Histone acetyltransferase CSRP2BP promotes the epithelial-mesenchymal transition and metastasis of cervical cancer cells by activating N-cadherin.

BACKGROUND: Dysregulated epithelial-mesenchymal transition (EMT) is involved in cervical cancer metastasis and associated with histone acetylation. However, the underlying molecular mechanisms of histone acetylation in cervical cancer EMT and metastasis are still elusive. METHODS: We systematically investigated the expression patterns of histone acetylation genes and their correlations with the EMT pathway in cervical cancer. The expression of CSRP2BP among cervical cancer tissues and cell lines was detected using Western blotting and immunohistochemistry analyses. The effects of CSRP2BP on cervical cancer cell proliferation and tumorigenicity were examined by cell growth curve, EdU assay, flow cytometry and xenotransplantation assays. Wound healing assays, transwell migration assays and pulmonary metastasis model were used to evaluate the effects of CSRP2BP on cell invasion and metastasis of cervical cancer cells in vivo and in vitro. RNA-seq, chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP) and luciferase reporter assays were used to uncover the molecular mechanisms of CSRP2BP in promoting cervical cancer EMT and metastasis. RESULTS: We prioritized a top candidate histone acetyltransferase, CSRP2BP, as a key player in cervical cancer EMT and metastasis. The expression of CSRP2BP was significantly increased in cervical cancer tissues and high CSRP2BP expression was associated with poor prognosis. Overexpression of CSRP2BP promoted cervical cancer cell proliferation and metastasis both in vitro and in vivo, while knockdown of CSRP2BP obtained the opposite effects. In addition, CSRP2BP promoted resistance to cisplatin chemotherapy. Mechanistically, CSRP2BP mediated histone 4 acetylation at lysine sites 5 and 12, cooperated with the transcription factor SMAD4 to bind to the SEB2 sequence in the N-cadherin gene promotor and upregulated N-cadherin transcription. Consequently, CSRP2BP promoted cervical cancer cell EMT and metastasis through activating N-cadherin. CONCLUSIONS: This study demonstrates that the histone acetyltransferase CSRP2BP promotes cervical cancer metastasis partially through increasing the EMT and suggests that CSRP2BP could be a prognostic marker and a potential therapeutic target for combating cervical cancer metastasis.

Systematical analyses of large-scale transcriptome reveal viral infection-related genes and disease comorbidities.

Perturbation of transcriptome in viral infection patients is a recurrent theme impacting symptoms and mortality, yet a detailed understanding of pertinent transcriptome and identification of robust biomarkers is not complete. In this study, we manually collected 23 datasets related to 6,197 blood transcriptomes across 16 types of respiratory virus infections. We applied a comprehensive systems biology approach starting with whole-blood transcriptomes combined with multilevel bioinformatics analyses to characterize the expression, functional pathways, and protein-protein interaction (PPI) networks to identify robust biomarkers and disease comorbidities. Robust gene markers of infection with different viruses were identified, which can accurately classify the normal and infected patients in train and validation cohorts. The biological processes (BP) of different viruses showed great similarity and enriched in infection and immune response pathways. Network-based analyses revealed that a variety of viral infections were associated with nervous system diseases, neoplasms and metabolic diseases, and significantly correlated with brain tissues. In summary, our manually collected transcriptomes and comprehensive analyses reveal key molecular markers and disease comorbidities in the process of viral infection, which could provide a valuable theoretical basis for the prevention of subsequent public health events for respiratory virus infections.

Deep immunophenotyping reveals clinically distinct cellular states and ecosystems in large-scale colorectal cancer.

Determining the diverse cell types in the tumor microenvironment (TME) and their organization into cellular communities, is critical for understanding the biological heterogeneity and therapy of cancer. Here, we deeply immunophenotype the colorectal cancer (CRC) by integrative analysis of large-scale bulk and single cell transcriptome of 2350 patients and 53,137 cells. A rich landscape of 42 cellular states and 7 ecosystems in TMEs is uncovered and extend the previous immune classifications of CRC. Functional pathways and potential transcriptional regulators analysis of cellular states and ecosystems reveal cancer hallmark-related pathways and several critical transcription factors in CRC. High-resolution characterization of the TMEs, we discover the potential utility of cellular states (i.e., Monocytes/Macrophages and CD8 T cell) and ecosystems for prognosis and clinical therapy selection of CRC. Together, our results expand our understanding of cellular organization in TMEs of CRC, with potential implications for the development of biomarkers and precision therapies.

Widespread transcriptomic alterations of transient receptor potential channel genes in cancer.

Ion channels, in particular transient-receptor potential (TRP) channels, are essential genes that play important roles in many physiological processes. Emerging evidence has demonstrated that TRP genes are involved in a number of diseases, including various cancer types. However, we still lack knowledge about the expression alterations landscape of TRP genes across cancer types. In this review, we comprehensively reviewed and summarised the transcriptomes from more than 10 000 samples in 33 cancer types. We found that TRP genes were widespreadly transcriptomic dysregulated in cancer, which was associated with clinical survival of cancer patients. Perturbations of TRP genes were associated with a number of cancer pathways across cancer types. Moreover, we reviewed the functions of TRP family gene alterations in a number of diseases reported in recent studies. Taken together, our study comprehensively reviewed TRP genes with extensive transcriptomic alterations and their functions will directly contribute to cancer therapy and precision medicine.

Dynamic transcriptome analyses reveal m6A regulated immune non-coding RNAs during dengue disease progression.

Dengue infection is one of the most prevalent arthropod-borne viral diseases, which can result in severe complications. Identification of genes and long non-coding RNAs (lncRNAs) involved in dengue infection would help in deciphering potential mechanisms responsible for the disease progression. We comprehensively analyzed the dynamic transcriptome during dengue disease progression and identified critical genes and lncRNAs with expression perturbations. Our findings revealed that the expression of genes (i.e., CCR10 and GNG7) and lncRNAs (i.e., CTBP1-AS and MAFG-AS1) were potentially regulated by m6A RNA methylation. Interestingly, dengue viral proteins prevalently interact with genes or lncRNAs with expression perturbations, which are involved in cell cycle, inflammation signaling pathways and immune response. Dynamically expressed genes and lncRNAs were likely to locate in the central regions of human protein-protein network, which play crucial roles in mediating signaling spread and helping viral replication. Immune microenvironments analysis revealed that plasma cells levels were increased and T cells infiltrations were decreased during dengue disease progression. Dynamically expressed genes and lncRNAs were correlated with immune cell infiltrations. Moreover, network analysis reveals the associations between dengue viral infections and human complex diseases (i.e., digestive diseases and neoplasms). Our comprehensive transcriptome analysis of dengue disease progression identified potential gene and lncRNA biomarkers, providing novel insights for understanding the pathogenesis of and developing effective therapeutic strategies for dengue infection.

Clinical and genomic characterization of mutational signatures across human cancers.

Mutational signatures, the generic patterns of mutations, are the footprints of both endogenous and exogenous factors that have influenced cancer development. To date, dozens of mutational signatures have been discerned through computational methods. However, the etiology, mutational properties, clonality, immunology and prognostic value of mutation signatures across cancer types are poorly understood. To address this, we extensively characterized mutational signatures across 8836 cancer samples spanning 42 cancer types. We confirmed and extended clinical and genomic features associated with mutation signatures. Mutation distribution analysis showed that most mutation processes were depleted in exons and APOBEC signatures (SBS2 and SBS13), the Pol-η related signature (SBS9) and SBS40 tended to contribute clustered mutations. We observed that age-related signatures (SBS1 and SBS5) and SBS40 tended to induce mutations affecting cancer genes and subclonal drivers posted by specific signatures (eg, mismatch repair deficiency-related signature SBS44) were unlikely subjected to positive selection. We also revealed early mutation signatures (eg, UV light exposure-related signature SBS7a) and signatures (eg, reactive oxygen species-related signature SBS18) predominated in the late stage of tumorigenesis. Comprehensive association analysis of mutation processes with microenvironment revealed that APOBEC- and mismatch repair deficiency-related signatures were positively associated with immune parameters, while age-related signatures showed negative correlations. In addition, prognostic association analysis showed that many signatures were favorable (eg, SBS9) or adverse factors (eg, SBS18) of patient survival. Our findings enhance appreciation of the role of mutational signatures in tumor evolution and underline their potential in immunotherapy guidance and prognostic prediction.

Pan-cancer illumination of TRIM gene family reveals immunology regulation and potential therapeutic implications.

BACKGROUND: The tripartite motif (TRIM) proteins function as important regulators in innate immunity, tumorigenesis, cell differentiation and ontogenetic development. However, we still lack knowledge about the genetic and transcriptome alterations landscape of TRIM proteins across cancer types. METHODS: We comprehensively reviewed and characterized the perturbations of TRIM genes across > 10,000 samples across 33 cancer types. Genetic mutations and transcriptome of TRIM genes were analyzed by diverse computational methods. A TRIMs score index was calculated based on the expression of TRIM genes. The correlation between TRIMs scores and clinical associations, immune cell infiltrations and immunotherapy response were analyzed by correlation coefficients and gene set enrichment analysis. RESULTS: Alterations in TRIM genes and protein levels frequently emerge in a wide range of tumors and affect expression of TRIM genes. In particular, mutations located in domains are likely to be deleterious mutations. Perturbations of TRIM genes are correlated with expressions of immune checkpoints and immune cell infiltrations, which further regulated the cancer- and immune-related pathways. Moreover, we proposed a TRIMs score index, which can accurately predict the clinical outcome of cancer patients. TRIMs scores of patients are correlated with clinical survival and immune therapy response across cancer types. Identifying the TRIM genes with genetic and transcriptome alterations will directly contribute to cancer therapy in the context of predictive, preventive, and personalized medicine. CONCLUSIONS: Our study provided a comprehensive analysis and resource for guiding both mechanistic and therapeutic analyses of the roles of TRIM genes in cancer.

Bioinformatics Methods for Modeling microRNA Regulatory Networks in Cancer.

MicroRNAs (miRNAs) play important roles in the physiology and development of cancers. The increase of multidimensional molecular profiles of tumor patients generated by high-throughput sequencing technologies has enabled computational analysis of miRNA regulatory networks in cancer. In this chapter, we first summarized currently widely used computational methods for identifying miRNA-gene interactions. In addition, crosstalk among miRNAs and competitive endogenous RNAs (ceRNAs) represent novel layers of gene regulation mediated by miRNAs, which also play important roles in cancer. We next reviewed computational methods for modeling miRNA-miRNA crosstalk and ceRNA-ceRNA interactions in cancer. These methods integrate multi-omics data and range from genomics to phenomics. MiRNA-miRNA networks are generally constructed based on genomic sequences, transcriptomes, miRNA-gene regulation, and functional pathways. Moreover, five types of computational methods for identifying ceRNA-ceRNA interactions are summarized in this chapter. Among these methods, two types of global ceRNA regulation and three types of context-specific methods are included. The application of these computational methods focused on miRNA regulation in cancer provides valuable functional insights into the underlying mechanism of cancer, as well as future precision medicine.

Long noncoding RNA LINC01132 enhances immunosuppression and therapy resistance via NRF1/DPP4 axis in hepatocellular carcinoma.

BACKGROUND: Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression and play fundamental roles in various types of cancer. Current developments in transcriptome analyses unveiled the existence of lncRNAs; however, their functional characterization remains a challenge. METHODS: A bioinformatics screen was performed by integration of multiple omics data in hepatocellular carcinoma (HCC) prioritizing a novel oncogenic lncRNA, LINC01132. Expression of LINC01132 in HCC and control tissues was validated by qRT-PCR. Cell viability and migration activity was examined by MTT and transwell assays. Finally, our results were confirmed in vivo mouse model and ex vivo patient derived tumor xenograft experiments to determine the mechanism of action and explore LINC01132-targeted immunotherapy. RESULTS: Systematic investigation of lncRNAs genome-wide expression patterns revealed LINC01132 as an oncogene in HCC. LINC01132 is significantly overexpressed in tumor and associated with poor overall survival of HCC patients, which is mainly driven by copy number amplification. Functionally, LINC01132 overexpression promoted cell growth, proliferation, invasion and metastasis in vitro and in vivo. Mechanistically, LINC01132 acts as an oncogenic driver by physically interacting with NRF and enhancing the expression of DPP4. Notably, LINC01132 silencing triggers CD8+ T cells infiltration, and LINC01132 knockdown combined with anti-PDL1 treatment improves antitumor immunity, which may prove a new combination therapy in HCC. CONCLUSIONS: LINC01132 functions as an oncogenic driver that induces HCC development via the NRF1/DPP4 axis. Silencing LINC01132 may enhance the efficacy of anti-PDL1 immunotherapy in HCC patients.

Pan-cancer analyses reveal the genetic and pharmacogenomic landscape of transient receptor potential channels.

Transient-receptor potential (TRP) channels comprise a diverse family of ion channels, which play important roles in regulation of intracellular calcium. Emerging evidence has revealed the critical roles of TRP channels in tumor development and progression. However, we still lack knowledge about the genetic and pharmacogenomics landscape of TRP genes across cancer types. Here, we comprehensively characterized the genetic and transcriptome alterations of TRP genes across >10,000 patients of 33 cancer types. We revealed prevalent somatic mutations and copy number variation in TRP genes. In particular, mutations located in transmembrane regions of TRP genes were likely to be deleterious mutations (p-values < 0.001). Genetic alterations were correlated with transcriptome dysregulation of TRP genes, and we found that TRPM2, TRPM8, and TPRA1 showed extent dysregulation in cancer. Patients with TRP gene alterations were with significantly higher hypoxia scores, tumor mutation burdens, tumor stages and grades, and poor survival. The alterations of TRP genes were significantly associated with the activity of cancer-related pathways. Moreover, we found that the expression of TRP genes were potentially useful for development of targeted therapies. Our study provided the landscape of genomic and transcriptomic alterations of TPRs across 33 cancer types, which is a comprehensive resource for guiding both mechanistic and therapeutic analyses of the roles of TRP genes in cancer. Identifying the TRP genes with extensive genetic alterations will directly contribute to cancer therapy in the context of predictive, preventive, and personalized medicine.

Shedding light on the hidden human proteome expands immunopeptidome in cancer.

Unrestrained cellular growth and immune escape of a tumor are associated with the incidental errors of the genome and transcriptome. Advances in next-generation sequencing have identified thousands of genomic and transcriptomic aberrations that generate variant peptides that assemble the hidden proteome, further expanding the immunopeptidome. Emerging next-generation sequencing technologies and a number of computational methods estimated the abundance of immune infiltration from bulk transcriptome have advanced our understanding of tumor microenvironments. Here, we will characterize several major types of tumor-specific antigens arising from single-nucleotide variants, insertions and deletions, gene fusion, alternative splicing, RNA editing and non-coding RNAs. Finally, we summarize the current state-of-the-art computational and experimental approaches or resources and provide an integrative pipeline for the identification of candidate tumor antigens. Together, the systematic investigation of the hidden proteome in cancer will help facilitate the development of effective and durable immunotherapy targets for cancer.

Pan-cancer assessment of mutational landscape in intrinsically disordered hotspots reveals potential driver genes.

Large-scale cancer genome sequencing has enabled the catalogs of somatic mutations; however, the mutational impact on intrinsically disordered protein regions (IDRs) has not been systematically investigated to date. Here, we comprehensively characterized the mutational landscapes of IDRs and found that IDRs have higher mutation frequencies across diverse cancers. We thus developed a computational method, ROI-Driver, to identify putative driver genes enriching IDR and domain hotspots in cancer. Numerous well-known cancer-related oncogenes or tumor suppressors that play important roles in cancer signaling regulation, development and immune response were identified at a higher resolution. In particular, the incorporation of IDR structures helps in the identification of novel potential driver genes that play central roles in human protein-protein interaction networks. Interestingly, we found that the putative driver genes with IDR hotspots were significantly enriched with predicted phase separation propensities, suggesting that IDR mutations disrupt phase separation in key cellular pathways. We also identified an appreciable number of clinically relevant genes enriching IDR mutational hotspots that exhibited differential expression patterns and are associated with cancer patient survival. In summary, combinations of mutational effects on IDRs significantly increase the sensitivity of driver detection and are likely to open new therapeutic avenues for various cancers.

Sensitive Techniques for POCT Sensing on the Residues of Pesticides and Veterinary Drugs in Food.

For the immense requirement on agriculture and animal husbandry, application of pesticides and veterinary drugs had become a normal state in the farming and ranching areas. However, to intently pursue the yields, large quantities of residues of pesticides and veterinary drugs have caused serious harm to both the environment and the food industry. To control and solve such an issue, a variety of novel techniques were developed in recent years. In this review, the development and features about point-of-care-testing (POCT) detection on the residues of pesticides and veterinary drugs, such as, electrochemistry (EC), enzyme-linked immunosorbent assay (ELISA) and nano-techniques, were systematically introduced. For each topic, we first interpreted the strategies and detailed account of such technical contributions on detection and assessment of the residues. Finally, the advantages and perspectives about mentioned techniques for ultrasensitive assessment and sensing on pesticides and veterinary drugs were summarized.

Dynamic Expression of m6A Regulators During Multiple Human Tissue Development and Cancers.

N6-methyladenosine (m6A) plays critical roles in human development and cancer progression. However, our knowledge regarding the dynamic expression of m6A regulators during human tissue development is still lacking. Here, we comprehensively analyzed the dynamic expression alterations of m6A regulators during seven tissue development and eight cancer types. We found that m6A regulators globally exhibited decreased expression during development. In addition, IGF2BP1/2/3 (insulinlike growth factor 2 MRNA-binding protein 1/2/3) exhibited reverse expression pattern in cancer progression, suggesting an oncofetal reprogramming in cancer. The expressions of IGF2BP1/2/3 were regulated by genome alterations, particularly copy number amplification in cancer. Clinical association analysis revealed that higher expressions of IGF2BP1/2/3 were associated with worse survival of cancer patients. Finally, we found that genes significantly correlated with IGF2BP1/2/3 were significantly enriched in cancer hallmark-related pathways. In summary, dynamic expression analysis will guide both mechanistic and therapeutic roles of m6A regulators during tissue development and cancer progression.

Cross-talk between 5-hydroxytryptamine and substance P in the melanogensis and apoptosis of B16F10 melanoma cells.

Skin pigmentation is a complex process controlled by many different factors. Substance P (SP) regulates many biological functions, including melanogenesis and stress. Our previous study indicated that regulation of SP on melanocyte function was mediated by neurokinin 1 receptor (NK1 receptor). Substantial evidence has accumulated that psychological stress can be associated with skin pigmentation, so that the impact of 5-hydroxytryptamine (5-HT), one of the important factors participating in stress process, on melanogenesis has also been concerned. It has been reported that 5-HT induces melanin synthesis via 5-HT2A receptor. Furthermore, 5-HT2A receptor and NK1 receptor are G-protein coupled receptors (GPCRs) and both expressed on melanocyte, the present study was designed to investigate whether SP has influence on the adjustment function of 5-HT. Our data demonstrated that, SP inhibited 5-HT2A receptor expression to neutralize the pro-melanogenesis effect of 5-HT on B16F10 cells. The up-regulation of NK1 receptor expression was simultaneous with the down-regulation of 5-HT2A receptor treated by SP. This inhibition of 5-HT2A receptor expression by SP could be reversed by NK1 receptor antagonist Spantide I. Our studies indicated that SP could directly induce B16F10 cells apoptosis in vitro. 5-HT and 5-HT2A receptor agonist could mitigate this apoptotic effect of SP. It is the strong evidence of possible cross-talk between GPCRs and giving enlightenments when screening desirable drugs for target receptors.