Transcriptional regulation of the apolipoprotein F (ApoF) gene by ETS and C/EBPα in hepatoma cells

Shen, Xuwei; Huang, Ling; Shao-hong, Zhang; Wang, Deping; Wu, Yunli; Chen, Wan-Nan; Xu, Shuai; Lin, Xu

doi:10.1016/j.biochi.2015.02.013

Cited by 15 publications

(11 citation statements)

References 41 publications

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“…Deletion or mutation of the biding site abolished AMACR expression in these tissues, suggesting that this site is one of the primary mediators of AMACR expression, although the definitive transcription factor binding to this C/EBP site has not been identified yet. ETS protein family members have been shown to interact with C/EBP and act synergistically to induce gene expression of p21 and apolipoprotein F in hepatocytes [53,54]. Since the TMPRSS2-ERG fusion contains the DNA binding/interaction domain, it is possible that interaction with the ERG fusion protein and as of yet unidentified C/EBP family member may link ERG and AMACR expression molecularly.…”

Section: Discussionmentioning

confidence: 97%

High alpha-methylacyl-CoA racemase (AMACR) is associated with ERG expression and with adverse clinical outcome in patients with localized prostate cancer

et al. 2016

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Alpha-methylacyl-CoA racemase (AMACR) is a well-characterized marker extensively utilized in prostate cancer (PCA) diagnosis. However, the prognostic value of AMACR expression and its relation to TMPRSS2-ERG gene rearrangement as one of the most common molecular alterations in PCA is not fully explored. AMACR expression was investigated in a cohort of 218 men with localized PCA treated by radical prostatectomy and correlated with ERG and various clinical and pathological parameters. In vitro studies assessed AMACR changes to ERG knockdown and other related genes. In addition, bioinformatics validated the significance of AMACR/ERG expression and assessed relevant genetic signatures in relation to AMACR/ERG expression. AMACR expression was significantly associated with disease progression and with ERG (p ∼0). Seventeen percent of cancer foci showed negative/weak AMACR expression while being ERG positive. High AMACR expression was significantly associated with positive surgical margins (p = 0.01), specifically in tumors with lower Gleason score <7, with ∼95 % exhibiting positive surgical margin (p = 0.008). High AMACR showed marginal association with PSA biochemical recurrence (BCR) (p = 0.06) which was slightly more pronounced in ERG-positive tumors (p = 0.04). This was validated in other public cohorts. However, in this cohort, the association with BCR was not statistically significant in multivariate analysis (p = 0.09). Using in vitro cellular models, AMACR messenger RNA (mRNA) expression, but not protein levels, showed an association with ERG expression. We report for the first time a significant association between AMACR and ERG with prognostic implication. Patients with high AMACR/ERG-positive PCA may be at higher risk for disease progression, and additional studies in larger cohorts are needed to confirm the above findings. Functional studies investigating the molecular pathways connecting AMACR and ERG may provide an additional insight into PCA progression pathways.

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Section: Discussionmentioning

confidence: 97%

High alpha-methylacyl-CoA racemase (AMACR) is associated with ERG expression and with adverse clinical outcome in patients with localized prostate cancer

et al. 2016

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“…The members of the C/EBP family are important players involved in the regulation of ApoF expression in hepatoma cell lines [18]. The C/EBP family comprises six related proteins from the larger family of basic region leucine zipper (bZIP) transcription factors; among these proteins, C/EBPα and C/EBPβ expression is enriched in the liver [19–21].…”

Section: Discussionmentioning

confidence: 99%

Decreased expression of ApoF associates with poor prognosis in human hepatocellular carcinoma

Wang

Zhou

Ling

et al. 2019

Gastroenterology Report

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BackgroundHepatocellular carcinoma (HCC) is frequently associated with metabolism dysfunction. Increasing evidence has demonstrated the crucial role of lipid metabolism in HCC progression. The function of apolipoprotein F (ApoF), a lipid transfer inhibitor protein, in HCC is incompletely understood. We aimed to evaluate the functional role of ApoF in HCC in this study.MethodsWe used quantitative reverse-transcription polymerase chain reaction (qRT-PCR) to detect ApoF mRNA expression in HCC tissues and hepatoma cell lines (SMMC-7721, HepG2, and Huh7). Immunohistochemistry was performed to detect the expression of ApoF in HCC tissues. The associations between ApoF expression and clinicopathological features as well as HCC prognosis were analyzed. The effect of ApoF on cellular proliferation and growth of SMMC-7721 and Huh7 cells was examined in vitro and in vivo.ResultsApoF expression was significantly down-regulated at both mRNA and protein levels in HCC tissues as compared with adjacent tissues. In SMMC-7721 and Huh7 HCC cells, ApoF overexpression inhibited cell proliferation and migration. In a xenograft nude mouse model, ApoF overexpression effectively controlled HCC growth. Kaplan–Meier analysis results showed that the recurrence-free survival rate of HCC patients with low ApoF expression was significantly lower than that of other HCC patients. Low ApoF expression was associated with several clinicopathological features such as liver cirrhosis, Barcelona Clinic Liver Cancer stage and tumor-node-metastasis stage.ConclusionsApoF expression was down-regulated in HCC, which was associated with low recurrence-free survival rate. ApoF may serve as a tumor suppressor in HCC and be a potential application for the treatment of this disease.

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“…Ets-1, generally viewed as a transcription factor, is widely expressed in multiple cells and tissues 34 . Although Ets-1 participates in apolipoprotein F transcription, the exact function of Ets-1 in hepatocytes remains unknown 35 . This study investigated whether Ets-1 was directly regulated by Smad2/3 in primary hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

Ets-1 deficiency alleviates nonalcoholic steatohepatitis via weakening TGF-β1 signaling-mediated hepatocyte apoptosis

Wang

et al. 2019

Cell Death Dis

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Hepatocyte apoptosis is a hallmark of nonalcoholic steatohepatitis (NASH) and contributes to liver injury, fibrosis, and inflammation. However, the molecular mechanisms underlying excessive hepatocyte apoptosis in NASH remain largely unknown. This study aimed to explore whether and how the v-ets avian erythroblastosis virus E26 oncogene homolog 1 (Ets-1) is involved in diet-induced hepatocyte apoptosis in mice. The study found that the expression level of hepatic Ets-1 was elevated in a NASH mouse model as a result of the activation of transforming growth factor beta1 (TGF-β1) signaling. In the presence of TGF-β1, phosphorylated mothers against decapentaplegic homolog 2/3 (p-Smad2/3) translocated to the binding sites of the Ets-1 promoter to upregulate the expression of Ets-1 in primary hepatocytes. In addition, Ets-1 bound directly to phosphorylated Smad3 (p-Smad3), thereby preventing the ubiquitination and proteasomal degradation of p-Smad3 and enhancing the activity of TGF-β1/Smad3 signaling. Consequently, elevated Ets-1 stimulated TGF-β1-induced hepatocyte apoptosis. However, Ets-1 knockdown alleviated diet-induced hepatocyte apoptosis and NASH with reduced liver injury, inflammation, and fibrosis. Taken together, Ets-1 had an adverse impact on hepatocyte survival under TGF-β1 treatment and accelerated the development of NASH in mice.

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Transcriptional regulation of the apolipoprotein F (ApoF) gene by ETS and C/EBPα in hepatoma cells

Cited by 15 publications

References 41 publications

High alpha-methylacyl-CoA racemase (AMACR) is associated with ERG expression and with adverse clinical outcome in patients with localized prostate cancer

High alpha-methylacyl-CoA racemase (AMACR) is associated with ERG expression and with adverse clinical outcome in patients with localized prostate cancer

Decreased expression of ApoF associates with poor prognosis in human hepatocellular carcinoma

Ets-1 deficiency alleviates nonalcoholic steatohepatitis via weakening TGF-β1 signaling-mediated hepatocyte apoptosis

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