ExoBCD: a comprehensive database for exosomal biomarker discovery in breast cancer.

Effective and safe implementation of precision oncology for breast cancer is a vital strategy to improve patient outcomes, which relies on the application of reliable biomarkers. As 'liquid biopsy' and novel resource for biomarkers, exosomes provide a promising avenue for the diagnosis and treatment of breast cancer. Although several exosome-related databases have been developed, there is still lacking of an integrated database for exosome-based biomarker discovery. To this end, a comprehensive database ExoBCD (https://exobcd.liumwei.org) was constructed with the combination of robust analysis of four high-throughput datasets, transcriptome validation of 1191 TCGA cases and manual mining of 950 studies. In ExoBCD, approximately 20 900 annotation entries were integrated from 25 external sources and 306 exosomal molecules (49 potential biomarkers and 257 biologically interesting molecules). The latter could be divided into 3 molecule types, including 121 mRNAs, 172 miRNAs and 13 lncRNAs. Thus, the well-linked information about molecular characters, experimental biology, gene expression patterns, overall survival, functional evidence, tumour stage and clinical use were fully integrated. As a data-driven and literature-based paradigm proposed of biomarker discovery, this study also demonstrated the corroborative analysis and identified 36 promising molecules, as well as the most promising prognostic biomarkers, IGF1R and FRS2. Taken together, ExoBCD is the first well-corroborated knowledge base for exosomal studies of breast cancer. It not only lays a foundation for subsequent studies but also strengthens the studies of probing molecular mechanisms, discovering biomarkers and developing meaningful clinical use.

B cell lymphoma 6 promotes hepatocellular carcinoma progression by inhibiting tumor infiltrating CD4+T cell cytotoxicity through ESM1.

Immunotherapy exhibited potential effects for advanced hepatocellular carcinoma, unfortunately, the clinical benefits are often countered by cancer adaptive immune suppressive response. Uncovering the mechanism how cancer cells evade immune surveillance would help to develop new immunotherapy approaches and combination therapy. In this article, by analyzing the transcriptional factors which modulate the differentially expressed genes between T cell infiltration high group and low group, we identified oncoprotein B cell lymphoma 6 (BCL6) suppresses the infiltration and activation of tumor infiltrating T lymphocytes, thus correlated with poorer clinical outcome. By using antibody deletion experiment, we further demonstrated that CD4+T cells but not CD8+T cells are the main lymphocyte population suppressed by Bcl6 to promote HCC development. Mechanistically, BCL6 decreases cancer cell expression of pro-inflammatory cytokines and T lymphocyte chemokines such as IL6, IL1F6, and CCL5. Moreover, BCL6 upregulates Endothelial cell-specific molecule 1 (ESM1) to inhibit T lymphocyte recruitment and activation possibly through ICAM-1/LFA-1 signaling pathway. Our findings uncovered an unappreciated paracrine mechanism how cancer cell-derived BCL6 assists cancer cell immune evasion, and highlighted the role of CD4+T cells in HCC immune surveillance.

BEX1 mediates sorafenib resistance in hepatocellular carcinoma by regulating AKT signaling.

Sorafenib is the first-line therapy for advanced hepatocellular carcinoma (HCC). However, acquired tolerance after sorafenib treatment significantly limits its therapeutic efficacy, and the mechanisms underlying resistance remains poorly characterized. In this study, we identified BEX1 as key mediator of sorafenib resistance in HCC. We found that BEX1 expression was significantly reduced in sorafenib-resistant HCC cells and xenograft models, moreover, BEX1 expression in HCC tissues was down-regulated compared with that normal liver tissues in The Cancer Genome Atlas (TCGA) database, K-M analysis demonstrated that reduced BEX1 expression was correlated with poor clinical prognosis in HCC patients. Loss- and gain-of-function studies showed that BEX1 regulates the cell-killing ability of sorafenib. Further studies revealed that BEX1 renders HCC cells sensitive to sorafenib via induction of apoptosis and negatively regulates the phosphorylation of Akt. In summary, our study uncover BEX1 may serve as a promising predictive biomarker for the prognosis of patients with HCC.

EDA-E7 Activated DCs Induces Cytotoxic T Lymphocyte Immune Responses against HPV Expressing Cervical Cancer in Human Setting.

Cervical cancer is a major cause of cancer death in women worldwide. Targeting human papillomavirus (HPV) viral oncoproteins E6 and E7 is a new strategy for cervical cancer immunotherapy and has been associated with resolution of HPV-induced lesions. How to efficiently induce T cell target killing of HPV infected cervical cancer is of great potential benefit for cervical cancer treatment. Fusion protein containing the extra domain A (EDA) from fibronectin, a natural ligand for Toll-like receptor 4 (TLR4), and HPVE7 (EDA-E7) has been shown to efficiently induce dendritic cells maturation and trigger specific antitumor CD8+ T cells response in mice. In this study, we constructed EDA-E7 fusion protein of human origin and tested its function in dendritic cell maturation as well as antitumor T cell response. We found that EDA-E7 could be efficiently captured by human PBMC derived dendritic cells (DCs) in vitro and induce DCs maturation. Importantly, this effect could work in synergy with the TLR ligand anti-CD40 agonist, polyinosinic-polycytidylic acid [poly (I:C)], R848, and CpG2216. EDA-E7 matured DCs could activate T cells and trigger an anti-tumor response in vitro. Single cell RNA sequencing and T cell targeted killing assay confirmed the activation of T cells by EDA-E7 matured DCs. Therefore, therapeutic vaccination with EDA-E7 fusion protein maybe effective for human cervical carcinoma treatment.

Identification of stage-associated exosome miRNAs in colorectal cancer by improved robust and corroborative approach embedded miRNA-target network.

Background: Colorectal cancer (CRC) is a common gastrointestinal tumor with high morbidity and mortality. At the molecular level, patients at different stages present considerable heterogeneity. Although the miRNA in exosome is an effective biomarker to reveal tumor progression, studies based on stage-associated exosome miRNA regulatory network analysis still lacking. This study aims to identify CRC stage-associated exosome miRNAs and reveal their potential function in tumor progression. Methods: In this study, serum and cellular exosome miRNA expression microarrays associated with CRC were downloaded from GEO database. Stage-common (SC) and stage-specific (SS) differentially expressed miRNAs were extracted and their targets were identified based on 11 databases. Furthermore, miRNA SC and SS regulatory function networks were built based on the CRC phenotypic relevance of miRNA targets, and the corresponding transcription factors were identified. Concurrently, the potential stage-associated miRNAs were identified by receiver-operating characteristic (ROC) curve analysis, survival analysis, drug response analysis, ceRNA analysis, pathway analysis and a comprehensive investigation of 159 publications. Results: Ten candidate stage-associated miRNAs were identified, with three SC (miR-146a-5p, miR-22-3p, miR-23b-3p) and seven SS (I: miR-301a-3p, miR-548i; IIIA: miR-23a-3p; IV: miR-194-3p, miR-33a-3p, miR-485-3p, miR-194-5p) miRNAs. Additionally, their targets were enriched in several vital cancer-associated pathways such as TGF-beta, p53, and hippo signaling pathways. Moreover, five key hotspot target genes (CCNA2, MAPK1, PTPRD, MET, and CDKN1A) were demonstrated to associated with better overall survival in CRC patients. Finally, miR-23b-3p, miR-301a-3p and miR-194-3p were validated being the most stably expressed stage-associated miRNAs in CRC serum exosomes, cell exosomes and tissues. Conclusions: These CRC stage-associated exosome miRNAs aid to further mechanism research of tumor progression and provide support for better clinical management in patients with different stages.

Identification of Potential Biomarkers for Anti-PD-1 Therapy in Melanoma by Weighted Correlation Network Analysis.

Melanoma is the most malignant form of skin cancer, which seriously threatens human life and health. Anti-PD-1 immunotherapy has shown clinical benefits in improving patients' overall survival, but some melanoma patients failed to respond. Effective therapeutic biomarkers are vital to evaluate and optimize benefits from anti-PD-1 treatment. Although the establishment of immunotherapy biomarkers is well underway, studies that identify predictors by gene network-based approaches are lacking. Here, we retrieved the existing datasets (GSE91061, GSE78220 and GSE93157, 79 samples in total) on anti-PD-1 therapy to explore potential therapeutic biomarkers in melanoma using weighted correlation network analysis (WGCNA), function validation and clinical corroboration. As a result, 13 hub genes as critical nodes were traced from the key module associated with clinical features. After receiver operating characteristic (ROC) curve validation by an independent dataset (GSE78220), six hub genes with diagnostic significance were further recovered. Moreover, these six genes were revealed to be closely associated not only with the immune system regulation, immune infiltration, and validated immunotherapy biomarkers, but also with excellent prognostic value and significant expression level in melanoma. The random forest prediction model constructed using these six genes presented a great diagnostic ability for anti-PD-1 immunotherapy response. Taken together, IRF1, JAK2, CD8A, IRF8, STAT5B, and SELL may serve as predictive therapeutic biomarkers for melanoma and could facilitate future anti-PD-1 therapy.