Project description:Pentatricopeptide repeat domain 1 (PTCD1) was reported to regulate mitochondrial metabolism and oxidative phosphorylation. However, the effect and mechanism of PTCD1 in the development of bladder urothelial carcinoma (BLCA) remain unclear. The databases from The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) were used to analyze the expression changes, clinical features, and prognostic values of PTCD1. A nomogram was built to predict the prognostic outcomes of BLCA cases. The potential genes interacting with PTCD1 were explored by Weighted Gene Coexpression Network Analysis (WGCNA). The estimation of associations between PTCD1 and tumor mutations, tumor immunities, and m6A methylations was performed. The study found that the gradual decrease of PTCD1 expression was observed with the increase of stage and grade. Low PTCD1 expression was greatly correlated with higher pathological stage, N stage, and poor prognosis in TCGA cohorts; interestingly, low-grade BLCA cases all exhibited high expression of PTCD1. HPA database analysis implied that the expression of PTCD1 protein in BLCA was lower than that in normal bladder tissue, and the protein expression of PTCD1 in high-grade BLCA was lower than that in low-grade BLCA. Multivariate Cox regression analysis indicated that PTCD1 may serve as an independent factor influencing prognosis of BLCA. Mechanistically, PTCD1 played a regulatory role in BLCA progression through multiple tumor-related pathways containing PI3K-Akt signaling, ECM-receptor interaction, oxidative phosphorylation, and extracellular matrix organization. WGCNA reported that PTCD1 had a strong positive correlation with POLR2J, ZNHT1, ATP5MF, PDAP1, BUD31, and COPS6. Besides, the mRNA expression of PTCD1 was negatively associated with immune cells' infiltrations, immune functions, and checkpoints, especially with some m6A methylation regulators in BLCA. In sum, downregulation of PTCD1 expression may be involved in the development of BLCA and remarkably correlated with poor prognosis. Meantime, it showed an influence in immune cell infiltration and may serve as an agreeable prognostic indicator in BLCA.

Project description:Background - Hepatocellular carcinomas (HCCs) are heterogeneous tumors with respect to etiology, cell of origin and biology. The course of the disease is unpredictable and is in part dependent on the tumor microenvironment. One of the microenvironmental factors is hypoxia, which is known to promote aggressiveness in other malignant tumors. We hypothesized that certain regions in HCC exist with chronic hypoxia and a characteristic gene expression pattern. Moreover, during the development of HCC there is an important contribution of this chronic hypoxia on prognosis via this gene expression. Until now, most research has been performed in acute hypoxic models (< 24 hours). Methods – Human hepatoblastoma cells HepG2 were cultured in either normoxic (20% O2) or hypoxic (2% O2) conditions for 72 hrs, the time it takes to adapt to chronic hypoxia. After 3 days the cells were harvested and analyzed by microarray technology. The highly significant differentially expressed genes were selected and used to assess the clinical value of our in vitro chronic hypoxia gene signature in four published patient studies. Three of these independent microarray studies on HCC patients were used as training sets to determine a minimal prognostic gene set and one study was used for validation. Gene expression analysis and correlation with clinical outcome was assessed with the bioinfomatic method of Goeman et al (). Results – In the HepG2 cells, 3592 genes were differentially expressed in cells cultured at 2% oxygen for 72 hrs. Out of these, 265 showed a high significant change (2-fold change and p=0.0001). The level of gene expression after 72 hrs was different from the acute hypoxic response (during the first 24 hours) and represented chronicity. Using computational methods we identified 7 out of the 265 highly significant genes that showed correlation with prognosis in all three different training sets and this was independently validated in a 4th dataset. With our approach we could include the largest number of HCC patients in one single study. Conclusion – We identified a 7-gene signature, which is associated with chronic hypoxia and predicts prognosis in patients with HCC. In the future this signature could be used as a diagnostic tool. In addition, chronic hypoxia gene expression information can be used in the search for new therapeutic targets. Two conditions were compared and each sample has a biological replicate. Samples are hybridized in dye-swap, resulting in 4 hybridizations.

Project description:BackgroundColorectal cancer (CRC) is the third most common cancer all around the world, and it seriously threats human health. PHF19 has been proved to be closely related to the prognosis of patients in a variety of malignant tumors, but the effect of PHF19 on the prognosis evaluation of CRC patients has not been confirmed.MethodsIn our study, we used GEO, TCGA database and IHC to verify the PHF19 expression in CRC samples. Survival analysis of PHF19 based on TCGA, GEO series, and our own CRC sample were performed. Cox regression was performed to reveal the relationship between PHF19 and prognosis. Co-expression was performed to find genes related to PHF19 expression. GO/KEGG enrichment analysis and GSEA analysis were used to confirm the most relevant signal pathway to PHF19. Next, cell experiments were performed to verify the effect of PHF19 on the proliferation, invasion and metastasis of CRC. Then, Western blot was used to verify the protein expression of the above two phenotypes. Finally, tumor formation experiments in nude mice were used to verify the role of PHF19 of tumor proliferation in vivo.ResultsWe found that PHF19 was significantly over-expressed in tumors compared with normal tissues. Kaplan-Meier (K-M) analysis indicated that high PHF19 in CRC associated with poor overall survival (OS) in CRC patients. Clinical correlation analysis showed that high expression of PHF19 was closely related to t umor progression in CRC patients, especially infiltration and metastasis. Bioinformatics revealed that PHF19 might affect tumor malignant phenotype by regulating the cell cycle in CRC. CCK-8 and clonal formation experiment showed that the proliferative ability of tumor cells was promoted. Flow cytometry showed that the cell cycle accelerated the transition from G1 to S phase. Western blot found that Cyclin D1, CDK4, and CDK6 expression were up-regulated. Transwell and wound-healing experiment found that invasive and migratory abilities was promoted after the over-expression of PHF19. Western blot showed that the expression of key proteins of Epithelial-Mesenchymal Transition (EMT) changed. Tumor formation experiments in nude mice showed that overexpression of PHF19 could promote tumor proliferation in vivo.ConclusionOur research proved that PHF19 could be an independent prognostic factor for CRC, PHF19 promoted the proliferative ability and the invasion and metastasis of CRC by up-regulating the expression of key molecules related to cell cycle and EMT pathway in vitro, promoting tumor proliferation in vivo.

Project description:Background - Hepatocellular carcinomas (HCCs) are heterogeneous tumors with respect to etiology, cell of origin and biology. The course of the disease is unpredictable and is in part dependent on the tumor microenvironment. One of the microenvironmental factors is hypoxia, which is known to promote aggressiveness in other malignant tumors. We hypothesized that certain regions in HCC exist with chronic hypoxia and a characteristic gene expression pattern. Moreover, during the development of HCC there is an important contribution of this chronic hypoxia on prognosis via this gene expression. Until now, most research has been performed in acute hypoxic models (< 24 hours). Methods – Human hepatoblastoma cells HepG2 were cultured in either normoxic (20% O2) or hypoxic (2% O2) conditions for 72 hrs, the time it takes to adapt to chronic hypoxia. After 3 days the cells were harvested and analyzed by microarray technology. The highly significant differentially expressed genes were selected and used to assess the clinical value of our in vitro chronic hypoxia gene signature in four published patient studies. Three of these independent microarray studies on HCC patients were used as training sets to determine a minimal prognostic gene set and one study was used for validation. Gene expression analysis and correlation with clinical outcome was assessed with the bioinfomatic method of Goeman et al (). Results – In the HepG2 cells, 3592 genes were differentially expressed in cells cultured at 2% oxygen for 72 hrs. Out of these, 265 showed a high significant change (2-fold change and p=0.0001). The level of gene expression after 72 hrs was different from the acute hypoxic response (during the first 24 hours) and represented chronicity. Using computational methods we identified 7 out of the 265 highly significant genes that showed correlation with prognosis in all three different training sets and this was independently validated in a 4th dataset. With our approach we could include the largest number of HCC patients in one single study. Conclusion – We identified a 7-gene signature, which is associated with chronic hypoxia and predicts prognosis in patients with HCC. In the future this signature could be used as a diagnostic tool. In addition, chronic hypoxia gene expression information can be used in the search for new therapeutic targets.

Dataset Information

Downregulation of castor zinc finger 1 predicts poor prognosis and facilitates hepatocellular carcinoma progression via MAPK/ERK signaling.

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Downregulation of castor zinc finger 1 predicts poor prognosis and facilitates hepatocellular carcinoma progression via MAPK/ERK signaling.

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