Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, reflecting incomplete characterization of underlying mechanisms and lack of early detection. Kru Β¨ppel-like factor 6 (KLF6) is a ubiquitously expressed zinc finger transcription factor that is deregulated in multiple cancers through loss of heterozygosity (LOH) and/or inactivating somatic mutation. We analyzed the potential role of the KLF6 tumor suppressor gene in 41 patients who had HCC associated with hepatitis C virus (16 patients), hepatitis B virus (12 patients, one of whom was coinfected with hepatitis C virus), and other etiologies (14 patients) by determining the presence of LOH and mutations. Overall, LOH and/or mutations were present in 20 (49%) of 41 tumors. LOH of the KLF6 gene locus was present in 39% of primary HCCs, and the mutational frequency was 15%. LOH and/or mutations were distributed across all etiologies of HCC evaluated, including patients who did not have cirrhosis. Functionally, wild-type KLF6 decreased cellular proliferation of HepG2 cells, while patient-derived mutants did not. In conclusion, we propose that KLF6 is deregulated by loss and/or mutation in HCC, and its inactivation may contribute to pathogenesis in a significant number of these tumors. (HEPATOLOGY 2004;40:1047-1052.) H epatocellular carcinoma (HCC) is the fifth most common cancer worldwide, typically arising within livers with cirrhosis in patients who have hepatitis B virus, hepatitis C virus, chronic alcohol abuse, and/or nonalcoholic fatty liver disease. The majority of HCCs are incurable, reflecting an incomplete understanding of pathogenic mechanisms and inadequate early detection.
Established genetic events in HCC include loss of tumor suppressor gene function through a combination of genetic and epigenetic events, including loss of an allele, mutation, or promoter methylation. 2-4 Amplification and/or mutation of oncogenes such as K-Ras and c-myc have also been described, as has cyclin overexpression. Combined, these studies highlight many genetic alterations that have been associated with the development and/or progression of HCC; however, many key pathways and gene involvement remain to be elucidated.
Kru Β¨ppel-like factor 6 (KLF6), a ubiquitously expressed zinc finger transcription factor, 6 has been identified as a tumor suppressor gene in prostate, 7,8 colon, 9 and nasopharyngeal 10 cancers, as well as astrocytic gliomas. 11 Moreover, downregulation of KLF6 messenger RNA levels has been described in lung and esophageal 14 cancers, the latter also being associated with promoter methylation. Reduced KLF6 expression levels in lung and prostate cancers have been reported ; the latter has also been correlated with increased likelihood of recurrence. 15 KLF6 also suppresses oncogenic transformation in glioblastoma. The principal aim of this study was to deter-