PTEN/MMAC1 Mutation and Frequent Loss of Heterozygosity Identified in Chromosome 10q in a Subset of Hepatocellular Carcinomas

Fujiwara, Yoshiyuki; Hoon, Dave S.B.; Yamada, Terumasa; Umeshita, Koji; Gotoh, Mitsukazu; Sakon, Masato; Nishisho, Isamu; Monden, Morito

doi:10.1111/j.1349-7006.2000.tb00943.x

Cited by 51 publications

(40 citation statements)

References 31 publications

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“…Both PTEN and DMBT1 were only altered in 25 ± 30% of glioblastomas, and in a signi®cant number of tumors with heterozygous deletions of 10q, alterations in either PTEN or DMBT1 could not be found (Liu et al, 1997;Tohma et al, 1998;Maier et al, 1998;Somerville et al, 1998;von Deimling et al, 2000). This lack of mutations in these genes was also demonstrated for other tumors which show frequent loss of distal regions of 10q, such as carcinomas of the respiratory tract (Petersen et al, 2000), melanoma (Herbst et al, 1999), endometrial cancers (Simpkins et al, 1998), hepatocellular carcinomas (Fujiwara et al, 2000;Yeh et al, 2000) and prostate carcinoma (Dong et al, 1998). Since Northern blot analysis indicates that WDR11 is expressed in a wide variety of human tissues, it may be a target for inactivation in these tumors as well.…”

Section: Discussionmentioning

confidence: 93%

A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells

et al. 2001

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Section: Discussionmentioning

confidence: 93%

A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells

et al. 2001

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“…In this survey, the 2 HCC cell lines, MAL-HAVU and NUK1, which both display HDs at the PTEN locus, were established from tumors with specific clinicopathologic contexts: in contrast to the majority of the HCC-derived cell line(s) analyzed, MALHAVU was established from an African patient whereas NUK1 was obtained from a metastatic HCC. 42 It is thus possible that PTEN is involved only in a specific subset of HCCs. In our screen, we also identified LRPDIT as a novel liver candidate TSG.…”

Section: Discussionmentioning

confidence: 99%

Homozygous Deletion Scanning in Hepatobiliary Tumor Cell Lines Reveals Alternative Pathways for Liver Carcinogenesis

et al. 2003

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Despite high rates of loss of heterozygosity affecting various chromosomes, the number of tumor suppressor genes (TSGs) found to be consistently involved in primary liver cancer is low. In the past decade, characterization of homozygous deletions (HDs) in tumors has become instrumental to identify new TSGs or to reveal the influence of a particular TSG on the development of a specific tumor type. We performed a detailed HD profiling at 238 critical loci on a collection of 57 hepatobiliary tumor cell lines (hepatocellular, cholangiocellular, and bile duct carcinomas, hepatoblastomas, and immortalized hepatocytes). We identified HDs at 9 independent loci, the analysis of which was extended to 17 additional hepatobiliary tumor cell lines. In total, 34 homozygous losses involving 9 distinct genes were detected in the 74 cell lines analyzed. Besides expected deletions at the p16-INK4A/p14-ARF, FHIT, AXIN1, and p53 genes, we detected HDs at the PTEN, NF2, STK11, BAX, and LRPDIT genes that were formerly not known to be implicated in human liver tumorigenesis. In conclusion, our data suggest that these genes may represent novel liver tumor suppressive targets. Additional tumorigenic pathways should be carefully considered in hepatocarcinogenesis. ( H epatocellular carcinoma (HCC), the main histologic form of primary liver cancer, is one of the most prevalent human tumors in the world. 1,2 Chronic infections of the liver by hepatitis B or hepatitis C viruses represent the dominant etiologies of HCC. 3 The historically recent spread of hepatitis C virus in human populations will result in a substantial increase in HCC incidence in developed countries and several epidemiologic surveys already have detected such a trend for the past 20 years in Japan, the United States, and Europe. 4,5 Until recently, chromosomal abnormalities occurring in HCC were defined poorly. We and others have performed allelotyping and comparative genomic hybridization studies to characterize the main chromosome targets in human liver tumorigenesis. 6-8 Only a handful of cancer genes are, however, consistently found mutated in this tumor type. p53 and AXIN1 genes are inactivated by somatic mutations in, respectively, 30% and 5% of cases, whereas p16-INK4A and SOCS1 are silenced through promoter hypermethylation in more than 50% of cases. 9-13 Finally, ␤-catenin, the only proto-oncogene previously found to be mutated in liver cancer, is activated in 20% of the samples. 14 The liver tumor-suppressive function of the product of the mannose-6-phosphate/insulinlike growth factor 2 receptor (IGF2/M6PR) gene is suspected but remains still controversial. 15,16 The past decade has seen the isolation of numerous tumor suppressor genes (TSGs) through the characterization of homozygous deletions (HDs) in primary tumors and cell lines. Although, HDs represent rare events, many of the TSG isolations, including WT1, p16-INK4A, BRCA2, FHIT, PTEN, SMAD4, and SNF5, were at least partly attributable to their detection. [17][18][19][20][21][22] In an attempt to

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“…Loss of this important tumor suppressor gene product, which modulates PI3K activity, occurs in a variety of human neoplasms (Steck et al, 1997). Mutational inactivation of PTEN has been detected in human HCC (Fujiwara et al, 2000;Yao et al, 1999;Yeh et al, 1999). Another phosphoinositide-speci®c phosphatase SHIP has been described (Lioubin et al, 1996;Dame et al, 1996).…”

Section: Roles Of Pi3k-mediated Nf-kb Activation Pathway In Hepatocarmentioning

confidence: 99%

Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling

et al. 2002

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The expression of P-glycoprotein encoded by the multidrug resistance (MDR1) gene is associated with the emergence of the MDR phenotype in cancer cells. Human MDR1 and its rodent homolog mdr1a and mdr1b are frequently overexpressed in liver cancers. However, the underlying mechanisms are largely unknown. The hepatocarcinogen 2-acetylamino¯uorene (2-AAF) e ciently activates rat mdr1b expression in cultured cells and in Fisher 344 rats. We recently reported that activation of rat mdr1b in cultured cells by 2-AAF involves a cis-activating element containing a NFkB binding site located 7167 to 7158 of the rat mdr1b promoter. 2-AAF activates IkB kinase (IKK), resulting in degradation of IkBb and activation of NF-kB. In this study, we report that 2-AAF could also activate the human MDR1 gene in human hepatoma and embryonic ®broblast 293 cells. Induction of MDR1 by AAF was mediated by DNA sequence located at 76092 which contains a NF-kB binding site. Treating hepatoma cells with 2-AAF activated phosphoinositide 3-kinase (PI3K) and its downstream e ectors Rac1, and NAD(P)H oxidase. Transient transfection assays demonstrated that constitutively activated PI3K and Rac1 enhanced the activation of the MDR1 promoter by 2-AAF. Treatment of hepatoma cells with 2-AAF also activated another PI3K downstream e ector Akt. Transfection of recombinant encoding a dominant activated Akt also enhanced the activation of MDR1 promoter activation by 2-AAF. These results demonstrated that 2-AAF up-regulates MDR1 expression is mediated by the multiple e ectors of the PI3K signaling pathway.

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PTEN/MMAC1 Mutation and Frequent Loss of Heterozygosity Identified in Chromosome 10q in a Subset of Hepatocellular Carcinomas

Cited by 51 publications

References 31 publications

A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells

A novel member of the WD-repeat gene family, WDR11, maps to the 10q26 region and is disrupted by a chromosome translocation in human glioblastoma cells

Homozygous Deletion Scanning in Hepatobiliary Tumor Cell Lines Reveals Alternative Pathways for Liver Carcinogenesis

Induction of human MDR1 gene expression by 2-acetylaminofluorene is mediated by effectors of the phosphoinositide 3-kinase pathway that activate NF-κB signaling

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