New role of gramicidin A in RIG-I-like receptors-mediated IFN signalling.

The pattern recognition receptors (PRRs) sense exogenous molecular patterns most commonly derived from invading pathogens, to active the interferon (IFN) signalling. In the cytoplasm, the viral double-stranded RNAs (dsRNAs) are sensed by retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated protein 5 (MDA5), depending on the length and chemical properties. Through the binding and oligomerizing onto the RNAs, they form filament to initiate the signalling cascade. Regulation of these receptors' activities are essential for manipulating the strength of IFN signalling. Here, through the virtual screening of chemical reagents using the published MDA5-dsRNA complex structure (PDB: 4GL2), we identified an antibiotic, gramicidin A as a stimulator that enhanced MDA5-mediated IFN signalling. Cytotoxic assay and IFN signalling assay suggested that disruption of lipid membrane, which is a well-defined mechanism of gramicidin A to perform its action, was dispensable in this process. Sucrose gradient ultracentrifugation assay showed that the gramicidin A treatment enhanced MDA5 oligomerization status in the presence of dsRNA. Our work implicated a new role of gramicidin A in innate immunity and presented a new tool to manipulate MDA5 activity.

Systemic analysis of the expression and prognostic significance of PAKs in breast cancer.

PAKs (p21-activated kinases) are reported to play crucial roles in a variety of cellular processes and participate in the progression of human cancers. However, the expression and prognostic values of PAKs remain poorly explored in breast cancers. In our study, we examined the mRNA and protein expression levels of PAKs and the prognostic value. We also analyzed the interaction network, genetic alteration, and functional enrichment of PAKs. The results showed that the mRNA levels of PAK1, PAK2, PAK4 and PAK6 were significantly up-regulated in breast cancer compared with normal tissues, while the reverse trend for PAK3 and PAK5 was found, furthermore, the proteins expression of PAK1, PAK2 and PAK4 in breast cancer tissues were higher than that in normal breast tissues. Survival analysis revealed breast cancer patients with low mRNA expression of PAK3 and PAK5 showed worse RFS, conversely, elevated PAK4 levels predicted worse RFS. In addition, the breast cancer patients with PAKs genetic alterations correlated with worse OS. These results indicated that PAKs might be promising potential biomarkers for breast cancer.

Identification of hub genes and pathways in adrenocortical carcinoma by integrated bioinformatic analysis.

Adrenocortical carcinoma (ACC), a rare malignant neoplasm originating from adrenal cortical cells, has high malignancy and few treatments. Therefore, it is necessary to explore the molecular mechanism of tumorigenesis, screen and verify potential biomarkers, which will provide new clues for the treatment and diagnosis of ACC. In this paper, three gene expression profiles (GSE10927, GSE12368 and GSE90713) were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were obtained using the Limma package. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were enriched by DAVID. Protein-protein interaction (PPI) network was evaluated by STRING database, and PPI network was constructed by Cytoscape. Finally, GEPIA was used to validate hub genes' expression. Compared with normal adrenal tissues, 74 up-regulated DEGs and 126 down-regulated DEGs were found in ACC samples; GO analysis showed that up-regulated DEGs were enriched in organelle fission, nuclear division, spindle, et al, while down-regulated DEGs were enriched in angiogenesis, proteinaceous extracellular matrix and growth factor activity; KEGG pathway analysis showed that up-regulated DEGs were significantly enriched in cell cycle, cellular senescence and progesterone-mediated oocyte maturation; Nine hub genes (CCNB1, CDK1, TOP2A, CCNA2, CDKN3, MAD2L1, RACGAP1, BUB1 and CCNB2) were identified by PPI network; ACC patients with high expression of 9 hub genes were all associated with worse overall survival (OS). These hub genes and pathways might be involved in the tumorigenesis, which will offer the opportunities to develop the new therapeutic targets of ACC.

OScc: an online survival analysis web server to evaluate the prognostic value of biomarkers in cervical cancer.

Aim: To establish a web server that can mutually validate prognostic biomarkers of cervical cancer. Methods: Four datasets including expression profiling and relative clinical follow-up data were collected from Gene Expression Omnibus and The Cancer Genome Atlas. The web server was developed by R software. Results: The web server was named OScc including 690 patients and can be accessed at http://bioinfo.henu.edu.cn/CESC/CESCList.jsp. The Kaplan-Meier survival curves with log-rank p-value and hazard ratio will be generated of interested gene in OScc. Compared with previous predictive tools, OScc had the advantages of registration-free, larger sample size and subgroup analysis. Conclusion: The OScc is highly valuable to perform the preliminary assessment and validation of new or interested prognostic biomarkers for cervical cancer.

OSkirc: a web tool for identifying prognostic biomarkers in kidney renal clear cell carcinoma.

Aim: To develop a free and quick analysis online tool that allows users to easily investigate the prognostic potencies of interesting genes in kidney renal clear cell carcinoma (KIRC). Patients & methods: A total of 629 KIRC cases with gene expression profiling data and clinical follow-up information are collected from public Gene Expression Omnibus and The Cancer Genome Atlas databases. Results: One web application called Online consensus Survival analysis for KIRC (OSkirc) that can be used for exploring the prognostic implications of interesting genes in KIRC was constructed. By OSkirc, users could simply input the gene symbol to receive the Kaplan-Meier survival plot with hazard ratio and log-rank p-value. Conclusion: OSkirc is extremely valuable for basic and translational researchers to screen and validate the prognostic potencies of genes for KIRC, publicly accessible at http://bioinfo.henu.edu.cn/KIRC/KIRCList.jsp.

Circulating Long Noncoding RNAs as Biomarkers for Predicting Head and Neck Squamous Cell Carcinoma.

BACKGROUND/AIMS: The anatomical complexity of the head and neck region and the lack of sufficiently specific and sensitive biomarkers often lead to the diagnosis of head and neck squamous cell carcinoma (HNSCC) at advanced stages. To identify novel biomarkers for early diagnosis of primary HNSCC through a minimally invasive method, we investigated circulating long noncoding RNA (lncRNA) levels in plasma of HNSCC patients. METHODS: The global lncRNA expression profiles of HNSCC patients were measured using microarray and next-generation RNA-sequencing (RNA-seq) data from both circulating and tissue samples. The diagnosis prediction model based on the lncRNA signatures and clinical features was evaluated by multi-stage validation and risk score analysis. RESULTS: The data showed that 432 lncRNA transcripts were differentially expressed by fold changes of > 4 in circulating samples and 333 in tissues samples, respectively. Only 12 lncRNAs consistently emerged in these two kinds of samples. After the risk score analysis including a multistage validation, we identified three lncRNAs, namely, HOXA11-AS, LINC00964 and MALAT1, which were up-regulated in the plasma of HNSCC patients compared with those in healthy controls with merged areas under the curve (AUCs) in training and validation sets of 0.925 and 0.839, respectively. CONCLUSION: HOXA11-AS, LINC00964 and MALAT1 might be potential circulating biomarkers for the early detection of HNSCC in the future.

Integrated Analysis and MicroRNA Expression Profiling Identified Seven miRNAs Associated With Progression of Oral Squamous Cell Carcinoma.

MicroRNAs have been used as diagnostic and prognostic biomarkers for many cancers including oral squamous cell carcinoma (OSCC). Several studies have been shown that microRNA (miRNA) play important roles during the progression of OSCC. However, the results vary largely in different studies due to different platforms and sample sizes. In this study, we systematically evaluated a large scale of miRNA profiles from current qualified OSCC samples, and further investigated the functions of genes regulated by these key miRNAs as well as the signaling pathways through which these miRNA effect carcinogenesis. Seven key miRNAs were identified, and of which three were significantly upregulated, including hsa-miR-21, hsa-miR-31, hsa-miR-338, and four were downregulated, namely hsa-miR-125b, hsa-miR-133a, hsa-miR-133b, and hsa-miR-139. The function enrichment analysis revealed that target genes of upregulated miRNAs were associated with cellular protein metabolic process, macromolecule metabolic process, and TGF-beta pathway, while the targets of downregulated were enriched in negative regulation of macromolecule biosynthetic process and gene expression, and p53, long-term potentiation and adherens junction pathways. Transcription factor analysis revealed that there were 67 (51.1%) transcription factors influenced by both up and downregulated miRNAs. In summary, seven key miRNAs were found to play essential role in progression of OSCC, as well as the target genes and transcription factors of these miRNAs. The potential functions of these target genes identified in our study may be profitable to diagnosis and prognostic prediction of OSCC as biomarkers. J. Cell. Physiol. 232: 2178-2185, 2017. © 2016 Wiley Periodicals, Inc.

Pingyangmycin Activates Oral Carcinoma Cell Autophagy via the Phosphorylation of the PI3K/AKT/mTOR Axis to Achieve the Purpose of Treating Oral Carcinoma.

Objective: The aim of the study is to investigate the role of pingyangmycin (PYM) in oral carcinoma (OC) cell autophagy via the PI3K/AKT/mTOR axis. Methods: 200 µL PYM culture solution with a concentration of 100 µg/ml (low PYM (L-PYM) group), 300 µg/ml (middle PYM (M-PYM) group), 500 µg/ml (high PYM (H-PYM) group), and the same amount of conventional medium (normal control (NC)) were added to the purchased OC cell line SCC-25, respectively, and the PI3K/AKT/mTOR pathway expression, autophagy protein levels, cell activity, and apoptosis rate were determined. Subsequently, we selected OC cells co-cultured with PYM with the concentration of the most significant intervention effect and 740Y-P, a specific activator of the PI3K/AKT/mTOR axis, and those treated with 740Y-P alone for the aforementioned detection. Results: L-PYM, M-PYM, and H-PYM groups all showed decreased PI3K, AKT, mTOR, and phosphorylated protein levels (P < 0.05). Beclin1 and LC3-II protein levels and apoptosis rate of PYM-intervened OC cells increased, but the activity decreased (P < 0.05). Under 740Y-P intervention, the PI3K/AKT/mTOR pathway was activated, cell activity was increased, and the apoptosis rate and autophagy were decreased (P < 0.05). Simultaneous use of PYM and 740Y-P led to no difference in cell condition compared with NC (P > 0.05P>0.05). Conclusion: PYM can activate OC cell autophagy by inhibiting the phosphorylation of the PI3K/AKT/mTOR axis, and thus, achieving the goal of killing tumor cells.

rtcisE2F promotes the self-renewal and metastasis of liver tumor-initiating cells via N6-methyladenosine-dependent E2F3/E2F6 mRNA stability.

Liver cancer is highly heterogeneous, and the tumor tissue harbors a variety of cell types. Liver tumor initiating cells (TICs) well contribute to tumor heterogeneity and account for tumor initiation and metastasis, but the molecular mechanisms of liver TIC self-renewal are elusive. Here, we identified a functional read-through rt-circRNA, termed rtcisE2F, that is highly expressed in liver cancer and liver TICs. rtcisE2F plays essential roles in the self-renewal and activities of liver TICs. rtcisE2F targets E2F6 and E2F3 mRNAs, attenuates mRNA turnover, and increases E2F6/E2F3 expression. Mechanistically, rtcisE2F functions as a scaffold of N-methyladenosine (m6A) reader IGF2BP2 and E2F6/E2F3 mRNA. rtcisE2F promotes the association of E2F6/E2F3 mRNAs with IGF2BP2, and inhibits their association with another m6A reader, YTHDF2. IGF2BP2 inhibits E2F6/E2F3 mRNA decay, whereas YTHDF2 promotes E2F6/E2F3 mRNA decay. By switching m6A readers, rtcisE2F enhances E2F6/E2F3 mRNA stability. E2F6 and E2F3 are both required for liver TIC self-renewal and Wnt/ß-catenin activation, and inhibition of these pathways is a potential strategy for preventing liver tumorigenesis and metastasis. In conclusion, the rtcisE2F-IGF2BP2/YTHDF2-E2F6/E2F3-Wnt/ß-catenin axis drives liver TIC self-renewal and initiates liver tumorigenesis and metastasis, and may provide a strategy to eliminate liver TICs.

Evaluation of the clinical efficacy and safety of modified alveolar cleft bone graft with cone-beam CT digital imaging in children.

Background: Cone-beam computed tomography (CBCT) is used to observe the bone density and bone height in children with modified alveolar bone graft (ABG) at different times after operation. In this study, the changes of labial-palatal bone mass in the stable period of bone union and in the bone graft area were investigated to provide reference for subsequent treatment. Methods: A total of 140 pediatric patients with unilateral complete alveolar cleft were selected and routinely underwent iliac bone grafting. The original data obtained by ProMax 3D (Planmeca) examination were stored in DICOM format at 3 and 6 months postoperatively, and the images were reconstructed by Simplant software (Dentsply Sirona). The bone density of the healthy side was measured at 3 months and 6 months, and the results were expressed as Hounsfield units (HU). The labial and palatal bone height at the bone graft site at 3 and 6 months postoperatively was classified according to the modified Bergland classification method, and was compared with panoramic film classification. Results: Mean bone density at 3 months after surgery (385.4800±78.39770 HU) was not significantly different from that at 6 months (356.1875±73.67164 HU; P>0.05). There were significant differences between the classification of lip and palatal bone height 3 months after operation and that of the classification of panorama film in the same month (P<0.05); between the classification of lip and palatal bone height 6 months after surgery compared with that of panorama film of the same month (P<0.05); and between the classification of bone height degree in labial, palatal, and panoramic slices at 3 months after operation and that at 6 months after operation (P<0.05). Conclusions: The labial and palatal classification is different, and the bone height classification 6 months after surgery is lower than that 3 months after surgery, indicating the persistence of bone resorption. CBCT can objectively evaluate the bone quality in the bone graft area, which has clinical application value for surgical evaluation value and posttreatment guidance.

OSgc: A Web Portal to Assess the Performance of Prognostic Biomarkers in Gastric Cancer.

Evaluating the prognostic value of genes of interest in different populations of gastric cancer (GC) is difficult and time-consuming for basic and translational researchers even though many datasets are available in public dataset depositories. In the current study, we developed a robust web-based portal called OSgc (Online consensus Survival analysis of gastric cancer) that enables easy and swift verification of known and novel biomarker candidates in GC. OSgc is composed of gene expression profiling data and clinical follow-up information of 1,824 clinical GC cases, which are collected from 7 public independent datasets derived from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). By OSgc, users input the official gene symbol and will promptly retrieve the Kaplan-Meier survival plot with hazard ratio (HR) and log rank p value on the output webpage, by which users could assess the prognostic value of interesting genes for GC patients. Five survival end points containing overall survival, progression-free survival, progression-free interval, relapse-free survival, and disease-free survival could be measured in OSgc. OSgc can greatly help cancer biologists and clinicians to explore the effect of gene expression on patient survival. OSgc is freely available without restrictions at http://bioinfo.henu.edu.cn/GC/GCList.jsp.

High APLN Expression Predicts Poor Prognosis for Glioma Patients.

Apelin (APLN) is an endogenous ligand of the G protein-coupled receptor APJ (APLNR). APLN/APLNR system was involved in a variety of pathological and physiological functions, such as tumorigenesis and development. However, its prognostic roles in patients with central nervous system (CNS) cancers remain unknown. The present study was designed to explore the expression profile, prognostic significance, and interaction network of APLN/APLNR by integrating data from Oncomine, GEPIA, LOGpc, STRING, GeneMANIA, and immunohistochemical staining. The results demonstrated that APLN and APLNR mRNA expression were significantly increased in CNS cancers, including both low-grade glioma (LGG) and glioblastoma (GBM), when compared with normal CNS tissues. The high APLN, but not APLNR, expression was significantly correlated with overall survival (OS), recurrence free survival (RFS), and progression free survival (PFS) of LGG patients. However, neither APLN nor APLNR expression was significantly related to prognostic value in terms of OS, disease free interval (DFI), disease specific survival (DSS), or progression free interval (PFI) for GBM patients. Additionally, immunohistochemistry staining confirmed the increased APLN expression in tissues of LGG patients with grade II than grade I. These results showed that an elevated APLN level could predict poor OS, RFS, and PFS for LGG patients, and it could be a promising prognostic biomarker for LGG.

Study on the synthesis and thermal stability of silicone resins reinforced by Si-O-Ph cross-linking.

A novel silicone resin (SR-OH) containing phenolic hydroxyl (Ph-OH) groups was designed and synthesized via co-hydrolysis/condensation and catalytic hydrogenation. During the curing process, the cross-linking degree of the resin was further increased by the Si-O-Ph bonds formed by the reaction of the Ph-OH and terminal Si-OH groups. Thermogravimetric analysis (TGA) showed that the cured resin product exhibited excellent thermal and thermo-oxidative stability, which was much higher than that of a typical methyl phenyl silicone resin (SR-Ph). The temperature at which 5% weight loss occurs (T d5) was up to 606 °C (nitrogen) and 542 °C (air), and its char yield at 800 °C was 91.1% and 85.3% in nitrogen and air, respectively. The significant improvement in thermal stability was mainly attributed to the formation of Si-O-Ph bonds which not only increases the cross-linking degree of the resin but also significantly prevents degradation by the 'back-biting' and oxidative cleavage.

OSov: An Interactive Web Server to Evaluate Prognostic Biomarkers for Ovarian Cancer.

Ovarian cancer is one of the most aggressive and highly lethal gynecological cancers. The purpose of our study is to build a free prognostic web server to help researchers discover potential prognostic biomarkers by integrating gene expression profiling data and clinical follow-up information of ovarian cancer. We construct a prognostic web server OSov (Online consensus Survival analysis for Ovarian cancer) based on RNA expression profiles. OSov is a user-friendly web server which could present a Kaplan-Meier plot, forest plot, nomogram and survival summary table of queried genes in each individual cohort to evaluate the prognostic potency of each queried gene. To assess the performance of OSov web server, 163 previously published prognostic biomarkers of ovarian cancer were tested and 72% of them had their prognostic values confirmed in OSov. It is a free and valuable prognostic web server to screen and assess survival-associated biomarkers for ovarian cancer.

Circular RNA cia-MAF drives self-renewal and metastasis of liver tumor-initiating cells via transcription factor MAFF.

Liver tumor-initiating cells (TICs) are involved in liver tumorigenesis, metastasis, drug resistance, and relapse, but the regulatory mechanisms of liver TICs are largely unknown. Here, we have identified a functional circular RNA, termed circRNA activating MAFF (cia-MAF), that is robustly expressed in liver cancer and liver TICs. cia-MAF-KO primary cells and cia-maf-KO liver tumors harbor decreased ratios of TICs, and display impaired liver tumorigenesis, self-renewal, and metastatic capacities. In contrast, cia-MAF overexpression drives liver TIC propagation, self-renewal, and metastasis. Mechanistically, cia-MAF binds to the MAFF promoter, recruits the TIP60 complex to the MAFF promoter, and finally promotes MAFF expression. Loss of cia-MAF function attenuates the combination between the TIP60 complex and the MAFF promoter. MAFF is highly expressed in liver tumors and liver TICs, and its antisense oligo (ASO) has therapeutic potential in treating liver cancer without MAFA/MAFG gene copy number alterations (CNAs). This study reveals an additional layer for liver TIC regulation as well as circRNA function, and provides an additional target for eliminating liver TICs, especially for liver tumors without MAFA/MAFG gene CNAs.

Adjuvant-free peptide vaccine targeting Clec9a on dendritic cells can induce robust antitumor immune response through Syk/IL-21 axis.

Dendritic cells (DCs) can process the antigens of cancer vaccine and thus stimulate the CD8+ T cells to recognize and kill the tumor cells that express these antigens. However, lack of promising carriers for presenting the antigens to DCs is one of the main barriers to the development of clinically effective cancer vaccines. Another limitation is the risk of inflammatory side effects induced by the adjuvants. It is still unclear how we can develop ideal adjuvant-free DC vaccine carriers without adjuvants. Methods: A 12-mer peptide carrier (CBP-12) with high affinity for Clec9a expressed on DCs was developed using an in silico rational optimization method. The therapeutic effects of the adjuvant-free vaccine comprising CBP-12 and exogenous or endogenous antigenic peptides were investigated in terms of antigen cross-presentation efficacy, specific cytotoxic T lymphocyte response, and antitumor activity. We also explored the mechanism involved in the antitumor effects of the adjuvant-free CBP-12 vaccine. Finally, we assessed the effects of the CBP-12 conjugated peptide vaccine combined with radiotherapy. Results: Here, we developed CBP-12 as a vaccine carrier that enhanced the uptake and cross-presentation of the antigens, thus inducing strong CD8+ T cell responses and antitumor effects in both anti-PD-1-responsive (B16-OVA) and -resistant (B16) models, even in adjuvant-free conditions. CBP-12 bound to and activated Clec9a, thereby stimulating Clec9a+ DC to product IL-21, but not IL-12 by activating of Syk. The antitumor effects of the CBP-12 conjugated peptide vaccines could be blocked by an IL-21 neutralizing antibody. We also observed the synergistic antitumor effects of the CBP-12 conjugated peptide vaccine combined with radiotherapy. Conclusions: CBP-12 could serve as an adjuvant-free peptide vaccine carrier for cancer immunotherapy.

Genomic, epigenomic, and immune subtype analysis of CTSL/B and SARS-CoV-2 receptor ACE2 in pan-cancer.

SARS-coronavirus 2 (SARS-CoV-2) has been spreading widely and posing an international challenge for both healthcare and society. At present, cancer has been identified as an individual risk factor for COVID-19. Angiotensin converting enzyme 2 (ACE2) and Cathepsin L/Cathepsin B (CTSL/B), which act as the receptor and entry-associated proteases of SARS-CoV-2 respectively, are pivotal for SARS-CoV-2 infection. To investigate the possible SARS-CoV-2 infection risk of pan-cancer, we analyzed the genetic alterations, RNA expression, DNA methylation, and the association with immune subtypes of ACE2 and CTSL/B with the prognosis in pan-cancer. Results showed the upregulation of CTSL/B and ACE2 in Pancreatic adenocarcinoma (PAAD) and Stomach adenocarcinoma (STAD) and demonstrated a positive correlation between copy number alteration (CNA) and gene expression for CTSB in PAAD and STAD. Hypomethylation and a negative correlation of gene expression and methylation for CTSB were detected in PAAD. In addition, ACE2 and CTSL/B are overexpressed in the IFN-gamma immune subtype of ovarian serous Cystadenocarcinoma (OV), Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), and Bladder urothelial carcinoma (BLCA). Our study presents a bioinformatics assessment for the potential risk of SARS-CoV-2 infection in pan-cancer.

Prognostic value of novel immune-related genomic biomarkers identified in head and neck squamous cell carcinoma.

BACKGROUND: The immune response within the tumor microenvironment plays a key role in tumorigenesis and determines the clinical outcomes of head and neck squamous cell carcinoma (HNSCC). However, to date, a paucity of robust, reliable immune-related biomarkers has been identified that are capable of estimating prognosis in HNSCC patients. METHODS: High-throughput RNA sequencing was performed in tumors and matched adjacent tissues from five HNSCC patients, and the immune signatures expression of 730 immune-related transcripts selected from the nCounter PanCancer Immune Profiling Panel were assessed. Survival analyzes were performed in a training cohort, consisting of 416 HNSCC cases, retrieved from The Cancer Genome Atlas (TCGA) database. A prognostic signature was built, using elastic net-penalized Cox regression and backward, stepwise Cox regression analyzes. The outcomes were validated by an independent cohort of 115 HNSCC patients, using tissue microarrays and immunohistochemistry staining. Cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was also used to estimate the relative fractions of 22 immune-cell types and their correlations coefficients with prognostic biomarkers. RESULTS: Collectively, 248 immune-related genes were differentially expressed in paired tumors and normal tissues using RNA sequencing. After process screening in the training TCGA cohort, four immune-related genes (PVR, TNFRSF12A, IL21R, and SOCS1) were significantly associated with overall survival (OS). Integrating these genes with Path_N stage, a multiplex model was built and suggested better performance in determining 5 years OS (receiver operating characteristic (ROC) analysis, area under the curve (AUC)=0.709) than others. Further protein-based validation was conducted in 115 HNSCC patients. Similarly, high expression of PVR and TNFRSF12A were associated with poor OS (Kaplan-Meier p=0.017 and 0.0032), while high expression of IL21R and SOCS1 indicated favorable OS (Kaplan-Meier p<0.0001 and =0.0018). The integrated model with Path_N stage still demonstrated efficacy in OS evaluation (Kaplan-Meier p<0.0001, ROC AUC=0.893). Besides, the four prognostic genes were significantly correlated with activated CD8+ T cells, CD4+ T cells, follicular helper T cells and regulatory T cells, implying the possible involvement of these genes in the immunoregulation and development of HNSCC. CONCLUSIONS: The well-established model encompassing both immune-related biomarkers and clinicopathological factor might serve as a promising tool for the prognostic prediction of HNSCC.

IL-6 promotes PD-L1 expression in monocytes and macrophages by decreasing protein tyrosine phosphatase receptor type O expression in human hepatocellular carcinoma.

BACKGROUND: We have previously discovered a relationship between the low expression of protein tyrosine phosphatase, receptor type O (PTPRO) in tumor-infiltrating T cells and immunosuppression. The aim of the present study was to investigate the relationship between decreased PTPRO and increased programmed death ligand 1 (PD-L1) in both the peripheral monocytes and tumor-infiltrating macrophages of human hepatocellular carcinoma (HCC). METHODS: The expression and correlation of all the indices were explored in monocytes and tumor-infiltrating macrophages within both human and mice HCC. The mechanic regulations were studied by using both in vitro and in vivo studies. RESULTS: We found a significant decrease in PTPRO in HCC peripheral monocytes that was associated with increased PD-L1 expression in peripheral monocytes and tumor-associated macrophages (TAMs) in HCC. Monocyte PD-L1 and PTPRO therefore could serve as valuable prognostic indicators for post-surgery patients with HCC and were associated with increased T-cell exhaustion (Tim3+T cells). A depletion of PTPRO promoted PD-L1 secretion in both monocytes and macrophages through the JAK2/STAT1 and JAK2/STAT3/c-MYC pathways. Increased IL-6 expression was associated with activation of JAK2/STAT3/c-MYC and with decreased PTPRO expression through the STAT3/c-MYC/miR-25-3 p axis. Monocytes and TAMs showed significantly increased miR-25-3 p expression, which could target the 3' untranslated region of PTPRO. The miR-25-3 p expression positively correlated with serum IL-6 levels, but inversely correlated with PTPRO in HCC monocytes. IL-6/STAT3/c-MYC activation enhanced in vitro miR-25-3 p transcription and decreased PTPRO, while further promoting PD-L1 secretion. Adoptive cell transfer of c-MYC/miR-25-3 p-modified monocytes promoted tumor growth by downregulating PTPRO and causing a PD-L1-induced immunosuppression in an orthotopic tumor transplantation model. CONCLUSIONS: Increased serum IL-6 downregulated PTPRO expression in HCC monocytes and macrophages by activating STAT3/c-MYC/miR-25-3 p and by further enhancing PD-L1 expression through JAK2/STAT1 and JAK2/STAT3/c-MYC signaling.

Systematic Analysis of microRNA Biomarkers for Diagnosis, Prognosis, and Therapy in Patients With Clear Cell Renal Cell Carcinoma.

The ever-increasing morbidity and mortality of clear cell renal cell carcinoma (ccRCC) urgently demands updated biomarkers. MicroRNAs (miRNAs) are involved in diverse biological processes such as cell proliferation, differentiation, apoptosis by regulating their target genes' expression. In kidney cancers, miRNAs have been reported to be involved in tumorigenesis and to be the diagnostic, prognostic, and therapeutic response biomarkers. Here, we performed a systematic analysis for ccRCC-related miRNAs as biomarkers by searching keywords in the NCBI PubMed database and found 118 miRNAs as diagnostic biomarkers, 28 miRNAs as prognostic biomarkers, and 80 miRNAs as therapeutic biomarkers in ccRCC. miRNA-21, miRNA-155, miRNA-141, miRNA-126, and miRNA-221, as significantly differentially expressed miRNAs between cancer and normal tissues, play extensive roles in the cell proliferation, differentiation, apoptosis of ccRCC. GO and KEGG enrichment analysis of these miRNAs' target genes through Metascape showed these target genes are enriched in Protein Domain Specific Binding (GO:0019904). In this paper, we identified highly specific miRNAs in the pathogenesis of ccRCC and explored their potential applications for diagnosis, prognosis, and treatment of ccRCC.