Prognostic Value of the Expression of DNA Repair–Related Biomarkers Mediated by Alcohol in Gastric Cancer Patients

Zhang, Yiyin; Wang, Hongyang; Yang, Feng; Ning, Jie; Li, Min; Zhao, Chenchen; Zhong, Shuming; Gu, Kai

doi:10.1016/j.ajpath.2017.10.010

Cited by 22 publications

(35 citation statements)

References 33 publications

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“…It suggests that upregulation of Brf1 and Pol III genes is closely related to liver tumorigenesis. These studies are consistent with recent reports that Brf1 is overexpressed in breast cancer, gastric cancer, and prostate carcinoma [10,38,39].…”

Section: Discussionsupporting

confidence: 93%

Mitogen- and Stress-Activated Protein Kinase 1 Mediates Alcohol-Upregulated Transcription of Brf1 and tRNA Genes to Cause Phenotypic Alteration

Lin

Huang

Ren

et al. 2020

Oxidative Medicine and Cellular Longevity

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Upregulation of Brf1 (TFIIB-related factor 1) and Pol III gene (RNA polymerase III-dependent gene, such as tRNAs and 5S rRNA) activities is associated with cell transformation and tumor development. Alcohol intake causes liver injury, such as steatosis, inflammation, fibrosis, and cirrhosis, which enhances the risk of HCC development. However, the mechanism of alcohol-promoted HCC remains to be explored. We have designed the complementary research system, which is composed of cell lines, an animal model, human samples, and experiments in vivo and in vitro, to carry out this project by using molecular biological, biochemical, and cellular biological approaches. It is a unique system to explore the mechanism of alcohol-associated HCC. Our results indicate that alcohol upregulates Brf1 and Pol III gene (tRNAs and 5S rRNA) transcription in primary mouse hepatocytes, immortalized mouse hepatocyte-AML-12 cells, and engineered human HepG2-ADH cells. Alcohol activates MSK1 to upregulate expression of Brf1 and Pol III genes, while inhibiting MSK1 reduces transcription of Brf1 and Pol III genes in alcohol-treated cells. The inhibitor of MSK1, SB-747651A, decreases the rates of cell proliferation and colony formation. Alcohol feeding promotes liver tumor development of the mouse. These results, for the first time, show the identification of the alcohol-response promoter fragment of the Pol III gene key transcription factor, Brf1. Our studies demonstrate that Brf1 expression is elevated in HCC tumor tissues of mice and humans. Alcohol increases cellular levels of Brf1, resulting in enhancement of Pol III gene transcription in hepatocytes through MSK1. Our mechanism analysis has demonstrated that alcohol-caused high-response fragment of the Brf1 promoter is at p-382/+109bp. The MSK1 inhibitor SB-747651A is an effective reagent to repress alcohol-induced cell proliferation and colony formation, which is a potential pharmaceutical agent. Developing this inhibitor as a therapeutic approach will benefit alcohol-associated HCC patients.

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Section: Discussionsupporting

confidence: 93%

Mitogen- and Stress-Activated Protein Kinase 1 Mediates Alcohol-Upregulated Transcription of Brf1 and tRNA Genes to Cause Phenotypic Alteration

Lin

Huang

Ren

et al. 2020

Oxidative Medicine and Cellular Longevity

Self Cite

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“…RPS-19, -21, -24 and ribosomal RNA) are upregulated in prostate cancer (PCa) [2,3]. BRF1 expression is elevated and associated with poor prognosis in hepatocellular, breast and gastric cancers [4][5][6] but its role in PCa remains unclear.…”

Section: Introductionmentioning

confidence: 99%

BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration

et al. 2019

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BRF1 is a rate-limiting factor for RNA Polymerase III-mediated transcription and is elevated in numerous cancers. Here, we report that elevated levels of BRF1 associate with poor prognosis in human prostate cancer. In vitro studies in human prostate cancer cell lines demonstrated that transient overexpression of BRF1 increased cell proliferation whereas the transient downregulation of BRF1 reduced proliferation and mediated cell cycle arrest. Consistent with our clinical observations, BRF1 overexpression in a Pten-deficient mouse (Pten Δ/Δ BRF1 Tg) prostate cancer model accelerated prostate carcinogenesis and shortened survival. In Pten Δ/Δ BRF1 Tg tumours, immune and inflammatory processes were altered, with reduced tumoral infiltration of neutrophils and CD4 positive T cells, which can be explained by decreased levels of complement factor D (CFD) and C7 components of the complement cascade, an innate immune pathway that influences the adaptive immune response. We tested if the secretome was involved in BRF1-driven tumorigenesis. Unbiased proteomic analysis on BRF1-overexpresing PC3 cells confirmed reduced levels of CFD in the secretome, implicating the complement system in prostate carcinogenesis. We further identify that expression of C7 significantly correlates with expression of CD4 and has the potential to alter clinical outcome in human prostate cancer, where low levels of C7 associate with poorer prognosis.

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“…A randomized clinical trial found that drinking could increase serum IL-10 while could decrease serum IL-16, monocyte chemotactic protein-1 and vascular cell adhesion molecule-1 (24). Even alcohol consumption could induce GC tissues expressing high levels of transcription factor IIB-related factor 1 and myeloperoxidase-positive cell infiltration, which were identified as independent prognostic factors for overall survival (25). Thus, championing of temperance in the high incidence area of GC was necessary.…”

Section: Controlsmentioning

confidence: 99%

Relationship between serum inflammatory cytokines and lifestyle factors in gastric cancer

Sun

Xiang

et al. 2019

mol clin onc

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Chronic inflammation is associated with increased risk of gastric cancer (GC), and GC risk is significantly associated with lifestyle. The aim of the present study was to explore the association between serum inflammatory cytokines and lifestyle factors in GC. A total of 20 serum inflammatory cytokines were measured in a hospital-based case-control population with 142 GC patients and 98 healthy controls. Controls without the selected healthy lifestyle factors were regarded as baseline, and correlation analysis was conducted to establish the association between serum inflammatory cytokines and lifestyle factors. The results demonstrated that several lifestyle factors (including eating fried and salty foods, eating quickly, smoking and drinking) could increase the risk of GC, while only eating fresh fruits could decrease the risk of GC. Correlation analysis revealed that increased serum interleukin (IL)-12/IL-23P40 levels was associated with GC risk as significant differences were observed in all lifestyle factors. Increased serum IL-8 was closely associated with smoking in GC patients, while increased IL-17α and IL-8 levels were associated with GC patients who ate salty foods. Increased IL-10 and decreased TGF-β levels were also associated with GC patients who ate fresh fruits. In conclusion, GC risk was strongly affected by lifestyle factors, which may regulate the expression of inflammatory cytokines and promote gastric carcinogenesis.

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Prognostic Value of the Expression of DNA Repair–Related Biomarkers Mediated by Alcohol in Gastric Cancer Patients

Cited by 22 publications

References 33 publications

Mitogen- and Stress-Activated Protein Kinase 1 Mediates Alcohol-Upregulated Transcription of Brf1 and tRNA Genes to Cause Phenotypic Alteration

Mitogen- and Stress-Activated Protein Kinase 1 Mediates Alcohol-Upregulated Transcription of Brf1 and tRNA Genes to Cause Phenotypic Alteration

BRF1 accelerates prostate tumourigenesis and perturbs immune infiltration

Relationship between serum inflammatory cytokines and lifestyle factors in gastric cancer

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