Ninjurin1 increases p21 expression and induces cellular senescence in human hepatoma cells

Toyama, Takashi; Sasaki, Yutaka; Horimoto, Masayoshi; Iyoda, Kenya; Yakushijin, Takayuki; Ohkawa, Kazuyoshi; Takehara, Tetsuo; Kasahara, Akinori; Araki, Toshiyuki; Hori, Masatsugu; Hayashi, Norio

doi:10.1016/j.jhep.2004.06.027

Cited by 20 publications

(12 citation statements)

References 23 publications

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“…This view is supported by the new target genes identified here, such as NINJ1 (Fig. 5), which may play a role in regulating cellular senescence by inducing the expression of p21, a cell cycle inhibitor gene,41 and is consistent with our previous findings that the p21 gene ( CDKN1A ) itself is a direct target of HNF4α 23. Other new HNF4α target genes related to anti‐growth effects are: CIDEC , which induces fragmentation of DNA upon apoptosis; ATPIF1, which inhibits an adenosine triphosphatase involved in angiogenesis; and STEAP3 , which is induced by tumor suppressor p53 and whose down‐regulation is associated with a transition from cirrhosis to hepatocellular carcinoma 42.…”

Section: Discussionsupporting

confidence: 58%

Integrated Approach for the Identification of Human Hepatocyte Nuclear Factor 4α Target Genes Using Protein Binding Microarrays

et al. 2010

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Hepatocyte nuclear factor 4 alpha (HNF4α), a member of the nuclear receptor superfamily, is essential for liver function and is linked to several diseases including diabetes, hemophilia, atherosclerosis, and hepatitis. Although many DNA response elements and target genes have been identified for HNF4α the complete repertoire of binding sites and target genes in the human genome is unknown. Here, we adapt protein binding microarrays (PBMs) to examine the DNA-binding characteristics of two HNF4α species (rat and human) and isoforms (HNF4α2 and HNF4α8) in a high-throughput fashion. We identified ~1400 new binding sequences and used this dataset to successfully train a Support Vector Machine (SVM)model that predicts an additional ~10,000 unique HNF4α-binding sequences; we also identify new rules for HNF4α DNA binding. We performed expression profiling of an HNF4α RNA interference knockdown in HepG2 cells and compared the results to a search of the promoters of all human genes with the PBM and SVM models, as well as published genome-wide location analysis. Using this integrated approach, we identified ~240 new direct HNF4α human target genes, including new functional categories of genes not typically associated with HNF4α, such as cell cycle, immune function, apoptosis, stress response, and other cancer-related genes. Conclusion We report the first use of PBMs with a full-length liver-enriched transcription factor and greatly expand the repertoire of HNF4α-binding sequences and target genes, thereby identifying new functions for HNF4α. We also establish a web-based tool, HNF4 Motif Finder, that can be used to identify potential HNF4α-binding sites in any sequence.

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Section: Discussionsupporting

confidence: 58%

Integrated Approach for the Identification of Human Hepatocyte Nuclear Factor 4α Target Genes Using Protein Binding Microarrays

et al. 2010

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“…The cytokine, TGF-β, has been demonstrated to up-regulate p21 [ 43 ], and A549 cells treated with TGF-β over a long period were forced to undergo senescence and senescent A549 cells were not tumorigenic in nude mice [ 44 ]. Increased p21 expression has been associated with G1 growth arrest and senescence in hepatoma cells treated with ninjurin 1, a novel adhesion molecule that promotes regeneration in nervous tissue but senescence in liver tissue [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Stable low-level expression of p21WAF1/CIP1 in A549 human bronchogenic carcinoma cell line-derived clones down-regulates E2F1 mRNA and restores cell proliferation control

et al. 2006

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Background: Deregulated cell cycle progression and loss of proliferation control are key properties of malignant cells. In previous studies, an interactive transcript abundance index (ITAI) comprising three cell cycle control genes, [MYC × E2F1]/p21 accurately distinguished normal from malignant bronchial epithelial cells (BEC), using a cut-off threshold of 7,000. This cut-off is represented by a line with a slope of 7,000 on a bivariate plot of p21 versus [MYC × E2F1], with malignant BEC above the line and normal BEC below the line. This study was an effort to better quantify, at the transcript abundance level, the difference between normal and malignant BEC. The hypothesis was tested that experimental elevation of p21 in a malignant BEC line would decrease the value of the [MYC × E2F1]/p21 ITAI to a level below this line, resulting in loss of immortality and limited cell population doubling capacity. In order to test the hypothesis, a p21 expression vector was transfected into the A549 human bronchogenic carcinoma cell line, which has low constitutive p21 TA expression relative to normal BEC.

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“…Ninj1 is highly expressed in hepatocellular carcinoma (HCC) patients with cirrhosis related to viral infection . Ninj1 expression in human hepatoma cells induces p21 expression and G1 cell cycle arrest, and Ninj1 overexpression produces the characteristic features of cellular senescence . Ninj1 is also expressed in B‐lineage acute lymphoblastic leukemia (ALL) cells at higher levels than in normal B‐cell progenitors .…”

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confidence: 99%

“…6 Ninj1 expression in human hepatoma cells induces p21 expression and G1 cell cycle arrest, and Ninj1 overexpression produces the characteristic features of cellular senescence. 7 Ninj1 is also expressed in B-lineage acute lymphoblastic leukemia (ALL) cells at higher levels than in normal B-cell progenitors. 8 Interestingly, Ninj1 is transcriptionally regulated by p53 and can be induced by DNA damage.…”

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Ninjurin1 suppresses metastatic property of lung cancer cells through inhibition of interleukin 6 signaling pathway

Jang

Kang

Woo

et al. 2016

Intl Journal of Cancer

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Nerve injury-induced protein 1 (Ninjurin1, Ninj1) is a cell surface molecule that can mediate homophilic adhesion and promote neurite outgrowth from cultured dorsal root ganglion (DRG) neurons. Interestingly, Ninj1 overexpressed in human cancer; however, its role in metastasis is not clear. This study showed that inhibition of Ninj1 promotes lung cancer metastasis through interleukin 6 (IL-6)/STAT3 signaling. Ninj1 levels were relatively low in highly motile lung cancer cells. While inhibition of Ninj1 enhanced cell migration in lung cancer cells, overexpression of Ninj1 significantly suppressed it. We found that inhibition of Ninj1 significantly increased expression and secretion of IL-6 in A549 cells. We also found that inhibition of IL-6 decreased intercellular adhesion molecule 1 (ICAM-1) expression. In addition, inhibition of Ninj1 significantly increased cell motility and invasiveness of lung cancer cells. In an in vivo model, we found that Ninj1 suppression did not affect tumor growth but induced significant increase in incidence of lung metastasis, and sizes and number of tumor nodules. Taken together, our data clearly demonstrate that Ninj1 suppresses migration, invasion and metastasis of lung cancer via inhibition of the IL-6 signaling pathway in vitro and in vivo.

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Ninjurin1 increases p21 expression and induces cellular senescence in human hepatoma cells

Cited by 20 publications

References 23 publications

Integrated Approach for the Identification of Human Hepatocyte Nuclear Factor 4α Target Genes Using Protein Binding Microarrays

Integrated Approach for the Identification of Human Hepatocyte Nuclear Factor 4α Target Genes Using Protein Binding Microarrays

Stable low-level expression of p21WAF1/CIP1 in A549 human bronchogenic carcinoma cell line-derived clones down-regulates E2F1 mRNA and restores cell proliferation control

Ninjurin1 suppresses metastatic property of lung cancer cells through inhibition of interleukin 6 signaling pathway

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