• The Korean Journal of Physiology and Pharmacology
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• v.20 no.3
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• pp.297-304
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• 2016

Klotho functions as a tumor suppressor predominantly expressed in renal tubular cells, the origin of clear cell renal cell carcinoma (ccRCC). Altered expression and/or activity of growth factor receptor have been implicated in ccRCC development. Although Klotho suppresses a tumor progression through growth factor receptor signaling including insulin-like growth factor-1 receptor (IGF-1R), the role of Klotho acting on IGF-1R in ccRCC and its clinical relevance remains obscure. Here, we show that Klotho is favorable prognostic factor for ccRCC and exerts tumor suppressive role for ccRCC through inhibiting IGF-1R signaling. Our data shows the following key findings. First, in tumor tissues, the level of Klotho and IGF-1R expression are low or high, respectively, compared to that of adjacent non-neoplastic parenchyma. Second, the Klotho expression is clearly low in higher grade of ccRCC and is closely associated with clinical outcomes in tumor progression. Third, Klotho suppresses IGF-1-stimulated cell proliferation and migration by inhibiting PI3K/Akt pathway. These results provide compelling evidence supporting that Klotho acting on IGF-1R signaling functions as tumor suppressor in ccRCC and suggest that Klotho is a potential carcinostatis substance for ccRCC.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.2
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• pp.1077-1082
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• 2013

Background: Renal cell carcinoma (RCC) is a malignancy with a poor prognosis. We aimed to explore whether the expression of Long Non-Coding RNA (LncRNA) growth arrest-specific transcript 5 (GAS5) is associated with RCC genesis. Methods: We selected twelve clinical samples diagnosed for renal clear cell carcinoma and found that the LncRNA GAS5 transcript levels were significantly reduced relative to those in adjacent unaffected normal renal tissues. Results: In addition, expression of GAS5 was lower in the RCC cell line A498 than that in normal renal cell line HK-2. Furthermore, using functional expression cloning, we found that overexpression of GAS5 in A498 cells inhibited cell proliferation, induced cell apoptosis and arrested cell cycling. At the same time, the migration and invasion potential of A498 cells were inhibited compared to control groups. Conclusion: Our study provided the first evidence that a decrease in GAS5 expression is associated with RCC genesis and progression and overexpression of GAS5 can act as a tumor suppressor for RCC, providing a potential attractive therapeutic approach for this malignancy.

• Environmental Mutagens and Carcinogens
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• v.26 no.1
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• pp.1-6
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• 2006

To enhance our understanding of toxicity mediated through the pathway by which TCDD stimulates gene expression, we have investigated genes whose expressions are changed after treatment with TCDD and/or MNNG in human Chang liver cell. First, we treated with MNNG and TCDD for two weeks to transform human Chang liver cell. We obtained cell looks like to be transformed and compared the differential gene expression by using cDNA chip (Macrogen) which carrys genes related with signal transduction pathways, oncogenes and tumor suppressor genes, etc. We found that TCDD up- or down-regulated 203 and 111 genes including oncogenes and tumor suppressor genes in human Chang liver cell two fold or more, respectively. Second, we compared the differential gene expression after treatment with TCDD only by using cDNA chip (Superarray) which carrys genes related with cell cycle regulations, and found that TCDD up regulated genes related with cell proliferation as well as cell growth inhibition in human Chang liver cell two fold or more, respectively. These results suggest that toxicity induced by TCDD may reflect sustained alterations in the expression of many genes and that the changes reflect both direct and indirect effects of TCDD.

• Molecules and Cells
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• v.40 no.10
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• pp.761-772
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• 2017

Glioblastoma is the most frequent and most aggressive brain tumor in adults. Solute carrier family 8 member 2 (SLC8A2) is only expressed in normal brain, but not present in other human normal tissues or in gliomas. Therefore, we hypothesized that SLC8A2 might be a glioma tumor suppressor gene and detected the role of SLC8A2 in glioblastoma and explored the underlying molecular mechanism. The glioblastoma U87MG cells stably transfected with the lentivirus plasmid containg SLC8A2 (U87MG-SLC8A2) and negative control (U87MG-NC) were constructed. In the present study, we found that the tumorigenicity of U87MG in nude mice was totally inhibited by SLC8A2. Overexpression of SLC8A2 had no effect on cell proliferation or cell cycle, but impaired the invasion and migration of U87MG cells, most likely through inactivating the extracellular signal-related kinases (ERK)1/2 signaling pathway, inhibiting the nuclear translocation and DNA binding activity of nuclear factor kappa B ($NF-{\kappa}B$), reducing the level of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA)-its receptor (uPAR) system (ERK1/2-$NF-{\kappa}B$-MMPs/uPA-uPAR), and altering the protein levels of epithelial to mesenchymal transitions (EMT)-associated proteins E-cardherin, vimentin and Snail. In addition, SLC8A2 inhibited the angiogenesis of U87MG cells, probably through combined inhibition of endothelium-dependent and endothelium-nondependent angiogenesis (vascular mimicry pattern). Totally, SLC8A2 serves as a tumor suppressor gene and inhibits invasion, angiogenesis and growth of glioblastoma.

• YAKHAK HOEJI
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• v.37 no.1
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• pp.9-17
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• 1993

Immune functions of mice bearing Lewis Lung Carcinoma (LLC) were significantly suppressed when evaluated with mitogen responsiveness, IL-2 production and non-specific suppressor activity. Based on these immunosuppressive characteristics of LLC bearing mice, immunomodulating activates of Copolang were investigated in this model. After 15 days of LLC inoculation, Copolang was intraperitoneally administered for 7 consecutive days with doses of 20 or 200 mg/kg. Immune functions were evaluated 3 days after the final administration of Copolang. The results showed that the growth of LLC solid tumor was not inhibited by Copolang. But, mitogens-induced proliferation, IL-2 production and responsiveness to recombinant IL-2 of splenocytes were significantly augmented by the treatment of Copolang. However suppressor cell activity was not affected by Copolang. These results indicate that Copolang expresses potent immunomodulating activates through the augmentations of IL-2 production and responsiveness to recombinant IL-2, which have been generally known to be suppressed in tumor bearing mice, without affecting the growth of tumor.

• Molecules and Cells
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• v.21 no.2
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• pp.167-173
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• 2006

The literature provides strong precedent for both pro-tumorigenic and tumor suppressor roles for the c-Jun N-terminal kinases (JNKs) in the setting of oncogenesis. Clearly, JNKs are activated by numerous oncogenes and growth factors and the literature documents a role for these MAP kinases in cell proliferation and transformation. By contrast, JNKs mediate signals from diverse stimuli that result in cell death or differentiation and a role for JNKs as tumor suppressors has emerged. This enigmatic nature of the JNKs in the setting of oncogenesis is considered herein. Further illumination of the complex and context-dependent functions of the JNKs in cancer cells is of obvious importance for the rational use of small molecule JNK inhibitors as therapeutics.

• BMB Reports
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• v.38 no.1
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• pp.1-8
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• 2005

Transforming growth factor-$\beta$ is a pleiotropic growth factor that has enthralled many investigators for approximately two decades. In addition to many reports that have clarified the basic mechanism of transforming growth factor-$\beta$ signal transduction, numerous laboratories have published on the clinical implication/application of transforming growth factor-$\beta$. To name a few, dysregulation of transforming growth factor-$\beta$ signaling plays a role in carcinogenesis, autoimmunity, angiogenesis, and wound healing. In this report, we will review these clinical implications of transforming growth factor-$\beta$.

• Toxicological Research
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• v.20 no.2
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• pp.109-116
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• 2004

For the safety evaluation of adenovirus-mediated gene transfer, we investigated differential gene expressions after transfecting adenoviral vector containing p16 tumor suppressor gene (Ad5CMV-p16) into human non-small cell lung cancer cells. In the previous study, we showed adenovirus-mediated $p16^{INK4a}$ gene transfer resulted in significant inhibition of cancer cell growth. We investigated gene expression changes after transfecting Ad5CMV-p16, Ad5CMV (null type, a mock vector) into A549 cells by using cDNA chip and oligonucleotide microarray chip (1200 genes) which carries genes related with signal transduction pathways, cell cycle regulations, oncogenes and tumor suppressor genes. We found that $p16^{INK4a}$ gene transfer down regulated 5 genes (cdc2, cyclin D3, cyclin B, cyclin E, cdk2) among 26 genes involved in cell cycle regulations. Compared with serum-free medium treated cells, Ad5CMV-p16 changed 27 gene expressions, two fold or more on oligonucleotide chip. In addition, Ad5CMV-p16 did not seem to increase the tumorigenicity-related gene expression in A549 cells. Further studies will be needed to investigate the effect of Ad5CMV-p16 on normal human cells and tissues for safety evaluation.

• Molecules and Cells
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• v.45 no.6
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• pp.413-424
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• 2022

Suppressor of mothers against decapentaplegic homolog (SMAD) 4 is a pluripotent signaling mediator that regulates myriad cellular functions, including cell growth, cell division, angiogenesis, apoptosis, cell invasion, and metastasis, through transforming growth factor β (TGF-β)-dependent and -independent pathways. SMAD4 is a critical modulator in signal transduction and functions primarily as a transcription factor or cofactor. Apart from being a DNA-binding factor, the additional SMAD4 mechanisms in tumor suppression remain elusive. We previously identified methyl malonyl aciduria cobalamin deficiency B type (MMAB) as a critical SMAD4 binding protein using a proto array analysis. This study confirmed the interaction between SMAD4 and MMAB using bimolecular fluorescence complementation (BiFC) assay, proximity ligation assay (PLA), and conventional immunoprecipitation. We found that transient SMAD4 overexpression down-regulates MMAB expression via a proteasome-dependent pathway. SMAD4-MMAB interaction was independent of TGF-β signaling. Finally, we determined the effect of MMAB downregulation on cancer cells. siRNA-mediated knockdown of MMAB affected cancer cell metabolism in HeLa cells by decreasing ATP production and glucose consumption as well as inducing apoptosis. These findings suggest that SMAD4 controls cancer cell metabolism by regulating MMAB.

• Journal of Korean Neurosurgical Society
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• v.29 no.4
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• pp.471-476
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• 2000

Objective : p16/INK4a, a kind of tumor suppressor genes, encodes a specific inhibitor of the cyclin D-dependent kinases CDK4 and CDK6. This prevents the association of CDK4 with cyclin D1, and subsequently inhibits phosphorylation of retinoblastoma tumor suppressor protein(pRb), thus preventing exit from the G1 phase. According to previous reports, over 50% of glioma tissue and 80% of glioma cell lines have been demonstrated inactivation of p16/INK4a gene. The purpose of this study was to determine whether recombinant adenovirus-p16 virus is a suitable candidate for gene replacement therapy in cases of glioma. Methods : Three human glioma cell lines(U251MG, U87MG and U373MG) that express mutant p16 protein were used. Replication-deficient adenovirus was utilized as an expression vector to transfer exogenous p16 cDNA into the cells ; control cells were infected with the Ad-${\beta}$-gal expressing ${\beta}$-galactosidase. To monitor gene transfer and the expression of exogenous genes, we used Western Blotting analysis. Flow cytometry studies of cellular DNA content were performed to determine the cell cycle phenotype of the glioma cells before and after treatment. Results : We showed here that restoration of p16/INK4a expression in p16 negative U87MG, U251MG and partially deleted U373MG by Ad-CMV-p16 induced growth suppression in vitro. Flow cytometric study revealed that Ad-CMV-p16 infected U87MG cells were arrested during the G0-G1 phase of the cell cycle. Expression of p16 transferred by Ad-CMV-p16 in glioma cells was highly efficient and maintained for more than seven days. Conclusions : Our results suggest that Ad-CMV-p16 gene therapy strategy is potentially useful and warrants further clinical investigation for the treatment of gliomas.