• Asian Pacific Journal of Cancer Prevention
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• v.13 no.4
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• pp.1297-1303
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• 2012

Aims: Primary hepatocellular carcinoma (HCC) is a common malignancy often related to hepatitis viral infection. Smad4 is known to mediate the TGF-${\beta}$ pathway to suppress tumorigenesis. However, the function of Smad4 in HCC is still controversial. In this study we compared levels of Smad4 in HCC tissues with or without hepatitis virus infection and adjacent normal-appearing liver. Methods: Samples from HCC patients were analyzed for Smad4 protein and mRNA expression by immunohistochemistry (IHC), RT-PCR and Western blotting. Results: We found that tumor tissues expressed less Smad4 mRNA and protein than the adjacent tissues. Most HCC tumor tissues were negative for Smad4 in IHC staining, while the majority of adjacent tissues were positively stained. Interestingly, protein levels were higher in HCC tissues with viral hepatitis than those without virus infection. Suppression of expression appeared closely related to HCC, so that Smad4 appears to function as a tumor suppressor gene (TSG). Conclusion: Patients with hepatitis viral infection, at higher risk for HCC, exhibited increased Smad4 protein expression suggesting hepatitis virus may modulate Smad4 expression, which is functionally distinct from its putative role as a TSG. Smad4 expression may thus be an applicable marker for diagnosis and/or a target to develop therapeutic agents for HCC.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.17
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• pp.7467-7471
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• 2014

SCY1-like 1-binding protein 1 (SCYL1BP1) is a newly identified transcriptional activator domain containing protein with many unknown biological functions. Recently emerging evidence has revealed that it is a novel regulator of the p53 pathway, which is very important for the development of human cancer. However, the effects of SCYL1BP1 on human lung squamous carcinoma cell biological behavior remain poorly understood. In this study, we present evidence that SCYL1BP1 can promote the degradation of MDM2 protein and further inhibit the G1/S transition of lung squamous carcinoma cell lines. Functional assays found that reintroduction of SCYL1BP1 into lung squamous carcinoma cell lines significantly inhibited cell proliferation, migration, invasion and tumor formation in nude mice, suggesting strong tumor suppressive function of SCYL1BP1 in lung squamous carcinoma. Taken together, our data suggest that the interaction of SCYL1BP1/MDM2 could accelerate MDM2 degradation, and may function as an important tumor suppressor in lung squamous carcinomas.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.6
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• pp.3757-3760
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• 2013

MicroRNAs (miRNAs) are small, non-coding RNAs (18-25 nucleotides) that post-transcriptionally modulate gene expression by negatively regulating the stability or translational efficiency of their target mRNAs. In this context, the present study aimed to evaluate the in vitro effects of miR-485 mimics in breast carcinoma T47D cells. Forty-eight hours after T47D cells were transfected with miR-485 mimics, an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was utilized to determine the effects on cell viability. Colony formation and cell migration assays were adopted to determine whether miR-485 affects the proliferation rates and cell migration of breast carcinoma T47D cells. Our results showed that ectopic expression of miR-485 resulted in a significant decrease in cell growth, cell colony formation, and cell migration. These findings suggest that miR-485 might play an important role in breast cancer by suppressing cell proliferation and migration.

• 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.

• BMB Reports
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• v.40 no.2
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• pp.142-150
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• 2007

Epigenetic alterations, represented by aberrant DNA methylation, are deeply involved in human cancers. In gastric cancers, tumor-suppressor genes are inactivated more frequently by promoter methylation than by mutations. We recently showed that H. pylori infection, a potent gastric carcinogenic factor, induces methylation of specific genes in the gastric mucosae. When the methylation levels were analyzed in the gastric mucosae of healthy volunteers, cases with a single gastric cancer, and cases with multiple gastric cancers, who have increasing levels of risks for gastric cancers, there was a significant increasing trend in the methylation levels among the individuals without current H. pylori infection. This finding unequivocally showed the presence of an epigenetic field for cancerization. The degree of the field defect was measured more conveniently using methylation levels of marker genes than using those of tumor-suppressor genes. The presence of an epigenetic field for cancerization has been indicated for liver, colon, Barrett's esophageal, lung, breast, and renal cancers. Since decreased transcription is involved in the specificity of methylated genes, it is likely that specific genes are methylated according to carcinogenic factors. These findings emphasize the usefulness of DNA methylation as a marker for past exposure to carcinogens and future risk of cancer development.

• BMB Reports
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• v.50 no.9
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• pp.454-459
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• 2017

Tumor suppressor candidate 2 (Tusc2, also known as Fus1) regulates calcium signaling, and $Ca^{2+}$-dependent nuclear factor of activated T-cells (NFAT) and nuclear factor kappa B ($NF-{\kappa}B$) pathways, which play roles in osteoclast differentiation. However, the role of Tusc2 in osteoclasts remains unknown. Here, we report that Tusc2 positively regulates the differentiation of osteoclasts. Overexpression of Tusc2 in osteoclast precursor cells enhanced receptor activator of nuclear factor ${\kappa}B$ ligand (RANKL)-induced osteoclast differentiation. In contrast, small interfering RNA-mediated knockdown of Tusc2 strongly inhibited osteoclast differentiation. In addition, Tusc2 induced the activation of RANKL-mediated $NF-{\kappa}B$ and calcium/calmodulin-dependent kinase IV (CaMKIV)/cAMP-response element (CRE)-binding protein CREB signaling cascades. Taken together, these results suggest that Tusc2 acts as a positive regulator of RANKL-mediated osteoclast differentiation.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.5
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• pp.2021-2023
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• 2012

Purpose: DBC2 (Deleted in Breast Cancer 2) has been indicated to be a tumor suppressor gene in many cancers including lung adenocarcinoma recently. In this study, we aimed to explore the expression status of DBC2 in different subtypes of lung adenocarcinoma (from pre-invasive to invasive lesions), and to determine if downregulation becomes more marked with pathological progression. Methods: We collected 172 tissue samples from different subtypes of lung adenocarcinoma and investigated the frequency of DBC2 loss by immunohistochemistry. Results: Our results indicated that DBC2 downregulation is a relatively frequent event in lung adenocarcinoma. Moreover, as the adenocarcinoma subtype turns to be more invasive, more downregulation occurred. Conclusion: We conclude that loss of DBC2 expression is an early and progressive event in the pathogenesis of lung adenocarcinoma. Positive DBC2 immunohistochemistry may become an indicator for early stage disease and better prognosis of lung adenocarcinomas.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.2
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• pp.917-923
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• 2014

Chondrosarcomas are malignant cartilage-forming tumors of bone which exhibit resistance to both chemotherapy and radiation treatment. miRNAs have been well demonstrated to regulate gene expression and play essential roles in a variety of biological processes, including proliferation, differentiation, migration, cell cycling and apoptosis. In this study, we obtained evidence that miR-100 acts as a tumor suppressor in human chondrosarcomas. Interestingly, cisplatin resistant chondrosarcoma cells exhibit decreased expression of miR-100 compared with parental cells. In addition, we identified mTOR as a direct target of miR-100. Overexpression of miR-100 complementary pairs to the 3' untranslated region (UTR) of mTOR, resulted in sensitization of cisplatin resistant cells to cisplatin. Moreover, recovery of the mTOR pathway by overexpression of S6K desensitized the chondrosarcoma cells to cisplatin, suggesting the miR-100-mediated sensitization to cisplatin dependent on inhibition of mTOR. In summary, the present studies highlight miR-100 as a tumor suppressor in chondrosarcoma contributing to anti-chemoresistance. Overexpression of miR-100 might be exploited as a therapeutic strategy along with cisplatin-based combined chemotherapy for the treatment of clinical chondrosarcoma patients.

• 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.

• 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.