• Molecules and Cells
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• v.43 no.2
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• pp.198-202
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• 2020

Comprehensive inhibition of RUNX1, RUNX2, and RUNX3 led to marked cell suppression compared with inhibition of RUNX1 alone, clarifying that the RUNX family members are important for proliferation and maintenance of diverse cancers, and "cluster regulation of RUNX (CROX)" is a very effective strategy to suppress cancer cells. Recent studies reported by us and other groups suggested that wild-type RUNX1 is needed for survival and proliferation of certain types of leukemia, lung cancer, gastric cancer, etc. and for their one of metastatic target sites such as born marrow endothelial niche, suggesting that RUNX1 often functions oncogenic manners in cancer cells. In this review, we describe the significance and paradoxical requirement of RUNX1 tumor suppressor in leukemia and even solid cancers based on recent our findings such as "genetic compensation of RUNX family transcription factors (the compensation mechanism for the total level of RUNX family protein expression)", "RUNX1 inhibition-induced inhibitory effects on leukemia cells and on solid cancers through p53 activation", and "autonomous feedback loop of RUNX1-p53-CBFB in acute myeloid leukemia cells". Taken together, these findings identify a crucial role for the RUNX cluster in the maintenance and progression of cancers and suggest that modulation of the RUNX cluster using the pyrrole-imidazole polyamide gene-switch technology is a potential novel therapeutic approach to control cancers.

• Reproductive and Developmental Biology
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• v.36 no.4
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• pp.275-281
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• 2012

Embryonic stem cell-preconditioned microenvironment is important for cancer cells properitities by change cell morphology and proliferation. This microenvironment induces cancer cell reprogramming and results in a change in cancer cell properties such as differentiation and migration. The cancer microenvironment affects cancer cell proliferation and growth. However, the mechanism has not been clarified yet. Using the ES-preconditioned 3-D microenvironment model, we provide evidence showing that the ES microenvironment inhibits proliferation and reduces oncogenic gene expression. But ES microenvironment has no effect on telomerase activity, cell viability, cellular senescence, and methylation on Oct4 promoter region. Furthermore, methylation of Nanog was increase on ES-preconditioned microenvironment and supports results that no difference on RNA expression levels. Taken together, these results demonstrated that in the ES-preconditioned 3-D microenvironment is a crucial role for cancer cell proliferation not senescence.

• Genomics & Informatics
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• v.17 no.4
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• pp.36.1-36.6
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• 2019

The incidence and mortality rate of cancer continues to gradually increase, although considerable research effort has been directed at elucidating the molecular mechanisms underlying biomarkers responsible for tumorigenesis. Accumulated evidence indicates that the long non-coding RNAs (lncRNAs), which are transcribed but not translated into functional proteins, contribute to cancer development. Recently, linc00152 (an lncRNA) was identified as a potent oncogene in various cancer types, and shown to be involved in cancer cell proliferation, invasiveness, and motility by sponging tumor-suppressive microRNAs acting as a competing endogenous RNA, binding to gene promoters acting as a transcriptional regulator, and binding to functional proteins. In this review, we focus on the oncogenic role of linc00152 in tumorigenesis and provided an overview of recent clinical studies on the effects of linc00152 expression in human cancers.

• BMB Reports
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• v.52 no.7
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• pp.415-423
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• 2019

Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription factor that regulates cell proliferation, differentiation, apoptosis, angiogenesis, inflammation and immune responses. Aberrant STAT3 activation triggers tumor progression through oncogenic gene expression in numerous human cancers, leading to promote tumor malignancy. On the contrary, STAT3 activation in immune cells cause elevation of immunosuppressive factors. Accumulating evidence suggests that the tumor microenvironment closely interacts with the STAT3 signaling pathway. So, targeting STAT3 may improve tumor progression, and anti-cancer immune response. In this review, we summarized the role of STAT3 in cancer and the tumor microenvironment, and present inhibitors of STAT3 signaling cascades.

• Journal of Life Science
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• v.30 no.12
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• pp.1070-1077
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• 2020

Treatment with anticancer drugs changes the expression of multiple genes related to cell proliferation, migration, and drug resistance. These changes in gene expression may be connected to regulatory networks for each other. This study showed that doxorubicin treatment induces the expression of oncogenic FosB and decreases the expression of oncogenic SETDB1 in A549 and H1299 human lung cancer cells, which are different in tumor suppressor p53 status. However, a small difference was detected in the quantitative expression of those proteins in the two kinds of cells. To examine the potential regulation of SETDB1 and FosB by p53, we predicted putative p53 binding sites on the genomic DNA of SETDB1 and FosB using a TF motif binding search program. These putative p53 binding sites were identified as 18 sites in the promoter regions of SETDB1 and 21 sites in the genomic DNA of FosB. A luciferase assay confirmed that p53 negatively regulated the promoter activities of SETDB1 and FosB. Furthermore, the results of RT-PCR, western blot, qPCR, and immunostaining experiments indicated that the transfection of exogenous p53 decreases the expression of SETDB1 and FosB in H1299 cells. This indicates that p53 negatively regulates the expression of SETDB1 and FosB at the transcriptional level. Collectively, the downregulation of SETDB1 and FosB by p53 may provide functional networks for apoptosis and for the survival of cancer cells during anticancer drug treatment.

• Animal cells and systems
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• v.1 no.3
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• pp.521-526
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• 1997

We isolated a mouse nck cDNA from the thymus cDNA expression library. The cDNA encodes a 377 amino acid protein and displays 97% amino acid sequence identity to human oncogenic protein nck, which is composed almost exclusivelv of three src homology 3 (SH3) domains and one SH2 domain. The sequence analysis also showed that the isolated cDNA is the mouse counterpart of the human nck and different from the mouse grb4, which has been reported to be highly similar to the human nck and, therefore considered as a mouse nck, Northern blot analysis showed that the transcript of the gene was 1.8 kb and was highly expressed in the testis, thymus, and brain but moderately in the liver and lymph node. Western blot analysis showed that the size of the protein was about 47 kDa. Overexpression of the mouse Nck transformed a mouse fibroblast cell line, NIH3T3. The results clearly indicate that normal nck gene has transforming ability and provide an argument against a suggested possibility that the transforming ability of the human nck gene is due to a mutation(s) in the gene.

• Genomics & Informatics
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• v.14 no.3
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• pp.78-84
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• 2016

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (NKTCL), is a malignant disorder of cytotoxic lymphocytes of NK or T cells. It is an aggressive neoplasm with a very poor prognosis. Although extranodal NKTCL reportedly has a strong association with Epstein-Barr virus, the molecular pathogenesis of NKTCL has been unexplored. The recent technological advancements in next-generation sequencing (NGS) have made DNA sequencing cost- and time-effective, with more reliable results. Using the Ion Proton Comprehensive Cancer Panel, we sequenced 409 cancer-related genes to identify somatic mutations in five NKTCL tissue samples. The sequencing analysis detected 25 mutations in 21 genes. Among them, KMT2D, a histone modification-related gene, was the most frequently mutated gene (four of the five cases). This result was consistent with recent NGS studies that have suggested KMT2D as a novel driver gene in NKTCL. Mutations were also found in ARID1A, a chromatin remodeling gene, and TP53, which also recurred in recent NGS studies. We also found mutations in 18 novel candidate genes, with molecular functions that were potentially implicated in cancer development. We suggest that these genes may result in multiple oncogenic events and may be used as potential bio-markers of NKTCL in the future.

• Molecules and Cells
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• v.37 no.12
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• pp.873-880
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• 2014

In our previous study, miRNA-183, a miRNA in the miR-96-182-183 cluster, was significantly over-expressed in esophageal squamous cell carcinoma (ESCC). In the present study, we explored the oncogenic roles of miR-183 in ESCC by gain and loss of function analysis in an esophageal cancer cell line (EC9706). Genome-wide mRNA micro-array was applied to determine the genes that were regulated directly or indirectly by miR-183. 3'UTR luciferase reporter assay, RT-PCR, and Western blot were conducted to verify the target gene of miR-183. Cell culture results showed that miR-183 inhibited apoptosis (p < 0.05), enhanced cell proliferation (p < 0.05), and accelerated G1/S transition (p < 0.05). Moreover, the inhibitory effect of miR-183 on apoptosis was rescued when miR-183 was suppressed via miR-183 inhibitor (p < 0.05). Western blot analysis showed that the expression of programmed cell death 4 (PDCD4), which was predicted as the target gene of miR-183 by microarray profiling and bioinformatics predictions, decreased when miR-183 was over-expressed. The 3'UTR luciferase reporter assay confirmed that miR-183 directly regulated PDCD4 by binding to sequences in the 3'UTR of PDCD4. Pearson correlation analysis further confirmed the significant negative correlation between miR-183 and PDCD4 in both cell lines and in ESCC patients. Our data suggest that miR-183 might play an oncogenic role in ESCC by regulating PDCD4 expression.

• BMB Reports
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• v.52 no.2
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• pp.157-162
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• 2019

Our previous study found that two novel cancer-related genes, PRR11 and SKA2, constituted a classic gene pair that was regulated by p53 and NF-Y in lung cancer. However, their role and regulatory mechanism in breast cancer remain elusive. In this study, we found that the expression levels of PRR11 and SKA2 were upregulated and have a negative prognotic value in breast cancer. Loss-of-function experiments showed that RNAi-mediated knockdown of PRR11 and/or SKA2 inhibited proliferation, migration, and invasion of breast cancer cells. Mechanistic experiments revealed that knockdown of PRR11 and/or SKA2 caused dysregulation of several downstream genes, including CDK6, TPM3, and USP12, etc. Luciferase reporter assays demonstrated that wild type p53 significantly repressed the PRR11-SKA2 bidirectional promoter activity, but not NF-Y. Interestingly, NF-Y was only essential for and correlated with the expression of PRR11, but not SKA2. Consistently, adriamycin-induced (ADR) activation of endogenous p53 also caused significant repression of the PRR11 and SKA2 gene pair expression. Notably, breast cancer patients with lower expression levels of either PRR11 or SKA2, along with wild type p53, exhibited better disease-free survival compared to others with p53 mutations and/or higher expression levels of either PRR11 or SKA2. Collectively, our study indicates that the PRR11 and SKA2 transcription unit might be an oncogenic contributor and might serve as a novel diagnostic and therapeutic target in breast cancer.

• Genomics & Informatics
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• v.19 no.4
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• pp.47.1-47.12
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• 2021

Kaposi's sarcoma-associated herpesvirus (KSHV) is one of the few human oncogenic viruses, which causes a variety of malignancies, including Kaposi's sarcoma, multicentric Castleman disease, and primary effusion lymphoma, particularly in human immunodeficiency virus patients. The currently available treatment options cannot always prevent the invasion and dissemination of this virus. In recent times, siRNA-based therapeutics are gaining prominence over conventional medications as siRNA can be designed to target almost any gene of interest. The ORF57 is a crucial regulatory protein for lytic gene expression of KSHV. Disruption of this gene translation will inevitably inhibit the replication of the virus in the host cell. Therefore, the ORF57 of KSHV could be a potential target for designing siRNA-based therapeutics. Considering both sequence preferences and target site accessibility, several online tools (i-SCORE Designer, Sfold web server) had been utilized to predict the siRNA guide strand against the ORF57. Subsequently, off-target filtration (BLAST), conservancy test (fuzznuc), and thermodynamics analysis (RNAcofold, RNAalifold, and RNA Structure web server) were also performed to select the most suitable siRNA sequences. Finally, two siRNAs were identified that passed all of the filtration phases and fulfilled the thermodynamic criteria. We hope that the siRNAs predicted in this study would be helpful for the development of new effective therapeutics against KSHV.