Alcohol consumption is generally thought to enhance liver fibrosis. Alcohol-induced liver fibrosis promotes formation of cirrhosis, which increases a risk of liver cancer. Cancer cells have a consistent cytological feature of nucleolar hypertrophy, enlarged nucleoli, where rRNAs are synthesized by RNA pol I and pol III. This implies that transformation in situ is closely linked to the deregulation of RNA pol I- and III-dependent transcription, because the size of the nucleolus reflects the levels of rRNA synthesis. RNA pol III genes encode a variety of untranslated RNAs, including tRNAs and 5S rRNAs. Deregulation of RNA pol III-dependent transcription, enhancing cellular tRNAs and 5S rRNAs production, leads to an increase in translational capacity to promote cell transformation. Although alcohol has been widely studied, nothing is yet known as to whether the transcription of RNA pol III-dependent genes might be affected by alcohol. Since deregulation of RNA pol III-dependent transcription is closely associated with cancers, addressing how alcohol affects this transcription will dramatically elevate our understanding of liver cancer development. Studies have shown that alcohol is able to activate MAP kinases, which are tightly linked to human cancers. Our hypothesis is that alcohol induces stress, activates MAP kinases, particularly the c-Jun N-terminal kinase-1 (JNK1), and increases RNA pol III- dependent transcription, leading to tumor development. First, we will test whether alcohol induces a major class of genes of RNA pol III-dependent transcription, tRNAs, in vivo and in vitro. Second, we will identify alcohol- induced changes in machinery of RNA pol III transcription. Third, we will further investigate the specific signal transduction pathways mediating the alcohol-induced deregulation of RNA pol III-dependent transcription. In addition, we will use liver tissues from chronically alcohol-fed NS5A transgenic mice and intragastric ethanol infusion mice to further identify the changes in RNA pol III-dependent transcription in vivo. Elucidating these key molecular events triggered by alcohol will provide new insights into the pathogenesis of alcohol-induced liver cancer to develop new therapeutic strategies for recovery from liver cancer. Public Health Relevance: The project seeks to elucidate the mechanism of alcohol-induced RNA pol III-dependent transcription in liver cancer and identify the specific pathway by determining MAP kinases, JNK1 and JNK2. Our new discovers of alcohol-induced changes in RNA pol III transcription machinery and our preliminary studies will provide valuable information to develop new drugs to therapy alcohol-associate liver diseases.

Public Health Relevance

The project seeks to elucidate the mechanism of alcohol-induced RNA pol III-dependent transcription in liver cancer and identify the specific pathway by determining MAP kinases, JNK1 and JNK2. Our new discovers of alcohol-induced changes in RNA pol III transcription machinery and our preliminary studies will provide valuable information to develop new drugs to therapy alcohol-associate liver diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AA017288-02
Application #
7847685
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Murray, Gary
Project Start
2009-06-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2012-05-31
Support Year
2
Fiscal Year
2010
Total Cost
$243,125
Indirect Cost
Name
University of Southern California
Department
Biochemistry
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Shi, Ganggang; Zhong, Shuping (2017) Alcohol-associated cancer and deregulation of Pol III genes. Gene 612:25-28
Yi, Yunfeng; Huang, Chenghao; Zhang, Yanmei et al. (2017) Exploring a common mechanism of alcohol-induced deregulation of RNA Pol III genes in liver and breast cells. Gene 626:309-318
Lei, Junxia; Chen, Songlin; Zhong, Shuping (2017) Abnormal expression of TFIIIB subunits and RNA Pol III genes is associated with hepatocellular carcinoma. Liver Res 1:112-120
Fang, Zeng; Yi, Yunfeng; Shi, Ganggang et al. (2017) Role of Brf1 interaction with ER?, and significance of its overexpression, in human breast cancer. Mol Oncol 11:1752-1767
Zhong, Qian; Xi, Shaoyan; Liang, Jianzhong et al. (2016) The significance of Brf1 overexpression in human hepatocellular carcinoma. Oncotarget 7:6243-54
Zhong, Qian; Shi, Ganggang; Zhang, Yanmei et al. (2015) Alteration of BRCA1 expression affects alcohol-induced transcription of RNA Pol III-dependent genes. Gene 556:74-9
Zhong, Qian; Shi, Ganggang; Zhang, Qingsong et al. (2014) Tamoxifen represses alcohol-induced transcription of RNA polymerase III-dependent genes in breast cancer cells. Oncotarget 5:12410-7
Zhang, Qingsong; Jin, Jian; Zhong, Qian et al. (2013) ER? mediates alcohol-induced deregulation of Pol III genes in breast cancer cells. Carcinogenesis 34:28-37
Zhong, Qian; Shi, Ganggang; Zhang, Yanmei et al. (2013) Elk1 and AP-1 sites in the TBP promoter mediate alcohol-induced deregulation of Pol III-dependent genes. Gene 526:54-60
Zhong, Qian; Shi, Ganggang; Zhang, Qingsong et al. (2013) Role of phosphorylated histone H3 serine 10 in DEN-induced deregulation of Pol III genes and cell proliferation and transformation. Carcinogenesis 34:2460-9

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