scholarly journals Dual‐Specificity Phosphatase 9 Regulates Cellular Proliferation and Predicts Recurrence After Surgery in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Kui Chen ◽  
Andre Gorgen ◽  
Avrilynn Ding ◽  
Lulu Du ◽  
Keruo Jiang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cellular Proliferation ◽  
Dual Specificity Phosphatase ◽  
Dual Specificity

scholarly journals Dual-specificity phosphatase 3 deletion promotes obesity, non-alcoholic steatohepatitis and hepatocellular carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sophie Jacques ◽  
Arash Arjomand ◽  
Hélène Perée ◽  
Patrick Collins ◽  
Alice Mayer ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Liver Damage ◽  
Chow Diet ◽  
Serum Triglycerides ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Steatohepatitis ◽  
Dual Specificity ◽  
Dual Specificity Protein Phosphatase

AbstractNon-alcoholic fatty liver disease (NAFLD) is the most common chronic hepatic pathology in Western countries. It encompasses a spectrum of conditions ranging from simple steatosis to more severe and progressive non-alcoholic steatohepatitis (NASH) that can lead to hepatocellular carcinoma (HCC). Obesity and related metabolic syndrome are important risk factors for the development of NAFLD, NASH and HCC. DUSP3 is a small dual-specificity protein phosphatase with a poorly known physiological function. We investigated its role in metabolic syndrome manifestations and in HCC using a mouse knockout (KO) model. While aging, DUSP3-KO mice became obese, exhibited insulin resistance, NAFLD and associated liver damage. These phenotypes were exacerbated under high fat diet (HFD). In addition, DEN administration combined to HFD led to rapid HCC development in DUSP3-KO compared to wild type (WT) mice. DUSP3-KO mice had more serum triglycerides, cholesterol, AST and ALT compared to control WT mice under both regular chow diet (CD) and HFD. The level of fasting insulin was higher compared to WT mice, though, fasting glucose as well as glucose tolerance were normal. At the molecular level, HFD led to decreased expression of DUSP3 in WT mice. DUSP3 deletion was associated with increased and consistent phosphorylation of the insulin receptor (IR) and with higher activation of the downstream signaling pathway. In conclusion, our results support a new role for DUSP3 in obesity, insulin resistance, NAFLD and liver damage.

scholarly journals Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hui Li ◽  
Yujuan Liu ◽  
Wei Jiang ◽  
Junhui Xue ◽  
Yuning Cheng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cancer ◽  
Cellular Proliferation ◽  
Chinese Herb ◽  
New Drugs ◽  
Phase Iii ◽  
P53 Expression ◽  
Expression Levels ◽  
Cellular Apoptosis ◽  
Afp Promoter

Abstract Background Icaritin, an active ingredient of the Chinese herb Epimedium, plays an anti-tumor role in liver cancer by inhibiting the proliferation of hepatocellular cells and promoting their apoptosis. In China, phase II and a large phase III clinical trial of icaritin reagent for the treatment of hepatocellular cancer is under-going, but the specific mechanism of icaritin action was unclear. Alpha-fetoprotein (AFP), an oncofetal protein, produced in the healthy fetal liver and yolk sac. Intracellular AFP promoted cellular proliferation and inhibited cellular apoptosis in hepatocellular carcinoma (HCC). The study was aimed to investigate the effect of icaritin on HCC through p53/AFP pathway. Methods Real-time RT PCR and western blot were used to detect p53 and AFP expression levels in HCC cells treated with icaritin. The mechanism of icaritin affecting p53 expression was verified by ubiquitination experiment, and the binding activity of icaritin on p53 in AFP promoter region was verified by luciferase experiment. EdU, MTT and flow cytometry were used to determine whether icaritin affected HCC cellular proliferation and apoptosis through p53/ AFP pathway. Expression levels of p53 and AFP in xenograft mouse model were determined by western blotting. Results Our results showed icaritin inhibited AFP expression at mRNA and protein level. AFP was also identified as the target gene of the p53 transcription factor. Icaritin abrogated murine double minute (Mdm) 2-mediated p53 ubiquitination degradation to improve the stability of p53. Up-regulated p53 protein levels then transcriptionally inhibited the AFP promoter. Icaritin-mediated decrease of AFP through Mdm2/p53 pathways inhibited HCC cellular proliferation and promoted HCC cellular apoptosis. Conclusion Our findings revealed the mechanism of icaritin in promoting apoptosis and inhibiting proliferation in liver cancer cells. The regulatory mechanism of icaritin in AFP protein down-regulation provides a theoretical and experimental basis for further research into new drugs for the treatment of liver cancer.

scholarly journals Multiplexed Proteomic Approach for Identification of Serum Biomarkers in Hepatocellular Carcinoma Patients with Normal AFP

2020 ◽  
Vol 9 (2) ◽  
pp. 323
Author(s):  
Young-Sun Lee ◽  
Eunjung Ko ◽  
Eileen L. Yoon ◽  
Young Kul Jung ◽  
Ji Hoon Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Hepatoma Cell ◽  
Multiple Reaction Monitoring ◽  
Serum Levels ◽  
Human Hepatoma Cell ◽  
Hepatoma Cell Lines ◽  
Proteomic Approach

Alpha fetoprotein (AFP) has been used as a serologic indicator of hepatocellular carcinoma (HCC). We aimed to identify an HCC-specific serum biomarker for diagnosis using a multiplexed proteomic technique in HCC patients with normal AFP levels. A total of 152 patients were included from Guro Hospital, Korea University. Among 267 identified proteins, 28 and 86 proteins showed at least a two-fold elevation or reduction in expression, respectively. Multiple reaction monitoring (MRM) analysis of 41 proteins revealed 10 proteins were differentially expressed in patients with liver cirrhosis and HCC patients with normal AFP. A combination of tripartite motif22 (Trim22), seprase, and bone morphogenetic protein1 had an area under receiver operating characteristic of 0.957 for HCC diagnosis. Real-time PCR and western blot analysis of the paired tumor/non-tumor liver tissue in HCC revealed a reduced expression of Trim22 in the tumor tissue. Also, serum levels of Trim22 were significantly reduced in HCC patients with normal AFP compared to those with liver cirrhosis (p = 0.032). Inhibition of Trim22 increased cellular proliferation in human hepatoma cell lines, whereas overexpression of Trim22 decreased cellular proliferation in hepatoma cell lines. In conclusion, the combination of three serum markers improved the chance of diagnosing HCC. MRM-based quantification of the serum protein in patients with normal AFP provides the potential for early diagnosis of HCC.

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