Cancer cells often exhibit large-scale genomic variations, such as circular extrachromosomal DNA (ecDNA) and structural variants (SVs), which have been highly correlated with the initiation and progression of cancer. Currently, no adequate method exists to unveil how these variations regulate gene expression in heterogeneous cancer cell populations at a single-cell resolution.

Neoadjuvant chemotherapy (NACT) represents a standard option for breast cancer. Unfortunately, about 55-80% of breast cancer patients do not have a favorable response to chemotherapy. Highly specific tumor biomarker that can predict the pathological response to neoadjuvant chemotherapy is lacking. Stearoyl-CoA desaturase 5 (SCD5) is an integral membrane protein of the endoplasmic reticulum that participates in lipid metabolism. Previous studies on the role of SCD5 in human cancers drew different conclusions. Therefore, the role of SCD5 in breast cancer remains unclear. Our study aims to understand its expression signature, prognosis value and correlation with pathological response to NACT in breast cancer using bioinformatics from public databases. Analysis of samples from public databases showed that SCD5 expression was down-regulated in some human cancers including breast cancer, and low expression of SCD5 was associated with more aggressive breast cancer phenotypes. Survival analysis revealed that SCD5 expression was related to prognosis in breast cancer. Integrated analysis of multiple public datasets indicated that SCD5 expression signature was associated with pathological response to NACT, particularly in TNBC. Based on functional enrichment analysis, the most affected biological functions in high SCD5-expressing breast cancer tissues were involved in negative regulation of cell cycle. Moreover, a significantly negative correlation between SCD5 expression and several cell cycle regulators was noted. Taken together, SCD5 was involved in the development and progression of breast cancer and might be a predictive biomarker for response to NACT. In conclusion, SCD5 could serve as a predictive biomarker of pathological response to NACT and play a carcinostatic role in breast cancer. These results provided us with clues to better understand SCD5 from the perspective of bioinformatics and highlighted the clinical importance of SCD5 in breast cancer, especially triple negative breast cancer (TNBC).

BACKGROUND The serine peptidase inhibitor Kazal type 13 (SPINK13) gene has tumor suppressor activity, but its role in renal cell carcinoma (RCC) remains unknown. This study aimed to investigate mRNA expression of SPINK13 in clear cell renal cell carcinoma (CCRCC) in human tissue and to use bioinformatics data to investigate the role of SPINK13 expression as a clinicopathological and prognostic biomarker for patients with CCRCC. MATERIAL AND METHODS Patients with CCRCC (N=533) with available RNA sequence data from The Cancer Genome Atlas (TCGA)-CCRCC database were analyzed with patients who had a tissue diagnosis of CCRCC (N=305) at the Fudan University Shanghai Cancer Center (FUSCC). Differential transcriptional and proteome expression profiles were obtained from the ONCOMINE cancer microarray database, TCGA, and the Human Protein Atlas (HPA) database. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) measured SPINK13 mRNA expression in 305 samples of CCRCC tissue from the FUSCC. The effects of clinicopathological parameters on progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier and log-rank test. RESULTS Transcriptional and proteome expression of SPINK13 were significantly increased CCRCC tissue samples. Increased SPINK13 mRNA expression was significantly associated with reduced PFS and OS in 838 patients with CCRCC patients from the two independent cohorts, the FUSCC and the TCGA-CCRCC cohorts (p<0.01). Gene set enrichment analysis (GSEA) showed that SPINK13 expression was involved in complement, apical junction, epithelial-mesenchymal transition (EMT), glycolysis, hypoxia, and inflammation signaling pathways. CONCLUSIONS Increased expression of SPINK13 was associated with poor prognosis in patients with CCRCC.

Intratumoral fibrosis is a frequent histologic finding in highly vascularized clear cell renal cell carcinoma (ccRCC). Here, we investigated the expression of a family of collagen-modifying enzymes, procollagen-lysine, 2-oxoglutarate 5-dioxygenases 1, 2, and 3 (PLOD1/2/3), in ccRCC tissues and assessed the prognostic value of wild-type and genetically mutated PLOD1/2/3 for ccRCC patients. Normal kidney and ccRCC mRNA and protein expression datasets were obtained from Oncomine, The Cancer Genome Atlas, and Human Protein Atlas databases. Associations between PLOD1/2/3 expression, clinicopathological variables, and patient survival were evaluated using Cox regression and Kaplan-Meier analyses. PLOD1/2/3 mRNA and protein expression levels were significantly elevated in ccRCC tissues compared with normal kidney. Increased PLOD1/2/3 mRNA expression was significantly associated with advanced tumor stage, high pathological grade, and shorter progression-free and overall survival (all p<0.01). Genetic mutation of PLOD1/2/3 was present in ~3% of ccRCC patients and was associated with significantly poorer prognosis compared with expression of wild-type PLOD1/2/3 (p<0.001). This study thus identifies tumor expression of wild-type or mutated PLOD1/2/3 mRNA as a potential predictive biomarker for ccRCC patients and sheds light on the underlying molecular pathogenesis of ccRCC.

Growing evidence has demonstrated immune reactivity as a confirmed important carcinogenesis and therapy efficacy for clear cell renal cell carcinoma (ccRCC). Aquaporin 9 (AQP9) is involved in many immune-related signals; however, its role in ccRCC remains to be elucidated. This study investigated AQP9 expression in tumor tissues and defined the prognostic value in ccRCC patients.

Bladder cancer (BLCA) is one of the common malignant tumors of the urinary system. The poor prognosis of BLCA patients is due to the lack of early diagnosis and disease recurrence after treatment. Increasing evidence suggests that gene products of the nuclear factor of activated T-cells (NFAT) family are involved in BLCA progression and subsequent interaction(s) with immune surveillance. In this study, we carried out a pan-cancer analysis of the NFAT family and found that NFAT2 is an independent prognostic factor for BLCA. We then screened for differentially expressed genes (DEGs) and further analyzed such candidate gene loci using gene ontology enrichment to curate the KEGG database. We then used Lasso and multivariate Cox regression to identify 4 gene loci (FER1L4, RNF128, EPHB6, and FN1) which were screened together with NFAT2 to construct a prognostic model based on using Kaplan-Meier analysis to predict the overall survival of BLCA patients. Moreover, the accuracy of our proposed model is supported by deposited datasets in the Gene Expression Omnibus (GEO) database. Finally, a nomogram of this prognosis model for BLCA was established which could help to provide better disease management and treatment.

To investigate the potential molecular mechanism of ovarian cancer (OC) evolution and immunological correlation using the integrated bioinformatics analysis.

Chronic stress underlies the etiology of both major depressive disorder (MDD) and irritable bowel syndrome (IBS), two highly prevalent and debilitating conditions with high rates of co-morbidity. However, it is not fully understood how the brain and gut bi-directionally communicate during stress to impact intestinal homeostasis and stress-relevant behaviours. Using the chronic social defeat stress (CSDS) model, we find that stressed mice display greater intestinal permeability and circulating levels of the endotoxin lipopolysaccharide (LPS) compared to unstressed control (CON) mice. Interestingly, the microbiota in the colon also exhibit elevated LPS biosynthesis gene expression following CSDS. Additionally, CSDS triggers an increase in pro-inflammatory colonic IFNγ+ Th1 cells and a decrease in IL4+ Th2 cells compared to CON mice, and this gut inflammation contributes to stress-induced intestinal barrier permeability and social avoidance behaviour. We next investigated the role of enteric neurons and identified that noradrenergic dopamine beta-hydroxylase (DBH)+ neurons in the colon are activated by CSDS, and that their ablation protects against gut pathophysiology and disturbances in social behaviour. Retrograde tracing from the colon identified a population of corticotropin-releasing hormone-expressing (CRH+) neurons in the paraventricular nucleus of the hypothalamus (PVH) that innervate the colon and are activated by stress. Chemogenetically activating these PVH CRH+ neurons is sufficient to induce gut inflammation, barrier permeability, and social avoidance behaviour, while inhibiting these cells prevents these effects following exposure to CSDS. Thus, we define a stress-activated brain-to-gut circuit that confers colonic inflammation, leading to impaired intestinal barrier function, and consequent behavioural deficits.

Precise vascular patterning is crucial for normal growth and development. The ERG transcription factor drives Delta-like ligand 4 (DLL4)/Notch signalling and is thought to act as a pivotal regulator of endothelial cell (EC) dynamics and developmental angiogenesis. However, molecular regulation of ERG activity remains obscure. Using a series of EC-specific focal adhesion kinase (FAK)-knockout (KO) and point-mutant FAK-knock-in mice, we show that loss of ECFAK, its kinase activity or phosphorylation at FAK-Y397, but not FAK-Y861, reduces ERG and DLL4 expression levels together with concomitant aberrations in vascular patterning. Rapid immunoprecipitation mass spectrometry of endogenous proteins identified that endothelial nuclear-FAK interacts with the deubiquitinase USP9x and the ubiquitin ligase TRIM25. Further in silico analysis confirms that ERG interacts with USP9x and TRIM25. Moreover, ERG levels are reduced in FAKKO ECs via a ubiquitin-mediated post-translational modification programme involving USP9x and TRIM25. Re-expression of ERG in vivo and in vitro rescues the aberrant vessel-sprouting defects observed in the absence of ECFAK. Our findings identify ECFAK as a regulator of retinal vascular patterning by controlling ERG protein degradation via TRIM25/USP9x.

Cancer/testis antigens (CTAs) are a special type of tumor antigen and are believed to act as potential targets for cancer immunotherapy.

Clear cell renal cell carcinoma (ccRCC) is a common and aggressive subtype of renal cancer. Here we conduct a comprehensive proteogenomic analysis of 232 tumor and adjacent non-tumor tissue pairs from Chinese ccRCC patients. By comparing with tumor adjacent tissues, we find that ccRCC shows extensive metabolic dysregulation and an enhanced immune response. Molecular subtyping classifies ccRCC tumors into three subtypes (GP1-3), among which the most aggressive GP1 exhibits the strongest immune phenotype, increased metastasis, and metabolic imbalance, linking the multi-omics-derived phenotypes to clinical outcomes of ccRCC. Nicotinamide N-methyltransferase (NNMT), a one-carbon metabolic enzyme, is identified as a potential marker of ccRCC and a drug target for GP1. We demonstrate that NNMT induces DNA-dependent protein kinase catalytic subunit (DNA-PKcs) homocysteinylation, increases DNA repair, and promotes ccRCC tumor growth. This study provides insights into the biological underpinnings and prognosis assessment of ccRCC, revealing targetable metabolic vulnerabilities.