also finding novel evidence for the deregulation of several tRNAs and a snoRNA. Keywords: ncRNA, miRNA, tRNA, snoRNA, Vault RNA, EBV, Differential expression, B cell
... First, RNA-Seq was used to identify differences in their transcriptomes (Supplementary document S1, available at Carcinogenesis Online). As revealed by the results of RNA-Seq, high expression of BC-specific genes, including TP63, KRT5, KRT6, KRT14, EGFR, CD44, CAV1, CAV2, ITGA6, and NGRF, was detected in HK1 cells, whereas C666-1 cells showed higher expression of LC-related genes, such as FOXA1, BAMBI, TJP3, CD74, MUC1, ABCA3, and KRT8 (Supplementary Figure S1A, available at Carcinogenesis Online), consistent with a previous report (GSE54174) (36). Differential expression of BC-or LC-related genes in these two cell lines was further verified by RT-PCR or western blotting analyses (Supplementary Figure S1B, C, available at Carcinogenesis Online). ...
Nasopharyngeal carcinoma (NPC) originates via malignant transformation of the pseudostratified nasopharyngeal epithelium, composed of basal and luminal cells. Super enhancers (SEs) are large clusters of cis-elements involved in the regulation of gene expression through epigenetic regulatory mechanisms. In this study, we demonstrated that basal cell-specific proteins are highly expressed, whereas luminal cell proteins are downregulated in NPC, implying a perturbation of basal-to-luminal differentiation during NPC development. We characterized NPC cell models according to different molecular signatures associated with their differentiation status and found that distinct SE landscapes are tightly associated with basal or luminal-like molecular signatures in NPC cells. Furthermore, the transcription of ΔNP63α, a prominent isoform of TP63, was found to be driven by SEs in NPC cells. Data from chromatin immunoprecipitation-sequencing showed that ΔNP63α largely occupied regions of SEs associated with basal cell-specific genes. Silencing of ΔNP63α led to a loss of H3K27ac occupancy at basal-type SEs and triggered a basal-to-luminal gene expression signature switch, suggesting that ΔNP63α is a master factor contributing to the perturbation of luminal differentiation. Integrative transcriptomics analysis also revealed that ΔNP63α acts as a core factor involved in the dysregulation of gene expression in NPC. Furthermore, ΔNP63α enhanced EGF-stimulated NF-κB activation in NPC cells by activating SE-mediated EGFR transcription. Finally, depletion of ΔNP63α in NPC cells induced robust growth inhibition of NPC cells in vitro and in vivo. Our data revealed that ΔNP63α-dependent SE reprogramming contributes to the blockade of luminal differentiation and uncontrolled proliferation in NPC.
... Version 3.7.1) was used to visualize the differentially expressed miRNAs and their differentially expressed target genes [28]. ...
... Carol Ying-Ying Szeto demonstrated the role of miRNAs in transcript expression and miRNA genomic variation through mRNA and miRNA sequencing in the NPC cell lines HK1, C666 and immortalized NP420 cells. The NGS data showed isomiRs that are worthy of study and identified that three quarters of the miRNAs had isomiRs, providing even more evidence that the functions of these EBV-encoded miRNAs need to be studied in NPC [125]. Recently, Li Guiyuan's team illuminated the characteristics of EBV genomic variations in NPC tissues using "capture-sequencing" analysis. ...
Epstein-Barr virus (EBV) is an oncogenic herpes virus that is closely associated with the initiation and development of nasopharyngeal carcinoma (NPC), lymphoma and other malignant tumors. EBV encodes 44 mature miRNAs that regulate viral and host cell gene expression and plays a variety of roles in biological functions and the development of cancer. In this review, we summarized the biological functions and molecular mechanisms of Epstein-Barr virus-encoded microRNAs (EBV miRNAs) in tumor immune evasion, proliferation, anti-apoptosis, invasion, metastasis and as a potential biomarker for NPC diagnosis and prognosis. The knowledge generated by EBV miRNAs can be used for EBV miRNA-based precision cancer treatments in the near future.
