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Long-chain non-coding RNA ASB16-AS1 has been proven to be an oncogene for many cancer types. However, the relationship between ASB16-AS1 and immunity is still under studied. This study aims to explore the expression and prognostic potential of ASB16-AS1, and to visualize the relationship between ASB16-AS1 expression and immune infiltration in pan-cancer. We clarified ASB16-AS1 expression patterns in pan-cancer and its relationship with prognosis through multi-platform and multi-database sources (TCGA, GEO, GTEx, ArrayExpress, and SRA), and verified the function of ASB16-AS1 in liver hepatocellular carcinoma (LIHC). Then, a variety of immune cell content evaluation methods were used to mutually verify the correlation between ASB16-AS1 and immune infiltration. Finally, the relationships between ASB16-AS1 and some molecular characteristics (immune checkpoints, tumor mutation burden, microsatellite instability, oncogenic signaling pathways) were further explored. In terms of comprehensive analysis, compared with non-tumor tissues, ASB16-AS1 was highly expressed in tumor tissues, and indicated the value of poor prognosis in multiple cancer types. Functional assays, such as CCK8 assay, transwell assay and wound scratch assay, verified that high ASB16-AS1 expression promoted tumor progression in LIHC. ASB16-AS1 was positively correlated with B cells, T cell CD4+ and T cell CD8+ in most cancer types, and negatively correlated with macrophages, dendritic cells and neutrophils in some cancer types, especially in neutrophils. In addition, there were different interaction modes between ASB16-AS1 and molecular features, such as the relationship with oncogenic signaling pathways, showing that the high ASB16-AS1 expression was related to alterations in oncogenic signaling pathways. Our study emphasizes that ASB16-AS1 is a potential pan-cancer prognostic marker, whichs is associated with the immune infiltration in multiple cancer types.

Hepatoblastoma is a kind of extreme malignancy frequently diagnosed in children. Although surgical resection is considered as the first-line treatment for hepatoblastoma, a relatively large population of patients have lost the preferred opportunity for surgery. Administration of locoregional ablation enables local tumor control but with the deficiency of insufficient ablation, residual tumor, and rapid progression. In this study, we integrated 219 hepatoblastoma and 121 non-cancer liver tissues to evaluate the expression of NR2F6, from which a higher NR2F6 level was found in hepatoblastoma compared with non-cancer livers with a standard mean difference (SMD) of 1.04 (95% CI: 0.79, 1.29). The overexpression of NR2F6 also appeared to be an efficient indicator in distinguishing hepatoblastoma tissues from non-cancer liver tissues from the indication of a summarized AUC of 0.90, with a pooled sensitivity of 0.76 and a pooled specificity of 0.89. Interestingly, nude mouse xenografts provided direct evidence that overexpressed NR2F6 was also detected in residual tumor compared to untreated hepatoblastoma. Chromatin immunoprecipitation-binding data in HepG2 cells and transcriptome analysis of HepG2 xenografts were combined to identify target genes regulated by NR2F6. We finally selected 150 novel target genes of NR2F6 in residual tumor of incomplete ablation, and these genes appeared to be associated with the biological regulation of lipid metabolism-related pathway. Accordingly, targeting NR2F6 holds a therapeutic promise in treating residual recurrent hepatoblastoma after incomplete ablation., GRAPHICAL ABSTRACT

Splicing factors (SFs) have been increasingly documented to perturb the genome of cancers. However, little is known about the alterations of SFs in hepatocellular carcinoma (HCC). This study comprehensively delineated the genomic and epigenomic characteristics of 404 SFs in HCC based on the multi-omics data from the Cancer Genome Atlas database. The analysis revealed several clinically relevant SFs that could be effective biomarkers for monitoring the onset and prognosis of HCC (such as, HSPB1, DDX39A, and NELFE, which were the three most significant clinically relevant SFs). Functional enrichment analysis of these indicators showed the enrichment of pathways related to splicing and mRNA processes. Furthermore, the study found that SF copy number variation is common in HCC and could be a typical characteristic of hepato-carcinogenesis; the complex expression regulation of SFs was significantly affected by copy number variant and methylation. Several SFs with significant mutation patterns were identified (such as, RNF213, SF3B1, SPEN, NOVA1, and EEF1A1), and the potential regulatory network of SFs was constructed to identify their potential mechanisms for regulating clinically relevant alternative splicing events. Therefore, this study established a foundation to uncover the broad molecular spectrum of SFs for future functional and therapeutic studies of HCC., Graphical abstract

Hepatocellular carcinoma (HCC) often occurs following chronic hepatitis B virus (HBV) infection, leading to high recurrence and a low 5-year survival rate. We developed an overall survival (OS) prediction model based on protein expression profiles in HBV-infected nontumor liver tissues. We aimed to demonstrate the feasibility of using protein expression profiles in nontumor liver tissues for survival prediction. A univariate Cox and differential expression analysis were performed to identify candidate prognostic factors. A multivariate Cox analysis was performed to develop the liver gene prognostic index (LGPI). The survival differences between the different risk groups in the training and validation cohorts were also estimated. A total of 363 patients, 159 in the training cohort, and 204 in the validation cohort were included. Of the 6478 proteins extracted from nontumor liver tissues, we identified 1275 proteins altered between HCC and nontumor liver tissues. A total of 1090 out of 6478 proteins were significantly related to OS. The prognostic values of the proteins in nontumor tissues were mostly positively related to those in the tumor tissues. Protective proteins were mainly enriched in the metabolism-related pathways. From the differentially expressed proteins, the top 10 most significant prognosis-related proteins were submitted for LGPI construction. In the training and validation cohorts, this LGPI showed a great ability for distinguishing patients' OS risk stratifications. After adjusting for clinicopathological features, the LGPI was an independent prognostic factor in the training and validation cohorts. We demonstrated the prognostic value of protein expression profiling in nontumor liver tissues. The proposed LGPI was a promising predictive model for estimating OS in HBV-related HCC.

Jing-Xiao Li,1 Jin-Shu Pang,2 Bin-Tong Yin,1 Gang Chen,1 Jun-Hong Chen,1 Jia-Yuan Luo,1 Xia Yang,1 Li-Ting Qin,1 Jiang-Hui Zeng,3 Peng Chen,4 Jia-Bo Chen,4 Deng Tang1 1Department of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 2Department of Medical Ultrasonics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China; 3Department of Clinical Laboratory, The Third Affiliated Hospital of Guangxi Medical University/Nanning Second People’s Hospital, Nanning, Guangxi Zhuang Autonomous Region, 530031, People’s Republic of China; 4Department of Pediatric Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, 530031, People’s Republic of ChinaCorrespondence: Deng TangDepartment of Pathology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of ChinaTel +86-7715356534Email tdnever@163.comPurpose: The molecular mechanisms and signal pathways of ferroptosis in hepatoblastoma (HB) have not yet been clarified. In previous studies, activating transcription factor 3 (ATF3) was reported to be correlated with several tumors, but the clinical significance of ATF3 has never been determined. Herein, we investigated the clinicopathological value and mechanisms of ATF3 in regulating ferroptosis in HB.Methods: The mRNA microarray and RNA-sequencing data of 402 samples from our hospital and public databases were used to estimate ATF3 expression and assess its clinical role in HB. The standard mean difference (SMD) and summary receiver operating characteristic curves were utilized to judge the discrimination ability of ATF3 between HB and non-HB liver tissues. We examined the expression variation of ATF3 in HB cells after the treatment with erastin. We also predicted the target genes of ATF3 as a transcriptional factor from public Chromatin Immunoprecipitation-sequencing data and selected the ferroptosis-related genes for a signaling pathway analysis.Results: In ten series, the pooled SMD for ATF3 was − 0.91, demonstrating that ATF3 expression was predominantly lower in HB than in non-HB liver tissues. ATF3 down-regulation showed moderate potential to distinguish HB from non-HB liver tissues (area under curves = 0.83, 95% confidence interval = 0.79– 0.86). Altogether, 4855 putative targets of ATF3 as a transcriptional factor were collected, among which, 60 genes were ferroptosis-related.Conclusion: The down-regulated ATF3 expression may play a vital role in the occurrence of HB possible partially by regulating ferroptosis.Keywords: transcription factor, ATF3, hepatoblastoma, ferroptosis

Purpose: Autophagy is a major catabolic system by which eukaryotic cells undergo self-degradation of damaged, defective, or unwanted intracellular components. An abnormal autophagic level is implicated in the pathogenesis of multiple diseases, including cancers. The aim of this study is to explore the prognostic value of autophagy in bladder cancer (BC), which is a major cause of cancer-related death globally. Patients and methods: First, 27 differentially expressed autophagy-related genes (ARGs) were identified in BC patients based on The Cancer Genome Atlas (TCGA) database. Functional enrichment analyses hinted that autophagy may act in a tumor-suppressive role in the initiation of BC. Then, the Cox proportional hazard regression model were employed to identify three key prognostic ARGs (JUN, MYC, and ITGA3), which were related with overall survival (OS) significantly in BC. The three genes represented important clinical significance and prognostic value in BC. Then a prognostic index (PI) was constructed. Results: The PI was constructed based on the three genes, and significantly stratified BC patients into high- and low-risk groups in terms of OS (HR=1.610, 95% CI=1.200-2.160, P=0.002). PI remained as an independent prognostic factor in multivariate analyses (HR=2.355, 95% CI=1.483-3.739, P

Alternative splicing (AS) is crucial a mechanism by which the complexity of mammalian and viral proteom increased overwhelmingly. There lacks systematic and comprehensive analysis of the prognostic significance of AS profiling landscape for uteri corpus endometrial carcinoma (UCEC). In this study, univariate and multivariate Cox regression analyses were conducted to identify candidate survival-associated AS events curated from SpliceSeq for the construction of prognostic index (PI) models. A correlation network between splicing factor-related AS events and significant survival-associated AS events were constructed using Cytoscape 3.5. As consequence, 28281 AS events from 8137 genes were detected from 506 UCEC patients, including 2630 survival-associated AS events. Kaplan Meier survival analysis revealed that six of the seven PI models (AD, AP, AT, ME, RI and ALL) exhibited good performance in stratifying the prognosis of low risk and high risk group (P

Purpose Treatment options for recurrent glioblastoma (rGBM) remain scarce, which may be due to the limited understanding of its molecular characteristics. Methods Based on gene expression profiling, the infiltration scores of 26 immune cell types were calculated using gene set variation analysis. The differences between rGBM and other cancer subtypes were estimated to characterize the specific immune characteristics of rGBM, and the prognostic value of immune cells in rGBM was estimated using univariate and multivariate Cox analysis. Subgroup analyses and Kaplan-Meier analyses were performed to identify whether CD8 T-cell infiltration could be useful in selecting treatment options for rGBM patients. Results We found that rGBM patients were associated with enrichment of activated CD8 T cells, and high CD8 T-cell infiltration was associated with superior overall survival. Patients exhibiting high CD8 T-cell infiltration who received treatment with bevacizumab and lomustine combination therapy experienced a significant benefit in overall survival and progression-free survival, whereas patients with low CD8 T-cell infiltration did not experience such a benefit. CD8 T cells remained an independent prognostic factor in multivariate analyses (cohort 1: hazard ratio [HR] = 0.546, 95% confidence interval [CI]: 0.316–0.945, P = 0.031; cohort 3: HR = 0.615, 95% CI: 0.387–0.978, P = 0.040) after adjusting for clinicopathological and molecular factors. Conclusions Activated CD8 T-cells is a promising biomarker for predicting overall survival in rGBM patients and could be used for assisting treatment selection.

Laryngeal squamous cell carcinoma (LSCC) is an aggressive type of head and neck squamous cell carcinoma (HNSCC) with a relatively high rate of morbidity and mortality. An altered miR-144-3p level in LSCC with a small number of patients has been previously reported. However, the clinical implication of miR-144-3p and its involved mechanism underlying this disease is not clearly elucidated. In this work, we aimed to confirm the expression of miR-144-3p with larger samples and also to identify target genes for the investigation of the underlying mechanism of miR-144-3p in LSCC. The levels of miR-144-3p were downregulated in 155 samples of LSCC tissues as compared to 26 non-LSCC samples (SMD: -0.78; 95% confidence interval (CI): -1.23, -0.32). The AUC of 0.90 in the summarized ROC curve also indicated a potential ability to differentiate LSCC from non-LSCC tissues, with a sensitivity of 0.78 and a specificity of 0.88. With respect to the molecular mechanism, we predicted the potential targets from online-based prediction, peer-reviewed publications, and RNA-seq and microarray data. In particular, the genes influenced by transfection with miR-144-3p in the LSCC FaDu cell line were collected from the microarray GSE56243. Lastly, 12 novel targets for miR-144-3p in LSCC were obtained by different algorithms. In conclusion, our study confirmed the loss or downregulation of miR-144-3p in LSCC, which might contribute to the LSCC tumorigenesis and progression via regulation of the 12 novel targets, such as IL24, ITGA6, and CEP55. In the future, further investigations are required to validate the present results.

An increasing number of studies have confirmed that survivin (BIRC5) plays essential roles in ovarian cancer. Nevertheless, inconsistent or controversial results exist in some studies. In the present study, we sought to determine the clinical significance of survivin and its potential molecular pathways.The correlation between survivin (BIRC5) expression and diagnostic value, prognostic value and clinicopathological features was assessed by meta-analysis with more than 4000 patients from literature, GEO and TCGA. In addition, the potential molecular mechanism of survivin in ovarian cancer was also determined.The pooled sensitivity and specificity were 0.71 (95%CI: 0.68-0.74) and 0.97 (95%CI: 0.94-0.98), respectively. The AUC of sROC was 0.8765. The results showed that there was also a significant relationship between survivin expression and poor overall survival (HR: 1.24, 95%CI: 1.14-1.35, p 0.001), disease-free survival (HR: 1.53, 95%CI: 0.57-4.09, p 0.001), as well as higher recurrence rate (HR: 1.11, 95%CI: 0.97-1.27). Moreover, survivin expression was also associated with tumor progression (cancerous vs. benign, OR: 11.29, 95%CI: 8.96-14.24, p 0.001), TNM stage (III + IV vs. I + II, OR: 5.38, 95%CI: 4.16-6.97, p 0.001), histological grades (G3 vs. G1 ∼ G2, OR: 4.36, 95%CI: 3.29-5.77, p 0.001), and lymphatic metastasis (metastasis vs. non-metastasis, 3.35, 95%CI 2.36-4.75, p 0.001). Bioinformatics analysis revealed the 50 most frequently altered neighboring genes of survivin in OC, and then Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted. GO analysis showed that these genes were related to signal conduction, cell cycle, apoptosis, and metabolism. KEGG pathways analysis indicated that these genes were primarily enriched in mitotic prometaphase, PLK1 signaling events and the regulation of glucokinase by the glucokinase regulatory protein.Survivin (BIRC5) expression might become a specific but low-sensitivity biomarker in ovarian cancer patients, and its presence indicated poor prognosis and worse TNM stages. This protein might function as an oncoprotein by influencing specific pathways involving the 50 genes identified herein. Additional studies are needed to confirm these results.

Breast cancer (BC) has a complex etiology and pathogenesis, and is the most common malignant tumor type in females, in USA in 2018, yet its relevant molecular mechanisms remain largely unknown. The collagen type V α‑1 chain (COL5A1) gene is differentially expressed in renal and ovarian cancer. Using bioinformatics methods, COL5A1 was determined to also be a significant gene in BC, but its association with BC has not been sufficiently reported. COL5A1 microarray and relevant clinical data were collected from the Gene Expression Omnibus, The Cancer Genome Atlas and other databases to summarize COL5A1 expression in BC and its subtypes at the mRNA and protein levels. All associated information was comprehensively analyzed by various software. The clinical significance of the mutation was obtained via the cBioPortal. Furthermore, Gene Ontology functional annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were also performed to investigate the mechanism of COL5A1 in BC. Immunohistochemistry was also conducted to detect and confirm COL5A1 expression. It was determined that COL5A1 was highly expressed in BC tissues, compared with normal tissues at the mRNA level [standard mean difference, 0.84; 95% confidence interval (CI), 0.60‑1.07; P=0.108]. The area under the summary receiver operator characteristic curve for COL5A1 was 0.87 (95% CI, 0.84‑0.90). COL5A1 expression was altered in 32/817 (4%) sequenced samples. KEGG analysis confirmed the most notable pathways, including focal adhesion, extracellular matrix‑receptor interaction and regulation of the actin cytoskeleton. Immunohistochemical detection was used to verify the expression of COL5A1 in 136 selected cases of invasive BC tissues and 55 cases of adjacent normal tissues, while the rate of high expression of COL5A1 in BC was up to 90.4%. These results indicated that COL5A1 is highly expressed at the mRNA and protein levels in BC, and the prognosis of patients with BC with high COL5A1 expression may be reduced; therefore, COL5A1 may be used independently or combined with other detection factors in BC diagnosis.

Breast cancer (BC) is a kind of malignant cancer that seriously threatens women’s health. Research scientists have found that BC occurs as the result of multiple effects of the external environment and internal genetic changes. Cell cycle checkpoint kinase 1 (CHEK1) is a crucial speed limit point in the cell cycle. Alterations of CHEK1 have been found in various tumors but are rarely reported or verified in BC. By mining database information, a large amount of mRNA and protein data was collected and meta-analyzed. Also, in-house immunohistochemistry was carried out to validate the results of the CHEK1 expression levels. Relative clinical features of BC patients were calculated with the CHEK1 expression levels to determine their diagnostic value. The mRNA levels of CHEK1 were higher in 1,089 cases of BC tissues than in 291 cases of non-BC tissues. We observed that the mRNA levels of CHEK1 are related to the clinical stages of BC patients (P = 0.008) and are also significant for overall survival (HR = 1.6, P = 0.0081). Using the immunohistochemistry method, we calculated and confirmed, using Fisher’s exact test (P < 0.001), that a high-level CHEK1 protein is exhibited in BC tissues. Overexpressed CHEK1 mRNA promotes the occurrence of BC. Also, up-regulated CHEK1 could serve as an independent risk biomarker in BC patients’ prognoses.

Papillary renal cell carcinoma (PRCC) accounts for 15‑20% of all kidney neoplasms and continually attracts attention due to the increase in the incidents in which it occurs. The molecular mechanism of PRCC remains unclear and the efficacy of drugs that treat PRCC lacks sufficient evidence in clinical trials. Therefore, it is necessary to investigate the underlying mechanism in the development of PRCC and identify additional potential anti‑PRCC drugs for its treatment. The differently expressed genes (DEGs) of PRCC were identified, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses for functional annotation. Then, potential drugs for PRCC treatment were predicted by Connectivity Map (Cmap) based on DEGs. Furthermore, the latent function of query drugs in PRCC was explored by integrating drug‑target, drug‑pathway and drug‑protein interactions. In total, 627 genes were screened as DEGs, and these DEGs were annotated using KEGG pathway analyses and were clearly associated with the complement and coagulation cascades, amongst others. Then, 60 candidate drugs, as predicted based on DEGs, were obtained from the Cmap database. Vorinostat was considered as the most promising drug for detailed discussion. Following protein‑protein interaction (PPI) analysis and molecular docking, vorinostat was observed to interact with C3 and ANXN1 proteins, which are the upregulated hub genes and may serve as oncologic therapeutic targets in PRCC. Among the top 20 metabolic pathways, several significant pathways, such as complement and coagulation cascades and cell adhesion molecules, may greatly contribute to the development and progression of PRCC. Following the performance of the PPI network and molecular docking tests, vorinostat exhibited a considerable and promising application in PRCC treatment by targeting C3 and ANXN1.

Gastric adenocarcinoma (GAC) is a challenging disease with dim prognosis even after surgery; hence, novel treatments for GAC are in urgent need. The aim of the present study was to explore new potential compounds interfering with the key pathways related to GAC progression. The differentially expressed genes (DEGs) between GAC and adjacent tissues were identified from The Cancer Genome Atlas (TCGA) and Genotype‑Tissue Expression (GTEx) database. Connectivity Map (CMap) was performed to screen candidate compounds for treating GAC. Subsequently, pathways affected by compounds were overlapped with those enriched by the DEGs to further identify compounds which had anti‑GAC potential. A total of 843 DEGs of GAC were identified. Via Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, 13 pathways were significantly enriched. Moreover, 78 compounds with markedly negative correlations with DEGs were revealed in CMap database (P