<i>PTEN/MMAC1</i> Mutations in Hepatocellular Carcinomas: Somatic Inactivation of Both Alleles in Tumors

Kawamura, Naoki; Nagai, Hisaki; Bando, Koichi; Koyama, Masaaki; Matsumoto, Satoshi; Tajiri, Takashi; Onda, Masahiko; Fujimoto, Jiro; Ueki, Takahiro; Konishi, Noboru; Shiba, Tadayoshi; Emi, Mitsuru

doi:10.1111/j.1349-7006.1999.tb00763.x

Cited by 48 publications

(35 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alterations, mainly mutations but also LOH, of PTEN have been reported in about 10% of HCC cases. Recently it was demonstrated that PTEN significantly lowers IGF secretion and also expression of secretory and cellular vascular endothelial growth factor proteins in HCC cell lines and could therefore inhibit tumorigenicity [19,42,62].…”

Section: Alterations Of the Tgf-β/igf-axismentioning

confidence: 99%

Genes involved in hepatocellular carcinoma: deregulation in cell cycling and apoptosis

Tannapfel

Wittekind

2002

Virchows Arch

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) accounts for 80-90% of liver cancers and is one of the most frequent carcinomas throughout the world. The disease is more prevalent in parts of Africa and Asia than in North and South America and Europe, with a strong etiological association with viral hepatitis, hemochromatosis, known liver (hepatic) carcinogens, and toxins (mycotoxins). Clinical and molecular medical analyses have yielded a considerable amount of information about liver carcinogenesis. Many genes undergo somatic aberrations, with a tendency to cluster at genes involved in cell cycle regulation, in the p53 and Wnt/catenin pathways of signal transduction and cellular adhesion, and in the TGF-beta/IGF axis. Since HCC may arise both in liver cirrhosis and in noncirrhotic liver, one may speculate that different hepatocarcinogenetic pathways exist. Recent results of high-output gene analysis using cDNA microarrays support the idea of different genetic alterations in HCC with or without cirrhosis.

show abstract

Section: Alterations Of the Tgf-β/igf-axismentioning

confidence: 99%

Genes involved in hepatocellular carcinoma: deregulation in cell cycling and apoptosis

Tannapfel

Wittekind

2002

Virchows Arch

View full text Add to dashboard Cite

show abstract

“…Mutations in another mismatch repair gene, referred to as MSH2, has been detected in about one-third of HCCs examined, and correlates with malignancy and poor survival (Yano et al, 1999). LOH at 10q may involve loss of the PTEN tumor suppressor gene at 10q23 and the MXI1 gene at 10q24-25 (Ding and Habib, 1995;Kawamura et al, 1999;Kusano et al, 1999). The former blocks growth stimulatory and survival signals mediated by PI3 kinase (Downward, 1998), while the latter appears to negatively regulate c-myc (Knuutila et al, 1999), which may partially explain how c-myc is overexpressed in most large tumors.…”

Section: Late Events In Hepatocarcinogenesis (Tumor Progression and Mmentioning

confidence: 99%

Genetic mechanisms of hepatocarcinogenesis

et al. 2002

View full text Add to dashboard Cite

The development of hepatocellular carcinoma (HCC) is a multistep process associated with changes in host gene expression, some of which correlate with the appearance and progression of tumor. Preneoplastic changes in gene expression result from altered DNA methylation, the actions of hepatitis B and C viruses, and point mutations or loss of heterozygosity (LOH) in selected cellular genes. Tumor progression is characterized by LOH involving tumor suppressor genes on many chromosomes and by gene ampli®cation of selected oncogenes. The changes observed in di erent HCC nodules are often distinct, suggesting heterogeneity on the molecular level. These observations suggest that there are multiple, perhaps redundant negative growth regulatory pathways that protect cells against transformation. An understanding of the molecular pathogenesis of HCC may provide new markers for tumor staging, for assessment of the relative risk of tumor formation, and open new opportunities for therapeutic intervention.

show abstract

“…The PTEN gene was initially identified by its frequent loss in glioblastomas (6), but subsequent studies have shown that PTEN is commonly mutated in prostate cancer (7)(8)(9)(10)(11)(12). In prostate tumors, the loss of PTEN occurs late in the tumorigenic process, suggesting that it is more important for tumor progression than tumor initiation (13,14).…”

mentioning

confidence: 99%

FOXO Proteins Regulate Tumor Necrosis Factor-related Apoptosis Inducing Ligand Expression

Modur

Nagarajan

Evers

et al. 2002

Journal of Biological Chemistry

343

299

View full text Add to dashboard Cite

Mutations in PTEN occur in 60 -80% of prostate cancers and lead to a constitutive activation of the phosphatidylinositol 3-kinase pathway and a resultant loss of activity of the FOXO family of forkhead transcription factors FKHRL1 and FKHR. To provide insight into the role of PTEN mutations in prostate cancer, we used microarrays to identify genes regulated by FKHRL1 and FKHR in LAPC4 prostate carcinoma cells. These studies revealed that adenoviral overexpression of FKHRL1 and FKHR in the LAPC4 prostate cancer cell line resulted in apoptosis and induced the expression of many genes that affect cellular proliferation or survival. The expression of one of these FOXO-regulated genes, TRAIL, a pro-apoptotic member of the tumor necrosis factor family, was decreased in human metastatic prostate tumors. The altered expression of TRAIL in these tumors correlated directly with decreased PTEN expression and the resultant loss of FKHRL1 and FKHR activity. Analysis of the effects of FOXO proteins on the TRAIL promoter localized the FKHRL1 responsive element of the TRAIL promoter to nucleotides ؊138 to ؊121 and demonstrated that TRAIL is a direct target of FKHRL1. These findings suggest that the decreased activity of FKHRL1 and FKHR in prostate cancers resulting from loss of PTEN leads to a decrease in TRAIL expression that may contribute to increased survival of the tumor cells.The forkhead transcription factors are DNA-binding proteins characterized by the presence of a conserved 110-amino acid winged helix DNA binding domain (1). They play important roles in embryogenesis, tumorigenesis, and maintenance of differentiation status. In Caenorhabditis elegans the forkhead transcription factor DAF-16 is under control of the insulin receptor/PI 3-kinase 1 pathway (2). The human orthologs of DAF-16 include FKHRL1, FKHR, and AFX and belong to the FOXO subfamily of forkhead transcription factors. The PI 3-kinase pathway, via activation of its downstream kinase Akt, phosphorylates each of the FOXO proteins at three different Ser/Thr residues (3). These phosphorylated FOXO proteins interact with 14-3-3 proteins and are subsequently sequestered in the cytoplasm where they are inactive. Inhibition of the PI 3-kinase pathway by PTEN overexpression or pharmacologic means leads to dephosphorylation and nuclear translocation of active FKHRL1, FKHR, and AFX, which in turn leads to cell cycle arrest and apoptosis (4). Conversely, loss of PTEN activity results in increased Akt activity leading to inhibition of FOXO protein activity through their phosphorylation and cytoplasmic sequestration. In addition, the expression of dominant negative FKHRL1 results in the inhibition of apoptosis, demonstrating that FOXO transcriptional activity controls cellular proliferation and apoptosis downstream of PTEN (5).The PTEN gene was initially identified by its frequent loss in glioblastomas (6), but subsequent studies have shown that PTEN is commonly mutated in prostate cancer (7-12). In prostate tumors, the loss of PTEN occurs late in the tumorigenic pro...

show abstract

PTEN/MMAC1 Mutations in Hepatocellular Carcinomas: Somatic Inactivation of Both Alleles in Tumors

Cited by 48 publications

References 23 publications

Genes involved in hepatocellular carcinoma: deregulation in cell cycling and apoptosis

Genes involved in hepatocellular carcinoma: deregulation in cell cycling and apoptosis

Genetic mechanisms of hepatocarcinogenesis

FOXO Proteins Regulate Tumor Necrosis Factor-related Apoptosis Inducing Ligand Expression

Contact Info

Product

Resources

About