Collagen stiffness promoted non-muscle-invasive bladder cancer progression to muscle-invasive bladder cancer Huier Zhu,1 Hui Chen,2 Jizhong Wang,3 Ling Zhou,4 Shaoyan Liu21Department of Emergency Surgery, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510150, People’s Republic of China; 2Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510150, People’s Republic of China; 3Biomedicine Research Center, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong 510150, People’s Republic of China; 4Special Clinic Center, Zhongshan People’s Hospital of Guangdong Province, Zhongshan, 528403, People’s Republic of ChinaPurpose: Bladder cancer (BCa) is generally considered one of the most prevalent deadly diseases worldwide. Patients suffering from muscle-invasive bladder cancer (MIBC) possess dismal prognoses, while those with non-muscle-invasive bladder cancer (NMIBC) generally have a favorable outcome after local treatment. However, some NMIBCs relapse and progress to MIBC, with an unclarified mechanism. Hence, insight into the genetic drivers of BCa progression has tremendous potential benefits for precision therapeutics, risk stratification, and molecular diagnosis.Methods: In this study, three cohorts profile datasets (GSE13507, GSE32584, and GSE89) consisting of NMIBC and MIBC samples were integrated to address the differently expressed genes (DEGs). Subsequently, the protein-protein interaction (PPI) network and pathway enrichment analysis of DGEs were performed.Results: Six collagen members (COL1A1, COL1A2, COL5A2, COL6A1, COL6A2, and COL6A3) were up-regulated and gathered in the ECM-receptor interaction signal pathway identified by KEGG pathway analysis and GSEA. Evidence derived from the Oncomine and TCGA databases indicated that the 6 collagen genes promote the progression of BCa and are negatively associated with patient prognosis. Moreover, taking COL1A1 as a further research object, the results showed that COL1A1 was up-regulated in MIBC and its knockdown significantly inhibited the proliferation, migration, and invasion of 5637 and T24 cells by inhibiting epithelial-mesenchymal transition (EMT) process and the TGF-β signaling pathway.Conclusion: With integrated bioinformatic analysis and cell experiments, we showed that 6 collagen family members are high progression risk factors and that they can be used as independent effective diagnostic and prognostic biomarkers for BCa.Keywords: genomic analysis, bladder cancer, invasion, diagnostic marker, prognostic markers

Background: Emerging evidence indicates that metabolism reprogramming and abnormal acetylation modification play an important role in lung adenocarcinoma (LUAD) progression, although the mechanism is largely unknown. Methods: Here, we used three public databases (Oncomine, Gene Expression Omnibus [GEO], The Cancer Genome Atlas [TCGA]) to analyze ESCO2 (establishment of cohesion 1 homolog 2) expression in LUAD. The biological function of ESCO2 was studiedusing cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models in vivo. ESCO2 interacting proteins were searched using gene set enrichment analysis (GSEA) and mass spectrometry. Pyruvate kinase M1/2 (PKM) mRNA splicing assay was performed using RT-PCR together with restriction digestion. LUAD cell metabolism was studied using glucose uptake assays and lactate production. ESCO2 expression was significantly upregulated in LUAD tissues, and higher ESCO2 expression indicated worse prognosis for patients with LUAD. Results: We found that ESCO2 promoted LUAD cell proliferation and metastasis metabolic reprogramming in vitro and in vivo. Mechanistically, ESCO2 increased hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) binding to the intronic sequences flanking exon 9 (EI9) of PKM mRNA by inhibiting hnRNPA1 nuclear translocation, eventually inhibiting PKM1 isoform formation and inducing PKM2 isoform formation. Conclusions: Our findings confirm that ESCO2 is a key factor in promoting LUAD malignant progression and suggest that it is a new target for treating LUAD.

Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related death worldwide. There is an urgent need to uncover the pathogenic mechanism to develop new treatments. Agmatinase (AGMAT) expression and its association with clinicopathological characteristics were analyzed via GEO, Oncomine, and TCGA databases, and IHC staining in human LUAD specimens. An EdU cell proliferation kit, propidiumiodide staining, colony formation, cell migration, and invasion assays, and a xenograft tumor model were used to detect the biological function of AGMAT in LUAD. Furthermore, the expression level of nitric oxide (NO) was detected using a DAF-FMDA fluorescent probe or nitrite assay kit, and further validated with Carboxy-PTIO (a NO scavenger). The roles of three isoforms of nitric oxide synthases (nNOS, eNOS, and iNOS) were validated using L-NAME (eNOS inhibitor), SMT (iNOS inhibitor), and spermidine (nNOS inhibitor). AGMAT expression was up-regulated in LUAD tissues. LUAD patients with high AGMAT levels were associated with poorer prognoses. AGMAT promoted LUAD tumorigenesis in NO released by iNOS both in vitro and in vivo. Importantly, NO signaling up-regulated the expression of cyclin D1 via activating the MAPK and PI3K/Akt-dependent c-myc activity, ultimately promoting the malignant proliferation of tumor cells. On the whole, AGMAT promoted NO release via up-regulating the expression of iNOS. High levels of NO drove LUAD tumorigenesis via activating MAPK and PI3K/Akt cascades. AGMAT might be a potential diagnostic and therapeutic target for LUAD patients.

SHP-1, a nonreceptor protein tyrosine phosphatase encoded by ptpn6, has been regarded as a regulatory protein of hematopoietic cell biology for years. However, there is now increasing evidence to support its role in tumors. Thus, the role of ptpn6 for prognosis and immune regulation across 33 tumors was investigated, aiming to explore its functional heterogeneity and clinical significance in pan-cancer. Differential expression of ptpn6 was found between cancer and adjacent normal tissues, and its expression was significantly correlated with the prognosis of tumor patients. In most cancers, ptpn6 expression was significantly associated with immune infiltration. This was further confirmed by ptpn6-related genes/proteins enrichment analysis. Additionally, genetic alterations in ptpn6 was observed in most cancers. As for epigenetic changes, it’s phosphorylation levels significantly altered in 6 tumors, while methylation levels significantly altered in 12 tumors. Notably, the methylation levels of ptpn6 were significantly decreased in 11 tumors, accompanied by its increased expression in 8 of them, suggesting that the hypomethylation may be related to its increased expression. Our results show that ptpn6 plays a specific role in tumor immunity and exerts a pleiotropic effect in a variety of tumors. It can serve as a prognostic factor for some cancers. Especially in LGG, KIRC, UCS and TGCT, the increased expression of ptpn6 is associated with poor prognosis and high immune infiltration. This aids in understanding the role of ptpn6 in tumor biology, and can provide insight into presenting a potential biomarker for poor prognosis and immune infiltration in cancers.

Background: Uterine serous carcinoma (USC) is an aggressive type of endometrial cancer that accounts for up to 40% of endometrial cancer deaths, creating an urgent need for prognostic biomarkers. Methods: USC RNA-Seq data and corresponding patients’ clinical records were obtained from The Cancer Genome Atlas and Genotype-Tissue Expression datasets. Univariate cox, Lasso, and Multivariate cox regression analyses were conducted to forge a prognostic signature. Multivariable and univariable cox regression analysis and ROC curve evaluated the prediction efficiency both in the training and testing sets. Results: We uncovered 1385 genes dysregulated in 110 cases of USC tissue relative to 113 cases of normal uterine tissue. Functional enrichment analysis of these genes revealed the involvement of various cancer-related pathways in USC. A novel 4-gene signature (KRT23, CXCL1, SOX9 and ABCA10) of USC prognosis was finally forged by serial regression analyses. Overall patient survival (OS) and recurrence-free survival (RFS) were significantly lower in the high-risk group relative to the low-risk group in both the training and testing sets. The area under the ROC curve of the 4-gene signature was highest among clinicopathological features in predicting OS and RFS. The 4-gene signature was found to be an independent prognostic indicator in USC and was a superior predictor of OS in early stage of USC. Conclusions: Our findings highlight the potential of the 4-gene signature as a guide for personalized USC treatment.