Smad7 Protein Induces Interferon Regulatory Factor 1-dependent Transcriptional Activation of Caspase 8 to Restore Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-mediated Apoptosis

Hong, Suntaek,Kim, Hye-Youn,Kim, Jooyoung,Ha, Huyen Trang,Kim, Young-Mi,Bae, Eunjin,Kim, Tae Hyung,Lee, Kang Choon,Kim, Seong-Jin American Society for Biochemistry and Molecular Bi 2013 The Journal of biological chemistry Vol.288 No.5

Connection between inflammation and carcinogenesis in gastrointestinal tract: focus on TGF-beta signaling.

Hong, Suntaek,Lee, Ho-Jae,Kim, Seong Jin,Hahm, Ki-Baik WJG Press 2010 WORLD JOURNAL OF GASTROENTEROLOGY Vol.16 No.17

<P>Inflammation is a primary defense process against various extracellular stimuli, such as viruses, pathogens, foods, and environmental pollutants. When cells respond to stimuli for short periods of time, it results in acute or physiological inflammation. However, if the stimulation is sustained for longer time or a pathological state occurs, it is known as chronic or pathological inflammation. Several studies have shown that tumorigenesis in the gastrointestinal (GI) tract is closely associated with chronic inflammation, for which abnormal cellular alterations that accompany chronic inflammation such as oxidative stresses, gene mutations, epigenetic changes, and inflammatory cytokines, are shared with carcinogenic processes, which forms a critical cross-link between chronic inflammation and carcinogenesis. Transforming growth factor (TGF)-beta is a multi-potent cytokine that plays an important role in regulation of cell growth, apoptosis and differentiation. Most importantly, TGF-beta is a strong anti-inflammatory cytokine that regulates the development of effector cells. TGF-beta has a suppressive effect on carcinogenesis under normal conditions by inhibiting abnormal cell growth, but on the other hand, many GI cancers originate from uncontrolled cell growth and differentiation by genetic loss of TGF-beta signaling molecules or perturbation of TGF-beta adaptors. Once a tumor has developed, TGF-beta exerts a promoting effect on the tumor itself and stromal cells to enhance cell growth, alter the responsiveness of tumor cells to stimulate invasion and metastasis, and inhibited immune surveillance. Therefore, novel development of therapeutic agents to inhibit TGF-beta-induced progression of tumor and to retain its growth inhibitory activities, in addition to anti-inflammatory actions, could be useful in oncology. In this review, we discuss the role of TGF-beta in inflammation and carcinogenesis of the GI tract related to abnormal TGF-beta signaling.</P>

RNA Binding Protein as an Emerging Therapeutic Target for Cancer Prevention and Treatment

Korean Society of Cancer Prevention 2017 Journal of cancer prevention Vol.22 No.4

<P>After transcription, RNAs are always associated with RNA binding proteins (RBPs) to perform biological activities. RBPs can interact with target RNAs in sequence- and structure-dependent manner through their unique RNA binding domains. In development and progression of carcinogenesis, RBPs are aberrantly dysregulated in many human cancers with various mechanisms, such as genetic alteration, epigenetic change, noncoding RNA-mediated regulation, and post-translational modifications. Upon deregulation in cancers, RBPs influence every step in the development and progression of cancer, including sustained cell proliferation, evasion of apoptosis, avoiding immune surveillance, inducing angiogenesis, and activating metastasis. To develop therapeutic strategies targeting RBPs, RNA interference-based oligonucleotides or small molecule inhibitors have been screened based on reduced RBP-RNA interaction and changed level of target RNAs. Identification of binding RNAs with high-throughput techniques and integral analysis of multiple datasets will help us develop new therapeutic drugs or prognostic biomarkers for human cancers.</P>

TMEM39A and Human Diseases: A Brief Review

Tran, Quangdon,Park, Jisoo,Lee, Hyunji,Hong, Youngeun,Hong, Suntaek,Park, Sungjin,Park, Jongsun,Kim, Seon-Hwan Korean Society of ToxicologyKorea Environmental Mu 2017 Toxicological Research Vol.33 No.3

Transmembrane Protein 39A (TMEM39A) is a member of TMEM family. The understanding about this protein is still limited. The earlier studies indicated that TMEM39A was a key mediator of autoimmune disease. TMEM39A seems to be involved in systemic lupus erythematosus and multiple sclerosis in numerous of populations. All of these works stop at insufficient information by using gene functioning methods such as: Genome-wide association studies (GWASs) and/or follow-up study. It is the fact that the less understood of TMEM39A actually is the attraction to the scientist in near future. In this review the current knowledge about TMEM39A and its possible roles in cell biology, physiology and pathology will be described.

TMEM39A and Human Diseases

Quangdon Tran,Jisoo Park,Hyunji Lee,Youngeun Hong,Suntaek Hong,Sungjin Park,Jongsun Park,Seon-Hwan Kim 한국독성학회 2017 Toxicological Research Vol.33 No.3

Transmembrane Protein 39A (TMEM39A) is a member of TMEM family. The understanding about this protein is still limited. The earlier studies indicated that TMEM39A was a key mediator of autoimmune disease. TMEM39A seems to be involved in systemic lupus erythematosus and multiple sclerosis in numerous of populations. All of these works stop at insufficient information by using gene functioning methods such as: Genome-wide association studies (GWASs) and/or follow-up study. It is the fact that the less understood of TMEM39A actually is the attraction to the scientist in near future. In this review the current knowledge about TMEM39A and its possible roles in cell biology, physiology and pathology will be described.

IMP2 and IMP3 cooperate to promote the metastasis of triple-negative breast cancer through destabilization of progesterone receptor

Kim, Hye-Youn,Ha Thi, Huyen Trang,Hong, Suntaek Elsevier 2018 Cancer letters Vol.415 No.-

<P><B>Abstract</B></P> <P>Triple-negative breast cancer (TNBC) is one of the most aggressive malignancies and is associated with high mortality rates due to the lack of effective therapeutic targets. In this study, we demonstrated that insulin-like growth factor-II mRNA-binding protein 2 and 3 (IMP2 and IMP3) are specifically overexpressed in TNBC and cooperate to promote cell migration and invasion. Downregulation of both IMP2 and IMP3 in TNBC cells was found to produce a synergistic effect in suppressing cell invasion and invadopodia formation, whereas overexpression of IMP2 and IMP3 in luminal subtype cells enhanced epithelial-mesenchymal transition and metastasis. We also showed that IMP2 and IMP3 are direct targets of microRNA-200a (miR-200a), which is downregulated in TNBC. Conversely, IMP2 and IMP3 suppressed the transcription of miR-200a by destabilizing progesterone receptor (PR) mRNA through recruitment of the CCR4-NOT transcription complex subunit 1 (CNOT1) complex. Together, our findings suggest that IMP2 and IMP3 partially determine the characteristic phenotype and synergistically promote the metastasis of TNBC by downregulating PR. The identified IMP2/3-miR-200a-PR axis represents a novel double-negative feedback loop and serves as a new potential therapeutic target for the treatment of TNBC.</P> <P><B>Highlights</B></P> <P> <UL> <LI> IMP2 and IMP3 synergistically promote the migration and metastasis of TNBC. </LI> <LI> miR-200a directly regulates the expression of IMP2 and IMP3. </LI> <LI> IMP2 and IMP3 negatively regulate the expression of miR-200a at transcriptional level. </LI> <LI> IMP2 and IMP3 reduce the stability of PR mRNA by recruiting the CNOT1 complex. </LI> <LI> IMP2/3-miR-200a-PR axis can be a novel therapeutic target against metastasis of TNBC. </LI> </UL> </P>

Src Is a Prime Target Inhibited by <i> Celtis choseniana</i> Methanol Extract in Its Anti-Inflammatory Action

Kim, Han Gyung,Choi, Subin,Lee, Jongsung,Hong, Yo Han,Jeong, Deok,Yoon, Keejung,Yoon, Deok Hyo,Sung, Gi-Ho,Lee, Seungihm,Hong, Suntaek,Yi, Young-Su,Kim, Jong-Hoon,Cho, Jae Youl Hindawi 2018 Evidence-based Complementary and Alternative Medic Vol.2018 No.-

<P><I>Celtis choseniana</I> is the traditional plant used at Korea as a herbal medicine to ameliorate inflammatory responses. Although<I> Celtis choseniana</I> has been traditionally used as a herbal medicine at Korea, no systemic research has been conducted on its anti-inflammatory activity. Therefore, the present study explored an anti-inflammatory effect and its underlying molecular mechanism using<I> Celtis choseniana </I>methanol extract (Cc-ME) in macrophage-mediated inflammatory responses.<I> In vitro</I> anti-inflammatory activity of Cc-ME was evaluated using RAW264.7 cells and peritoneal macrophages stimulated by lipopolysaccharide (LPS), pam3CSK4 (Pam3), or poly(I:C).<I> In vivo</I> anti-inflammatory activity of Cc-ME was investigated using acute inflammatory disease mouse models, such as LPS-induced peritonitis and HCl/EtOH-induced gastritis. The molecular mechanism of Cc-ME-mediated anti-inflammatory activity was examined by Western blot analysis and immunoprecipitation using whole cell and nuclear fraction prepared from the LPS-stimulated RAW264.7 cells and HEK293 cells. Cc-ME inhibited NO production and mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX-2), and tumor necrosis factor-alpha (TNF-<I>α</I>) in the RAW264.7 cells and peritoneal macrophages induced by LPS, pam3, or poly(I:C) without cytotoxicity. High-performance liquid chromatography (HPLC) analysis showed that Cc-ME contained anti-inflammatory flavonoids quercetin, luteolin, and kaempferol. Among those, the content of luteolin, which showed an inhibitory effect on NO production, was highest. Cc-ME suppressed the NF-<I>κ</I>B signaling pathway by targeting Src and interrupting molecular interactions between Src and p85, its downstream kinase. Moreover, Cc-ME ameliorated the morphological finding of peritonitis and gastritis in the mouse disease models. Therefore, these results suggest that Cc-ME exerted<I> in vitro</I> and<I> in vivo</I> anti-inflammatory activity in LPS-stimulated macrophages and mouse models of acute inflammatory diseases. This anti-inflammatory activity of Cc-ME was dominantly mediated by targeting Src in NF-<I>κ</I>B signaling pathway during macrophage-mediated inflammatory responses.</P>

Lower Salinomycin Concentration Increases Apoptotic Detachment in High-Density Cancer Cells

Kim, Ju-Hwa,Kim, Tae Young,Kim, Hyung Sik,Hong, Suntaek,Yoon, Sungpil Molecular Diversity Preservation International (MD 2012 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.13 No.10

<P>The present study identified a novel salinomycin (Sal) sensitization mechanism in cancer. We tested whether Sal reduced proliferation in a high-density population by counting attached cell numbers after Sal treatment. Sal reduced proliferation in high-density cell populations. Longer exposure to Sal further reduced proliferation. Sal concentrations of 0.1 and 5 μM had similar sensitization effects, suggesting that Sal toxicity was minimal with longer exposure to a high-density cell population. The results suggest that Sal can be applied at a relatively low concentration for a longer time to overcome drug-resistant solid tumors. The 0.5 μM Sal treatment resulted in fewer attached cells than that of the 5 μM Sal treatment with a longer exposure. The lower Sal concentration mainly increased the number of easily detachable cells on the surface. In particular, 0.5 μM Sal increased cellular detachment of newly produced daughter cells. The easily-detachable cells were undergoing apoptosis. It seems that the 0.5 μM Sal treatment also increased cellular toxicity. These novel findings may contribute to the development of Sal-based therapy for patients with drug-resistant cancer or a high-density solid tumor.</P>

Smad7 enhances ATM activity by facilitating the interaction between ATM and Mre11-Rad50-Nbs1 complex in DNA double-strand break repair.

Park, Sujin,Kang, Jin Muk,Kim, Staci Jakyong,Kim, Hyojung,Hong, Suntaek,Lee, Young Jae,Kim, Seong-Jin Birkhäuser ; Springer 2015 Cellular and molecular life sciences Vol.72 No.3

<P>Genomic instability is one of the representative causes in genetic disorder, where the proper cellular response to DNA damage is essential in maintaining genomic stability. ATM and the Mre11-Rad50-Nbs1 (MRN) complex play critical roles in the cellular response to DNA damage such as DNA double-strand break (DSB). In this study, we report that Smad7 is indispensible in DNA damage response as a novel component of MRN complex. Smad7 enhances cell survival against DNA damage by accelerating ATM dependent DNA repair signaling. In Smad7-deficient mouse embryonic fibroblast cells, the loss of Smad7 decreases ATM activation and inhibits recruitment of ATM to the sites of DSBs. Smad7 interacts with Nbs1, a member of MRN complex, and enhances the interaction between ATM and Nbs1 upon DNA damage response, leading to phosphorylation of downstream substrates. Ectopic expression of Smad7 in the skin of mice enhances the phosphorylation of ATM upon X-irradiation. We found that effect of Smad7 on enhancing DNA repair is independent of its inhibitory activity of TGF-β signaling. Taken together, our results highlight a critical function of Smad7 in DSB response and establish the novel mechanism in which Smad7 facilitates the recruitment of ATM to the MRN complex through direct interaction with Nbs1.</P>

The roles of TRIO and F-actin-binding protein in glioblastoma cells

Lee, Hyunji,Kim, Minhee,Park, Jisoo,Tran, Quangdon,Hong, Youngeun,Cho, Hyeonjeong,Park, Sungjin,Hong, Suntaek,Brazil, Derek P.,Kim, Seon-Hwan,Park, Jongsun SPANDIDOS PUBLICATIONS 2018 MOLECULAR MEDICINE REPORTS Vol. No.

<P>TRIO and F-actin-binding protein (TrioBP), which was initially discovered as a binding partner of Trio and F-actin, is a critical factor associated with hearing loss in humans. However, the function of TrioBP in cancer has not been investigated. In the present study, TrioBP expression was indicated to be highly elevated in U87-MG and U343-MG cells. Furthermore, the TrioBP mRNA expression level was markedly increased in U87-MG and U251-MG cells compared with that in cerebral cortex cells, as determined by deep sequencing. Comprehensive analysis of a public TCGA dataset confirmed that TrioBP expression is elevated in patients with glioblastoma. In summary, the present data indicate that TrioBP expression is increased in glioblastoma cell lines and in patients with glioma, suggesting that TrioBP has potential as a diagnostic marker or therapeutic agent for glioma.</P>