Hepatocyte Nuclear Factor (HNF)‐4α Induces Expression of Endothelial Fas Ligand (FasL) to Prevent Cancer Cell Transmigration: A Novel Defense Mechanism of Endothelium against Cancer Metastasis

Osanai, Makoto; Chiba, Hideki; Kojima, Takashi; Fujibe, Masato; Kuwahara, Kazuhide; Kimura, Hiromichi; Satoh, Masaaki; Sawada, Norimasa

doi:10.1111/j.1349-7006.2002.tb01288.x

Cited by 20 publications

(11 citation statements)

References 46 publications

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“…Consistent with that idea, Lazarevich et al (2004) reported that expression of HNF4a is downregulated in hepatocellular carcinoma and its restoration suppresses tumour growth. It has also been reported that HNF4a is downregulated in other types of tumours (Lemm et al, 1999) and that it induces expression of endothelial Fas ligand (FasL), which prevents cancer cell transmigration (Osanai et al, 2002). Collectively then, the summarised findings suggest that impairment of the HNF1b/ HNF4a signalling network may lead to tumour formation.…”

Section: Discussionmentioning

confidence: 89%

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

et al. 2006

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Transcription factor 2 gene (TCF2) encodes hepatocyte nuclear factor 1b (HNF1b), a transcription factor associated with development and metabolism. Mutation of TCF2 has been observed in renal cell cancer, and by screening aberrantly methylated genes, we have now identified TCF2 as a target for epigenetic inactivation in ovarian cancer. TCF2 was methylated in 53% of ovarian cancer cell lines and 26% of primary ovarian cancers, resulting in loss of the gene's expression. TCF2 expression was restored by treating cells with a methyltransferase inhibitor, 5-aza-2 0 deoxycitidine (5-aza-dC). In addition, chromatin immunoprecipitation showed deacetylation of histone H3 in methylated cells and, when combined with 5-aza-dC, the histone deacetylase inhibitor trichostatin A synergistically induced TCF2 expression. Epigenetic inactivation of TCF2 was also seen in colorectal, gastric and pancreatic cell lines, suggesting general involvement of epigenetic inactivation of TCF2 in tumorigenesis. Restoration of TCF2 expression induced expression of HNF4a, a transcriptional target of HNF1b, indicating that epigenetic silencing of TCF2 leads to alteration of the hepatocyte nuclear factor network in tumours. These results suggest that TCF2 is involved in the development of ovarian cancers and may represent a useful target for their detection and treatment.

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Section: Discussionmentioning

confidence: 89%

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

et al. 2006

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“…Taken together with observation that retinoids influence the proliferation of many cell types [30,[39][40][41], these results prompted us to investigate whether HNF-4a was also involved in the control of cell growth. Using F9 and rat lung endothelial (RLE) cells expressing Dox-inducible HNF-4a [38,42], we found in the present study that HNF-4a induced expression of p21, but not p15, p16, p18, p19, or p27 and inhibited cellular proliferation in a p53-independent fashion. We also demonstrated, by a transient transfection assay with p21 promoter-luciferase reporter constructs, that HNF-4a could directly activate expression of the p21 gene.…”

Section: Introductionmentioning

confidence: 78%

Activation of p21/ gene expression and inhibition of cell proliferation by overexpression of hepatocyte nuclear factor-4α

Chiba

Itoh

Satohisa

et al. 2005

Experimental Cell Research

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“…The bottom surface of the top chamber was wiped with cotton swabs, and cells that passed through the filters into the lower surface of wells were quantitated. Similarly, transmigration assay through the endothelial monolayer was done as described previously (22). Briefly, we did this assay by using 24-well cell culture inserts with 8 Am pores in a coculture system using both various cancer cell lines and RLE:rtTA:hepatocyte nuclear factor (HNF)-4a L23, which is an endothelial cell line with inducible expression of HNF-4a after doxycycline treatment.…”

Section: Methodsmentioning

confidence: 99%

Epigenetic Silencing of Occludin Promotes Tumorigenic and Metastatic Properties of Cancer Cells via Modulations of Unique Sets of Apoptosis-Associated Genes

Osanai¹,

Murata²,

et al. 2006

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Occludin is the first identified integral protein for the tight junction (TJ), and its long COOH-terminal domain is considered to have functions in receiving and transmitting cell survival signals. Loss of TJ-associated molecules, such as occludin, has been correlated with tumor progression in carcinogenesis; however, the precise molecular mechanisms explaining its loss of expression and whether occludin expression has any effects on cancer phenotypes remain to be clarified. Here, we show that forced expression of occludin in cancer cells exhibits enhanced sensitivity to differently acting apoptogenic factors, and thus inhibits the tumorigenicity of transformed cells, via modulation of unique sets of apoptosis-associated genes. In addition, studies using deletion mutants of occludin constructs show that 44 amino acids at the COOH-terminal end play a critical role in modifying the cellular phenotypes. Interestingly, occludin decreases cellular invasiveness and motility, thereby abrogating metastatic potencies of cancer cells. We also found that occludin expression is silenced by CpG island hypermethylation on its promoter region. Synergy with a demethylator and histone deacetylase inhibitor or retinoids that stimulate retinoic acid receptor A induces endogenous occludin, which is sufficient for apoptotic sensitization. Our results show the functional diversity of occludin and suggest that methylator phenotype of occludin provides enhanced tumorigenic, invasive, and metastatic properties of cancer cells, identifying occludin as a likely candidate for a tumor-suppressor gene in certain types of cancer. (Cancer Res 2006; 66(18): 9125-33)

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Hepatocyte Nuclear Factor (HNF)‐4α Induces Expression of Endothelial Fas Ligand (FasL) to Prevent Cancer Cell Transmigration: A Novel Defense Mechanism of Endothelium against Cancer Metastasis

Cited by 20 publications

References 46 publications

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

Epigenetic inactivation of TCF2 in ovarian cancer and various cancer cell lines

Activation of p21/ gene expression and inhibition of cell proliferation by overexpression of hepatocyte nuclear factor-4α

Epigenetic Silencing of Occludin Promotes Tumorigenic and Metastatic Properties of Cancer Cells via Modulations of Unique Sets of Apoptosis-Associated Genes

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