Decrease of 5-Hydroxymethylcytosine Is Associated with Progression of Hepatocellular Carcinoma through
Chungang LiuLimei LiuXuejiao ChenJunjie ShenJuanjuan ShanYanmin XuZhi YangLin WuFeng XiaPing BieYou‐Hong CuiXiu‐Wu BianCheng Qian
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5-Hydroxymethylcytosine
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Tumor progression
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HCCS
Ectopic expression
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Tumor progression
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Abstract Background Hepatocellular carcinoma (HCC) incidence is increasing worldwide and prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Circulating cell‐free DNA of tumour origin (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We determined the utility of ctDNA as a prognostic biomarker of survival in HCC. Methods Plasma cell‐free DNA and matched germline DNA were isolated from patients with HCC (n = 51) and cirrhosis (n = 10). Targeted, multiplex PCR ultra‐deep sequencing was performed using a liver cancer‐specific primer panel for genes ALB, AMPH, APC, ARID1A, ARID2, ATM, AXIN1, BAZ2B, BRAF, CSMD3, CTNNB1, DSE, ERBB2, HNF1A, IGFR2, IGSF10, KEAP1, MET, TP53, UBR3, USP25, ZIC3 and ZNF226 . Associations between mutations in ctDNA and overall survival were analysed using Cox proportional hazards modelling. Results 114 putative mutations (70 unique) in were detected in plasma ctDNA in 35 of 51 patients with HCC (69%). On univariable analysis, CSMD3 gene mutations were associated with shorter overall survival (Logrank HR 3.18, 95% CI 1.14‐8.86, P = .027). The median survival time was 15.5 months (IQR 7.77‐16.5 months) in patients with CSMD3 mutations compared with the median survival of 26.5 months (IQR 16.93‐46.07 months) in patients without CSMD3 mutations. Other factors associated with overall survival were advanced BCLC stage (HR 16.52, 95% CI 2.22‐122.94, P = .006) and Child‐Pugh Class (CPC HR 7.98, 95% CI 2.31‐27.61, P = .001). Cox proportional hazards modelling showed mutations in CSMD3 remained a significant independent risk for shorter overall survival in HCC when adjusted for age, BCLC stage and Child‐Pugh class (HR 4.91, 95% CI 1.60‐15.02, P = .005). Conclusion Detection of CSMD3 mutations in plasma ctDNA is associated with reduced overall survival in HCC patients, adjusted for potential confounding factors.
Liver Cancer
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Aim/Background: Oncoprotein 18 (OP18) is a recognized oncoprotein upregulated in various solid tumors. OP18 promotes microtubule disassembly and modulates tumor growth and migration activity. However, the mechanisms associated with genetic regulation of OP18 are yet to be elucidated. In the current study, we identified OP18 as a target gene of thyroid hormone (T3) in the HepG2 hepatoma cell line using microarray analysis.Methods: The expression profiles and transcriptional mechanism of T3-suppressed OP18 were analyzed by molecular biology protocols. To verify if T3-regulated OP18 plays a functional role in liver tumorigenesis, OP18 knockdown tumor cell was generated and tumorigenicity was assessed.Results: OP18 mRNA and protein expression levels were significantly suppressed in the presence of T3. Thyroid hormone receptor directly targeted the OP18 upstream element to regulate transcriptional activity. Furthermore, thyroid hormone receptor expression was negatively correlated with OP18 in a portion of clinical hepatocellular carcinoma (HCC) specimens. Specific knockdown of OP18 suppressed cell proliferation and xenograft tumor growth in mice. In addition, cell cycle distribution was altered, with increased G2 and reduced G1 phases, in OP18 knockdown cells.Conclusions: Our results suggest that oncogenic OP18 is transcriptionally downregulated by T3 in liver. This T3-mediated suppression of STMN supports the theory that the thyroid hormone plays an inhibitory role in HCC tumor growth, and lack of TR expression or regulation may lead to elevated OP18 expression and malignant growth.Disclosure: All authors have declared no conflicts of interest. Aim/Background: Oncoprotein 18 (OP18) is a recognized oncoprotein upregulated in various solid tumors. OP18 promotes microtubule disassembly and modulates tumor growth and migration activity. However, the mechanisms associated with genetic regulation of OP18 are yet to be elucidated. In the current study, we identified OP18 as a target gene of thyroid hormone (T3) in the HepG2 hepatoma cell line using microarray analysis. Methods: The expression profiles and transcriptional mechanism of T3-suppressed OP18 were analyzed by molecular biology protocols. To verify if T3-regulated OP18 plays a functional role in liver tumorigenesis, OP18 knockdown tumor cell was generated and tumorigenicity was assessed. Results: OP18 mRNA and protein expression levels were significantly suppressed in the presence of T3. Thyroid hormone receptor directly targeted the OP18 upstream element to regulate transcriptional activity. Furthermore, thyroid hormone receptor expression was negatively correlated with OP18 in a portion of clinical hepatocellular carcinoma (HCC) specimens. Specific knockdown of OP18 suppressed cell proliferation and xenograft tumor growth in mice. In addition, cell cycle distribution was altered, with increased G2 and reduced G1 phases, in OP18 knockdown cells. Conclusions: Our results suggest that oncogenic OP18 is transcriptionally downregulated by T3 in liver. This T3-mediated suppression of STMN supports the theory that the thyroid hormone plays an inhibitory role in HCC tumor growth, and lack of TR expression or regulation may lead to elevated OP18 expression and malignant growth. Disclosure: All authors have declared no conflicts of interest.
Stathmin
Thyroid hormone receptor
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Expression (computer science)
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Hepatitis B
Liver Cancer
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Hepatocellular carcinoma (HCC) is a liver disease with a complex underlying mechanism, and patients with HCC have low survival rates. Iron metabolism plays a crucial role in the pathogenesis of HCC; however, the prognostic value of iron metabolism-related and methylated genes for HCC needs to be further explored. In the present study, we identified differentially expressed genes (DEGs) that play a role in iron metabolism and DNA methylation in HCC from The Cancer Genome Atlas. Four of these DEGs, whose expression levels are correlated with HCC prognosis, namely, RRM2, FTCD, CYP2C9, and ATP6V1C1, were further used to construct a prognostic model for HCC, wherein the risk score was calculated using the gene expression of the four DEGs. This could be used to predict the overall survival of HCC patients for 1, 3, and 5 years. Results of a multivariate Cox regression analysis further indicated that the risk score was an independent variable correlated with the prognosis of HCC patients. The identified gene signature was further validated using an independent cohort of HCC patients from the International Cancer Genome Consortium. Weighted gene co-expression network analysis and gene set enrichment analysis were performed to identify potential regulatory mechanisms of the gene signature in HCC. Taken together, we identified key prognostic factors of iron metabolism-related and methylated genes for HCC, providing a potential treatment strategy for HCC.
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Hepatocellular carcinoma is one of the malignant tumors with highest mortality. Nuclear factor κB (NF-κB) as the mediator of many pathways, such as metabolic pathway, angiogenesis and adherence factor, is implicated in the onset and progression of hepatocellular carcinoma. Through the literature retrieval, the activity of NF-κB and its implication in the onset, progression, invasion and metastasis have been reviewed in the article.
Key words:
NF-kappa B; Liver neoplasms; Review
Mediator
Tumor progression
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