PARP1 bound to XRCC2 promotes tumor progression in colorectal cancer.

BACKGROUND: By complexing poly (ADP-ribose) (PAR) in reaction to broke strand, PAR polymerase1 (PARP1) acts as the key enzyme participated in DNA repair. However, recent studies suggest that unrepaired DNA breaks results in persistent PARP1 activation, which leads to a progressively reduce in hexokinase1 (HK1) activity and cell death. PARP-1 is TCF-4/ß-A novel co activator of gene transactivation induced by catenin may play a role in the development of colorectal cancer. The molecular mechanism of PARP1 remains elusive. METHODS: 212 colorectal cancer (CRC) patients who had the operation at our hospital were recruited. PARP1 expression was evaluated by immunohistochemistry. Stable CRC cell lines with low or high PARP1 expression were constructed. Survival analysis was computed based on PARP1 expression. The cell proliferation was tested by CCK-8 and Colony formation assay. The interaction of PARP1 and XRCC2 was detected by immunoprecipitation (IP) analysis. RESULTS: Compared with matching adjacent noncancerous tissue, PARP1 was upregulated in CRC tissue which was correlated with the degree of differentiation, TNM stage, depth of invasion, metastasis, and survival. In addition, after constructing CRC stable cell lines with abnormal expression of PARP1, we found that overexpression of PARP1 promoted proliferation, and demonstrated the interaction between PARP1 and XRCC2 in CRC cells through immunoprecipitation (IP) analysis. Moreover, the inhibitor of XRCC2 can suppress the in vitro proliferation arousing by upregulation of PARP1. CONCLUSIONS: PARP1 was upregulated in CRC cells and promoted cell proliferation. Furthermore, the expression status of PARP1 was significantly correlated with some clinicopathological features and 5-year survival.

Identification of tumor antigens and immune subtypes of hepatocellular carcinoma for mRNA vaccine development.

BACKGROUND: mRNA vaccines have been investigated in multiple tumors, but limited studies have been conducted on their use for hepatocellular carcinoma (HCC). AIM: To identify candidate mRNA vaccine antigens for HCC and suitable subpopulations for mRNA vaccination. METHODS: Gene expression profiles and clinical information of HCC datasets were obtained from International Cancer Genome Consortium and The Cancer Genome Atlas. Genes with somatic mutations and copy number variations were identified by cBioPortal analysis. The differentially expressed genes with significant prognostic value were identified by Gene Expression Profiling Interactive Analysis 2 website analysis. The Tumor Immune Estimation Resource database was used to assess the correlation between candidate antigens and the abundance of antigen-presenting cells (APCs). Tumor-associated antigens were overexpressed in tumors and associated with prognosis, genomic alterations, and APC infiltration. A consensus cluster analysis was performed with the Consensus Cluster Plus package to identify the immune subtypes. The weighted gene coexpression network analysis (WGCNA) was used to determine the candidate biomarker molecules for appropriate populations for mRNA vaccines. RESULTS: AURKA, CCNB1, CDC25C, CDK1, TRIP13, PES1, MCM3, PPM1G, NEK2, KIF2C, PTTG1, KPNA2, and PRC1 were identified as candidate HCC antigens for mRNA vaccine development. Four immune subtypes (IS1-IS4) and five immune gene modules of HCC were identified that were consistent in both patient cohorts. The immune subtypes showed distinct cellular and clinical characteristics. The IS1 and IS3 immune subtypes were immunologically "cold". The IS2 and IS4 immune subtypes were immunologically "hot", and the immune checkpoint genes and immunogenic cell death genes were upregulated in these subtypes. IS1-related modules were identified with the WGCNA algorithm. Ultimately, five hub genes (RBP4, KNG1, METTL7A, F12, and ABAT) were identified, and they might be potential biomarkers for mRNA vaccines. CONCLUSION: AURKA, CCNB1, CDC25C, CDK1, TRIP13, PES1, MCM3, PPM1G, NEK2, KIF2C, PTTG1, KPNA2, and PRC1 have been identified as candidate HCC antigens for mRNA vaccine development. The IS1 and IS3 immune subtypes are suitable populations for mRNA vaccination. RBP4, KNG1, METTL7A, F12, and ABAT are potential biomarkers for mRNA vaccines.

Long-term survival of patients with hepatocellular carcinoma with hepatic, pulmonary, peritoneal and rare colon metastasis: A case report.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly malignant cancer that often metastasizes and has a poor prognosis. Gastrointestinal tract metastases are rare, and colon metastases are even rarer. The long-term survival of patients with multiple intrahepatic and extrahepatic metastases, especially to the colon, has not been previously reported. CASE SUMMARY: We present an atypical clinical case of a patient with liver, right lung, peritoneal, and colon metastases diagnosed successively following hepatic resection for primary HCC. Comprehensive treatment, including partial liver, lung and colon resection, palliative management such as systemic chemotherapy, trans-arterial chemoembolization, targeted therapy with sorafenib, and cryotherapy were attempted. Despite his early metastases, the patient remained relatively healthy for 8 years after diagnosis. CONCLUSION: This case indicates that comprehensive treatment is beneficial for certain patients with metastatic HCC. Clinicians should be alert as to the possibility of rare site metastatic tumors that may be easily misdiagnosed as primary tumors.

Over-expression of NFYB affects stromal cells reprogramming and predicts worse survival in gastric cancer patients.

Gastric cancer (GC) is the fifth most common cancer worldwide and the third most fatal. Cancer-associated fibroblasts (CAFs) play an essential role in promoting the occurrence and development of gastric cancer in all stages. NFYB is highly expressed in multiple tumors and promotes tumor invasion, metastasis, and drug resistance, but its role in the occurrence and development of gastric cancer remains unclear. Hence, we used TCGA, TIMER, Kaplan-Meier Plot, and UALCAN databases to analyze the expression of NFYB in pan-cancers and assess its clinical prognostic value. We found that high expression of NFYB may be a promising prognostic biomarker in patients with gastric cancer. High expression of NFYB was associated with high T stage, high histological grade, diffuse gastric cancer, and early-onset GC. Moreover, High expression of NFYB was associated with CAFs infiltration in the GC microenvironment. The prognosis of GC patients with high expression of NFYB and high infiltration of CAFs was worse. Therefore, NFYB may serve as a potential prognostic biomarker in patients with GC.

Antisense long non-coding RNAs in gastric cancer.

Gastric cancer is a global health problem with high mortality. The incidence of gastric cancer has significant regional differences. Helicobacter pylori (H. pylori) infection and its interaction with epigenetics are closely related to the occurrence of gastric cancer. It is of great significance to explore the early diagnosis and effective therapeutic targets of gastric cancer. Emerging evidence indicates that antisense long non-coding RNAs (lncRNAs) are closely associated with various biological and functional aspects of gastric cancer. However, diverse antisense lncRNAs in gastric cancer have not been compiled and discussed. In this review, we summarize the predisposing factors and compile the interaction between H. pylori and epigenetics in gastric cancer. Moreover, we focus on the underlying molecular mechanism and regulatory role of each antisense lncRNA in gastric cancer. In addition, we provide a new insight into the potential diagnosis and treatment of antisense lncRNAs in gastric cancer.

Overexpression of CISD1 Predicts Worse Survival in Hepatocarcinoma Patients.

Background: Ferroptosis plays a vital role in hepatocellular carcinoma (HCC). CISD1 is known to regulate ferroptosis negatively. However, the correlations of CISD1 to prognosis in HCC and its potential mechanism remain unclear. Aim: To investigate the expression level and prognostic value of CISD1 in HCC. Methods: Gene expression and clinical data for 33 cancer types in TCGA were downloaded from the UCSC Xena platform. Pan-cancer analysis was performed to determine the expression profile and prognostic value of CISD1 in human cancers. GEO datasets and Human Protein Atlas (HPA) were used to verify the mRNA and protein expression levels. The influence of CISD1 on clinical prognosis in HCC was evaluated using a Kaplan-Meier plotter. The PPI network was constructed using the STRING database and Cytoscape. GO and KEGG pathways were constructed using the "clusterProfiler" R package with the FDR cutoff of 0.05. The methylation at the CISD1 promoter was detected using UALCAN and GEO datasets. The correlations between CISD1 and HCC immune infiltrates were investigated via TIMER. Results: Pan-cancer analysis of TCGA data showed that CISD1 is differentially expressed in multiple tumors. Data of gene expression microarrays reveal that the mRNA expression of CISD1 is higher in HCC than that in normal tissue. The protein level of CISD1, validated by the Human Protein Atlas (HPA) database, was upregulated consistently with mRNA levels in HCC samples. High CISD1 expression was associated with better overall survival (OS), disease-free survival (DFS), disease-specific survival (DSS), and progression-free survival (PFS) in LGG, but with poorer OS, DFS, DSS, and PFS in LIHC. Protein-protein interaction (PPI) analysis and GO/KEGG analysis showed that the PPI network and GO term of CISD1 were mainly associated with energy and iron metabolism. Promoter hypomethylation correlated with overexpression of CISD1. CISD1 expression was positively correlated with infiltrating levels of CD8+ T cells, macrophages, neutrophils, and dendritic cells (DCs) in HCC. Conclusions: These findings suggest that hypomethylation of the CISD1 promoter increases its expression in HCC. CISD1 is associated with prognosis and immune infiltrating levels of CD8+ T cells, macrophages, neutrophils, and DCs in HCC patients. These findings suggest that CISD1 can be used as a prognostic biomarker for determining prognosis in HCC.

The mechanisms and roles of melatonin in gastrointestinal cancer.

Gastrointestinal (GI) cancer is a global health problem with wide lesions and numerous cases. The increased morbidity and mortality of GI cancer is a socio-economic challenge for decades to come. Melatonin, a nature indolamine, exerts a crucial role in molecular interactions involved in multiple functional and physiological processes. Increasing evidence indicates that melatonin can modulate GI tract, decrease the occurrence of GI cancer, and enhance the sensitivity to chemoradiotherapy. However, little is known about the exact role of melatonin in anti-carcinogenesis. In this review, we discuss the action of the beneficial effects of melatonin in GI carcinogenesis. Furthermore, we compile the understanding of the role of melatonin in GI cancer, including esophageal cancer (EC), gastric cancer (GC), hepatocellular carcinoma (HCC), colorectal cancer (CRC), and pancreatic cancer (PC). In addition, the potential therapeutic application and clinical evaluation of melatonin in GI cancer are also discussed.

Low expression of miR-199 in hepatocellular carcinoma contributes to tumor cell hyper-proliferation by negatively suppressing XBP1.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related mortality worldwide, and microRNAs (miRs) are considered to serve important functions in the pathogenesis of HCC by regulating the expression of specific target genes. The present study was conducted to investigate the role of miR-199 and its putative target X-box binding protein 1 (XBP1) in HCC, as well as of the downstream gene cyclin D. The expression levels of miR-199, XBP1 and cyclin D were detected in clinical HCC specimens. The effect of miR-199 on the regulation of HCC cell proliferation and its underlying mechanism were examined in Hep3B2.1-7 cells, through expression assays and measurement of cell proliferation (via Cell Counting Kit-8, and 5-ethynyl-2'-deoxyuridine and DAPI double-staining assays) coupled with gain- and lose- of function experiments. The expression of XBP1 and cyclin D was significantly increased in HCC tissues when compared with adjacent non-HCC tissues, while the expression of miR-199 was decreased. Exogenous miR-199 significantly suppressed the expression of XBP1 and cyclin D in Hep3B2.1-7 cells. However, the expression of XBP1 and cyclin D significantly increased on treatment with miR-199 inhibitor. Consistently, Hep3B2.1-7 cells co-transfected with a wild type reporter plasmid [XBP1-3'untranslated region (UTR)-WT] and exogenous miR-199 exhibited lower relative luciferase enzyme activity than cells co-transfected with negative control miRNA and XBP1-3'UTR-WT, while cells co-transfected with mutated plasmid (XBP1-3'UTR-MU) and miR-199 exhibited no change. It was further observed that knockdown of XBP1 by small interfering RNA significantly decreased the expression of cyclin D in Hep3B2.1-7 cells. Additionally, exogenous miR-199 decreased the proliferation of Hep3B2.1-7 cells, which was contrary to the effect of miR-199 inhibitor. In conclusion, it was demonstrated that miR-199 negatively regulated the expression of XBP1 by directly binding to its 3'UTR and that XBP1 impacted cyclin D expression, which was associated with the cell cycle regulation in Hep3B2.1-7 cells. These findings suggested that a miR-199/XBP1/cyclin D axis may serve an important role in the pathogenesis of HCC.