Frequent inactivation of the tumor suppressor Kruppel-like factor 6 ( KLF6 ) in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide, reflecting incomplete characterization of underlying mechanisms and lack of early detection. Krüppel-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.

In vivo regulation of p21 by the Kruppel-like factor 6 tumor-suppressor gene in mouse liver and human hepatocellular carcinoma

“…KLF6 LOH was reported in 36% of 14 informative HCC patient samples and somatic mutations were detected in three patient samples (Wang et al, 2004). These findings complement our original report describing frequent loss and somatic mutation in primary HCC tumor samples (Kremer-Tal et al, 2004). In a separate study, somatic mutations were identified in 8.7% of (Wang et al, 2004).…”

“…Functional inactivation of the KLF6 gene occurs through several mechanisms, including loss of heterozygosity (LOH), somatic mutation and/or increased alternative splicing that yields a dominantnegative splice isoform, KLF6-SV1. KLF6 dysregulation has been demonstrated in a number of human cancers including prostate (Narla et al, 2001;Chen et al, 2003), colorectal , non-smallcell lung (Ito et al, 2004), gastric (Cho et al, 2005), nasopharyngeal (Chen et al, 2002), hepatocellular (Kremer-Tal et al, 2004) and ovarian carcinomas (DiFeo et al, 2006b) as well as glioma (Jeng et al, 2003). Furthermore, decreased KLF6 mRNA expression is associated with reduced patient survival in prostate (Singh et al, 2002;Glinsky et al, 2004) and lung cancers (Kettunen et al, 2004).…”

KLF6 and TP53 mutations are a rare event in prostate cancer: distinguishing between Taq polymerase artifacts and true mutations

“…In contrast with the other studies, they only analyzed exon 2. None of the other studies included methods to [10][11][12][13] (ranging between 0 and 15%) and colorectal carcinoma [14][15][16][17][18] (ranging between 0 and 44%). Similar to prostate cancer, the first studies conducted on these other tumors indicated a high frequency of mutation, but this was not reproduced in subsequent reports.…”

“…9 The reported frequency of KLF6 mutations in different types of human cancer varies in the different published studies. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] In prostate cancer, four studies have analyzed the frequency of KLF6 mutations. 6,[30][31][32] In the first published study, Narla et al 6 showed a very high frequency, 55%, whereas in the following study, Chen et al 30 obtained a lower frequency, around 15%.…”

Recent updates of genetic and genomic alterations in hepatocellular carcinoma

“…[2][3][4] Other mutated genes such as SMAD2/SMAD4 in the transforming growth factor beta (TGF-β) pathway, caspase 8 (CASP8), and Kruppel-like factor 6 were identified with mutation frequency around 10% in HCC, [5][6][7] while most other mutated genes were identified with relatively low frequency of < 10% in HCC. [2] Germline mutations in the TP53 gene have been identified in patients with Li-Fraumeni syndrome, which is an inherited cancer predisposition syndrome characterized by a wide spectrum of neoplasms.…”