The overall goal of this project is to elucidate the role of KLF6 tumor suppressor in hepatocellular cancer (HCC) a highly prevalent tumor in patients with liver disease and cirrhosis. In HCC, KLF6 is deleted and/or mutated in a number of tumors and accumulates in the cytoplasm of both preneoplastic and HCC cells, suggesting that dysregulation of KLF6 may also occur in a premalignant milieu. The hypotheses are that a) KLF6 is a growth suppressor in normal hepatocytes, and its inactivation through loss, mutation or alternative splicing contributes to the development of hepatocellular cancer and; b) Alternative splicing of KLF6 is an early event in malignant transformation of hepatocytes, leading to loss of wild type function and gain-of-function of new transcriptional targets that contribute to carcinogenesis. We will test these hypotheses by following three Specific Aims: 1) To correlate the relative expression of KLF6 alternative splice forms by real-time PCR with histologic progression from human to cirrhosis HCC, and examine the possible release of KLF6 splice form mRNA or protein into the circulation in patients with HCC; 2) To replicate KLF6 dysregulation associated with human HCC in mouse models by: a. Generating a liver transgenic mouse overexpressing the predominant splice form found in human HCC downstream of the transthyretin promoter; b. Determining the response of KLF6 mice, which are phenotypically normal, to carcinogenic stress induced by either chemical or genetic means (KLF6 -/- are embryonic lethal) c. Abrogating wild type KLF6 function in liver in vivo through administration of siRNA that specifically downregulates wild type but not splice forms of KLF6; 3. To generate animals with conditional deletion of KLF6 in adult mouse liver using a tamoxifen-inducible cre-recombinase vector. The findings from these studies could lead to important new insights into the pathogenesis of HCC, ultimately yielding novel diagnostic and therapeutic strategies for this often-fatal neoplasm in millions of patients at risk worldwide.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK037340-22
Application #
7251884
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Doo, Edward
Project Start
1987-01-01
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
22
Fiscal Year
2007
Total Cost
$329,471
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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