Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation

Kremer-Tal, Sigal; Narla, Goutham; Chen, Yingbei; Hod, Eldad A.; DiFeo, Analisa; Yea, Steven; Lee, Ju Seog; Schwartz, Myron; Thung, Swan N.; Fiel, Isabel; Banck, Michaela S.; Zimran, Eran; Thorgeirsson, Snorri S.; Mazzaferro, Vincenzo; Bruix, Jordi; Martignetti, John A.; Llovet, Josep M.; Friedman, Scott L.

doi:10.1016/j.jhep.2006.10.012

Cited by 79 publications

(84 citation statements)

References 40 publications

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“…Functional inactivation of the KLF6 gene, including loss of heterozygosity (LOH), somatic mutation, and/or increased alternative splicing, has been implicated in a number of human cancers, including prostate [5,6], colorectal [7,8], nonsmall cell lung [9,10], gastric [11], glioma [12,13], nasopharyngeal [14], hepatocellular [15][16][17][18], pancreatic [19], and ovarian carcinomas [20]. To date, three alternatively spliced KLF6 isoforms, KLF6-SV1, -SV2 and -SV3, have been identified [21].…”

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confidence: 99%

A small interfering RNA targeting the KLF6 splice variant, KLF6-SV1, as gene therapy for gastric cancer

Chen

Sun

et al. 2011

Gastric Cancer

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Background Accumulating evidence suggests that the tumor suppressor gene Kruppel-like factor 6 (KLF6) and its dominant-negative splice form KLF6-SV1 play important roles in both the development and progression of cancer. However, the role of KLF6-SV1 in gastric cancer remains largely unknown. Methods KLF6-SV1 expression was detected in various human gastric cancer cell lines and gastric cancer patient samples by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting. Small interfering RNA (siRNA) was used to inhibit KLF6-SV1 expression in BGC-823 and SGC-7901 cell lines. The effects of downregulation of KLF6-SV1 by siRNA on cell proliferation, migration, invasion, and tumor growth were examined in vitro and in vivo.

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Section: Introductionmentioning

confidence: 99%

A small interfering RNA targeting the KLF6 splice variant, KLF6-SV1, as gene therapy for gastric cancer

Chen

Sun

et al. 2011

Gastric Cancer

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“…Combined, these results suggest that KLF6 is a critical regulator of hepatocyte proliferation and liver size in vivo, at least in part through upregulation of the cyclin-dependent kinase inhibitor p21. We have previously described decreased wtKLF6 mRNA expression in primary HCC samples compared with matched surrounding tissue (ST) (Kremer-Tal et al, 2006). ST analysed here were either cirrhotic or non cirrhotic livers (Lee et al, 2004;see Supplementary Figure 4).…”

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confidence: 99%

“…However, methodologic differences may account for these discrepant results (Narla et al, 2003). We and others have demonstrated significant downregulation of wtKLF6 expression by both quantitative real-time polymerase chain reaction (qRT-PCR) analysis and microarray studies in both HBV-and HCV-derived HCC patient samples (Lee et al, 2004;Kremer-Tal et al, 2006). Although the frequency of somatic mutation in the KLF6 gene is quite variable, the bulk of evidence from published studies supports a role for the KLF6 tumor-suppressor gene in the development and progression of HCC, through either KLF6 loss and/ or somatic mutation and decreased wtKLF6 expression.…”

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

et al. 2007

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Kruppel-like factor (KLF) 6 is a tumor-suppressor gene functionally inactivated by loss of heterozygosity, somatic mutation and/or alternative splicing that generates a dominant-negative splice form, KLF6-SV1. Wild-type KLF6 (wtKLF6) expression is decreased in many human malignancies, which correlates with reduced patient survival. Additionally, loss of the KLF6 locus in the absence of somatic mutation in the remaining allele occurs in a number of human cancers, raising the possibility that haploinsufficiency of the KLF6 gene alone contributes to cellular growth dysregulation and tumorigenesis. Our earlier studies identified the cyclin-dependent kinase inhibitor p21 as a transcriptional target of the KLF6 gene in cultured cells, but not in vivo. To address this issue, we have generated two genetic mouse models to define the in vivo role of KLF6 in regulating cell proliferation and p21 expression. Transgenic overexpression of KLF6 in the liver resulted in a runted phenotype with decreased body and liver size, with evidence of decreased hepatocyte proliferation, increased p21 and reduced proliferating cell nuclear antigen expression. In contrast, mice with targeted deletion of one KLF6 allele (KLF6 þ /À) display increased liver mass with reduced p21 expression, compared to wild type littermates. Moreover, in primary hepatocellular carcinoma samples, there is a significant correlation between wtKLF6 and p21 mRNA expression. Combined, these data suggest that haploinsufficiency of the KLF6 gene may regulate cellular proliferation in vivo through decreased transcriptional activation of the cyclin-dependent kinase inhibitor p21. Oncogene (2007) 26, 4428-4434; doi:10.1038/sj.onc.1210223; published online 5 February 2007 Keywords: KLF6; Kruppel-like factor; tumor-suppressor gene; p21; haploinsufficiency Kruppel-like factor 6 (KLF6) belongs to the Kruppellike family of transcription factors, which play roles in the regulation of diverse cellular processes including development, differentiation, proliferation and apoptosis (Bieker, 2001). 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). Interestingly, reconstitution of KLF6 decreases cell proliferation and reverts tumorigenicity in glioblastoma cell lines (Kimmelman et al., 2004).Depending on the cell type and context, KLF6's growth-suppressive prop...

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“…Decreased expression of KLF6 has been associated with poor prognosis in lung adenocarcinoma and prostate cancer. 30,[36][37][38][39] The role that KLF6 polymorphisms play in increasing the risk of developing prostate cancer is also controversial. Narla et al 40 proposed that the presence of a germline single-nucleotide polymorphism (SNP) (IVS1 -27G4A) in KLF6 could produce a splicing variant that would reduce the activation of p21.…”

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

et al. 2008

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Krü ppel-like factor 6 (KLF6) has been reported to act as a tumor suppressor gene involved in the regulation of the cell cycle by activating p21 in a p53-independent manner. Many studies suggest that KLF6 is inactivated by allelic loss and somatic mutation. However, there is a high variability in the reported frequency of mutations (from 1 to 55%). TP53 also regulates the cell cycle through the activation of p21. In prostate cancer, the reported frequency of TP53 mutations ranges from 3 to 42%. In all these reports, there is a considerable degree of methodological heterogeneity. Our aim was to determine the frequency of KLF6 and TP53 mutations in a welldefined group of prostate tumors with different stages and Gleason grades. The four exons of KLF6 and exons 4-9 of TP53 were studied in 103 cases, including 90 formalin-fixed, paraffin-embedded (FFPE) and 13 frozen samples. All tumors were analyzed through PCR and direct sequencing. All changes found were confirmed by a second independent PCR and sequencing reaction. For KLF6, mutation (E227G) was only detected in one tumor (1%) and for TP53, three different mutations (L130H, H214R, and Y234C) were detected in five tumors (5%). This low mutation index is in keeping with recent papers on the subject. Our study strongly supports the notion that KLF6 and TP53 mutations are not frequent events in prostate cancer. When using FFPE tissues, it is mandatory to perform at least two independent rounds of PCR and sequencing to confirm mutations and exclude Taq polymerase-induced artifacts. Two of these genes are Krü ppel-like factor 6 (KLF6) and TP53.KLF6 is a transcription factor that interacts with DNA through three zinc-fingers in its COOHterminal domain. KLF6 belongs to the KLF family, a family that is broadly involved in cell differentiation, development, growth-related signal transduction, cell proliferation, apoptosis, and angiogenesis. 5 It has been suggested that KLF6 could be involved in the regulation of the cell cycle by activating p21 in a p53-independent manner. 6 This has been proven in several in vitro 5 and in vivo assays. 7 KLF6 is believed to regulate cancer development and progression through the downregulation of the c-Jun oncoprotein 8 and the activation of E-cadherin. 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%. The results of two recent reports provided frequencies of 0 and 1%. 31,32 It should be noted that there were considerable

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Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation

Cited by 79 publications

References 40 publications

A small interfering RNA targeting the KLF6 splice variant, KLF6-SV1, as gene therapy for gastric cancer

A small interfering RNA targeting the KLF6 splice variant, KLF6-SV1, as gene therapy for gastric cancer

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

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

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