Role of Kruppler-like factor 6 in the hepatocellular carcinoma development

Hepatocellular cancer (HCC) is a highly prevalent neoplasm and common cause of death in patients with advanced liver disease and cirrhosis. While a growing number of molecular abnormalities have been identified, much is still unknown about its pathogenesis, particularly those early events that could lead to improved diagnosis and prognosis. The in vivo activity of KLF6, combined with its localization in humans on chromosomal locus 10P15, a commonly deleted region in many cancers, led to the evaluation of KLF6 as a bona fide tumor suppressor gene that might be lost and/or inactivated in human cancer. These efforts culminated in the discovery of KLF6 mutation and loss in a majority of human prostate cancers, a neoplasm evaluated initially because it reportedly harbored 10p deletions. Tumor-derived mutations of KLF6 were unable to upregulate p21, partially explaining the loss of growth suppression. Broader efforts at identifying both the prevalence of KLF6 inactivation in human cancer and the mechanisms of wild type KLF6 function have been remarkably fruitful, and validated by outside laboratories. KLF6 inactivation and/or loss have been identified in colorectal cancer, glioblastoma, ovarian cancer, and, most importantly, HCC. These exciting findings lead to key hypotheses that are tested in the experiments described in this study: KLF6 is a growth suppressor in normal hepatocytes, and its inactivation through loss, mutation or alternative splicing contributes to the development of HCC. To test these hypotheses 1. we correlated the relative expression of KLF6 by real-time PCR with histological progression from normal human liver to cirrhosis and HCC; 2. we replicated KLF6 dysregulation associated with human HCC in mouse models by determining the response of KLF6 +/- mice, which are phenotypically normal, to a chemical induced carcinogenic stress.