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: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.

Project description:Absence of effective prognostic biomarkers and therapeutic targets for reversing chemoresistance of endometrial carcinoma (EC) remains a huge challenge for clinicians. Mitophagy plays a crucial role in carcinogenesis and chemoresistance. FUN14 domain-containing protein 1 (FUNDC1) is a novel mitophagy receptor protein involved in tumorigenesis under hypoxic conditions. However, the implication of FUNDC1 in EC progression, chemoresistance in particular, remains unclear. Based on The Cancer Genome Atlas (TCGA) cohort, comprised of 403 EC patients, the association of FUNDC1 mRNA levels with hypoxia-inducible factor 1α (HIF-1α) expression, clinicopathologic features and prognosis in EC was analyzed, and subsequently verified utilizing immunohistochemistry of 288 EC specimens. Analysis of the cohort in TCGA showed that patients with higher FUNDC1 levels exhibited worse OS, with the shortest OS exhibited by patients with co-upregulated FUNDC1 and HIF-1α (P < 0.05). Analysis of the validation cohort indicated that OS and PFS rates of high-FUNDC1 patients were lower than that of low-FUNDC1 group (P < 0.05). Cases with co-downregulation of FUNDC1 and HIF-1α had higher OS and PFS rates than those with co-upregulation of these two proteins (88.8% vs. 71.2%, P = 0.002; 85.6% vs. 71.2%, P = 0.009). Higher FUNDC1 expression was observed in platinum-resistant patients. Multivariate Cox regression analysis revealed that FUNDC1 expression, FIGO stage, lymphatic invasion, depth of myometrial invasion, and ascites were independent risk factors for OS and PFS. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that FUNDC1 was closely related to spliceosome, neurodegeneration pathways of multiple diseases, and cell cycle signaling pathways. Significantly enriched RNA splicing and ncRNA processing were identified in Gene Ontology (GO) analysis. Gene set enrichment analysis (GSEA) indicated that abnormal expression of FUNDC1 was involved in endometrial cancer, NOD-like receptor signaling pathway and cytokine signaling in the immune system. In addition, immune cell infiltration analysis by Tumor Immune Estimation Resources (TIMER) database and the Xiantao academic tool demonstrated that FUNDC1 expression was strongly associated with the infiltration of Th2, NK, Th17, Tem, pDC, neutrophil, MDSC, CD4+ T, and γδ T cells. Knockdown of FUNDC1 using shRNA in HEC-1B and Ishikawa EC cells inhibited proliferation, migration and invasion, accompanied by enhanced chemotherapeutic susceptibility to carboplatin and paclitaxel. Accordingly, FUNDC1 could be a prospective prognostic biomarker and potential therapeutic target for EC.

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NSUN5 promotes progression and predicts poor prognosis in hepatocellular carcinoma.

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NSUN5 promotes progression and predicts poor prognosis in hepatocellular carcinoma.

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