Chromosome assignment of aberrant NotI restriction DNA fragments in primary hepatocellular carcinoma

Yoshikawa, H; Nagai, Hisaki; Oh, Kyung Sook; Tamai, Shingo; Fujiyama, Asao; Nakanishi, Toshio; Kajiyama, Goro; Matsubara, Kazuo

doi:10.1016/s0378-1119(97)00251-5

Cited by 6 publications

(2 citation statements)

References 20 publications

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“…Using restriction landmark genomic scanning (RLGS) analysis in which genomic NotI sites were compared between normal and hepatocellular carcinoma (HCC) samples, an aberrant NotI site, termed spot 3, has been assigned to chromosome 17 in HCC (Yoshikawa et al, 1997). SOCS-3 has been reported to be silenced in lung cancer cells (He et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma

et al. 2005

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We identified that suppressor of cytokine signaling-3 (SOCS-3) gene was aberrantly methylated in its CpG island in three of 10 human hepatocellular carcinoma (HCC) cell lines. SOCS-3 RNA was undetectable in five of the 10 HCC cell lines including the three methylated cell lines, and a demethylating agent, 5-aza-2 0 -deoxycytidine, reactivated SOCS-3 expression in three cell lines tested. The DNA region where we found aberrant DNA methylation includes a signal transducers and activators of transcription (STAT) binding consensus sequence. When the DNA region was used as a promoter, DNA methylation markedly reduced promoter activity. SOCS-3 was also aberrantly methylated in six of 18 primary HCC samples. SOCS-3 expression was reduced in three of the three methylated and one of the three unmethylated primary samples examined. Restoration of SOCS-3 in cells lacking SOCS-3 expression suppressed STAT3 phosphorylation and cell growth. We found that IL-6 acted as a growth factor in HCC cells. Inhibition of SOCS-3 expression in cells whose growth was induced by IL-6 enhanced STAT3 phosphorylation and cell growth. In addition, AG490, a chemical JAK2 inhibitor, suppressed cell growth and downregulated STAT3 phosphorylation, but not FAK phosphorylation. We also found that SOCS-3 physically interacted with phosphorylated FAK and Elongin B in HCC cells. Restoration of SOCS-3 decreased FAK phosphorylation as well as FAK protein level. Inhibition of SOCS-3 expression increased FAK phosphorylation, resulting in enhancement of cell migration. These data indicate that SOCS-3 negatively regulates cell growth and cell motility by inhibiting Janus kinase (JAK)/STAT and FAK signalings in HCC cells. Thus, loss of SOCS-3 by the associated DNA methylation confers cells advantage in growth and migration.

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Section: Introductionmentioning

confidence: 99%

Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma

et al. 2005

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“…Another aberrant NotI restriction DNA fragment that reduced the intensity in HCC samples compared with the normal counterparts has been found in the RLGS analysis (Nagai et al, 1994). This DNA contained a part of the human WNT10B gene, and it was mapped to chromosome 12q13 (Yoshikawa et al, 1997), where WNT10B is localized (Bui et al, 1997). Because WNT10B has been minimally studied in human cancer, we analyzed promoter DNA methylation, expression, and functions with respect to tumor development.…”

Section: Introductionmentioning

confidence: 99%

WNT10B Functional Dualism: β-Catenin/Tcf-dependent Growth Promotion or Independent Suppression with Deregulated Expression in Cancer

Yoshikawa

Matsubara

Zhou

et al. 2007

MBoC

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We found aberrant DNA methylation of the WNT10B promoter region in 46% of primary hepatocellular carcinoma (HCC) and 15% of colon cancer samples. Three of 10 HCC and one of two colon cancer cell lines demonstrated low or no expression, and 5-aza-2'deoxycytidine reactivated WNT10B expression with the induction of demethylation, indicating that WNT10B is silenced by DNA methylation in some cancers, whereas WNT10B expression is up-regulated in seven of the 10 HCC cell lines and a colon cancer cell line. These results indicate that WNT10B can be deregulated by either overexpression or silencing in cancer. We found that WNT10B up-regulated beta-catenin/Tcf activity. However, WNT10B-overexpressing cells demonstrated a reduced growth rate and anchorage-independent growth that is independent of the beta-catenin/Tcf activation, because mutant beta-catenin-transduced cells did not suppress growth, and dominant-negative hTcf-4 failed to alleviate the growth suppression by WNT10B. Although WNT10B expression alone inhibits cell growth, it acts synergistically with the fibroblast growth factor (FGF) to stimulate cell growth. WNT10B is bifunctional, one function of which is involved in beta-catenin/Tcf activation, and the other function is related to the down-regulation of cell growth through a different mechanism. We suggest that FGF switches WNT10B from a negative to a positive cell growth regulator.

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Molecular Genetic Alterations in Primary Hepatocellular Neoplasms

Grisham¹

2002

The Molecular Basis of Human Cancer

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Chromosome assignment of aberrant NotI restriction DNA fragments in primary hepatocellular carcinoma

Cited by 6 publications

References 20 publications

Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma

Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma

WNT10B Functional Dualism: β-Catenin/Tcf-dependent Growth Promotion or Independent Suppression with Deregulated Expression in Cancer

Molecular Genetic Alterations in Primary Hepatocellular Neoplasms

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