Publications by authors named "Seung-Nam Jung"

26 Publications

  • Page 1 of 1

EGR1/GADD45α Activation by ROS of Non-Thermal Plasma Mediates Cell Death in Thyroid Carcinoma.

Cancers (Basel) 2021 Jan 19;13(2). Epub 2021 Jan 19.

Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Korea.

(1) Background: Nonthermal plasma (NTP) induces cell death in various types of cancer cells, providing a promising alternative treatment strategy. Although recent studies have identified new mechanisms of NTP in several cancers, the molecular mechanisms underlying its therapeutic effect on thyroid cancer (THCA) have not been elucidated. (2) Methods: To investigate the mechanism of NTP-induced cell death, THCA cell lines were treated with NTP-activated medium -(NTPAM), and gene expression profiles were evaluated using RNA sequencing. (3) Results: NTPAM upregulated the gene expression of early growth response 1 (). NTPAM-induced THCA cell death was enhanced by EGR1 overexpression, whereas EGR1 small interfering RNA had the opposite effect. NTPAM-derived reactive oxygen species (ROS) affected EGR1 expression and apoptotic cell death in THCA. NTPAM also induced the gene expression of growth arrest and regulation of DNA damage-inducible 45α () gene, and EGR1 regulated through direct binding to its promoter. In xenograft in vivo tumor models, NTPAM inhibited tumor progression of THCA by increasing EGR1 levels. (4) Conclusions: Our findings suggest that NTPAM induces apoptotic cell death in THCA through a novel mechanism by which NTPAM-induced ROS activates EGR1/GADD45α signaling. Furthermore, our data provide evidence that the regulation of the EGR1/GADD45α axis can be a novel strategy for the treatment of THCA.
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http://dx.doi.org/10.3390/cancers13020351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833439PMC
January 2021

Growth Differentiation Factor 15 Is a Cancer Cell-Induced Mitokine That Primes Thyroid Cancer Cells for Invasiveness.

Thyroid 2021 Jan 7. Epub 2021 Jan 7.

Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon, South Korea.

Mitochondrial stress is known to activate the mitochondrial unfolded protein response (UPR). The UPR results in the secretion of mitochondrial cytokines (mitokines), which can promote a hormetic response cell nonautonomously, and has been reported to be protumorigenic. Growth differentiation factor 15 (GDF15) is a well-characterized mitokine, which is reported to have a mitohormetic effect. Thus, we investigated whether GDF15 induction could prime a subpopulation of thyroid cancer cells to provide invasive advantages. The UPR, including mitokine expression, was assessed in the context of thyroid cancer and . GDF15 expression in 266 patients with papillary thyroid carcinoma (PTC) was determined by immunohistochemistry. The serum levels of GDF15 were measured in healthy subjects and PTC patients. In addition, our own and The Cancer Genome Atlas data were analyzed to determine the expression level of in thyroid cancers. The role of GDF15 in tumor aggressiveness was investigated by observing the effects of GDF15 knockdown in BCPAP, TPC-1, 8505C, and FRO cells. Pharmacological inhibition of mitochondrial oxidative phosphorylation function in thyroid cancer cells robustly increased GDF15 expression. The expression of GDF15 was associated with activation of the mitochondrial integrated stress response pathway in PTC patients. Circulating GDF15 levels were significantly higher in PTC patients than in the controls, and tumor expression of GDF15 was related to tumor aggressiveness. and knockdown of GDF15 in a thyroid cancer model showed decreased viability, migration, and invasion compared with the control cells via regulation of STAT3. In this study, we demonstrated that GDF15 is a mitokine induced in thyroid cancer cells upon mitochondrial stress. GDF15-induced STAT3 activation determined tumor progression in thyroid cancer. The GDF15-STAT3 signaling axis may be a target in aggressiveness of thyroid cancer.
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http://dx.doi.org/10.1089/thy.2020.0034DOI Listing
January 2021

Effect of Urban Particulate Matter on Vocal Fold Fibrosis through the MAPK/NF-κB Signaling Pathway.

Int J Mol Sci 2020 Sep 10;21(18). Epub 2020 Sep 10.

Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Korea.

Particulate matter (PM) is an environmental exposure factor that adversely affects human health. PM is a risk factor for various diseases. However, the mechanism by which PM affects the vocal folds (VF) has not yet been evaluated. Thus, we investigated the cytotoxic effects of PM on human vocal fold fibroblasts (hVFF) and the underlying signaling pathways. hVFF were isolated from human VF. The effect of PM on hVFF, and the underlying mechanism, were analyzed using Western blot, quantitative real-time polymerase chain reaction, and flow cytometry. In addition, a histological evaluation was performed in animal experiments. Cell proliferation decreased after the PM treatment. PM increased the expression of interleukin (IL)-6 and IL-1β. The generation of reactive oxygen species (ROS) in PM-treated hVFF and subsequent activation of the mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathways were confirmed. Furthermore, PM increased the expression of fibrosis-related markers and induced the accumulation of collagen in the extracellular matrix. As a result, PM exposure significantly enhances the inflammatory response on VF through the ROS-mediated activation of the MAPK and NF-κB signaling pathways. In addition, PM promotes differentiation into myofibroblasts and induces fibrosis. These results suggest that PM triggers an inflammatory reaction through ROS production and causes VF fibrosis.
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http://dx.doi.org/10.3390/ijms21186643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555340PMC
September 2020

Brn3a/Pou4f1 Functions as a Tumor Suppressor by Targeting c-MET/STAT3 Signaling in Thyroid Cancer.

J Clin Endocrinol Metab 2020 09;105(9)

Department of Otolaryngology-Head and Neck Surgery, Chungnam National University College of Medicine, Daejeon, Korea.

Background: Brn3a/Pou4f1 is a class IV POU domain-containing transcription factor and has been found to be expressed in a variety of cancers. However, the mechanism and action of Brn3a in thyroid cancer has not been investigated.

Purpose: To investigate the role of Brn3a in thyroid cancer progression and its clinical implication.

Methods: We examined Brn3a expression status in patients with thyroid cancer and analyzed relationships between Brn3a expression and clinicopathological findings using The Cancer Genome Atlas (TCGA) database. For functional in vitro analysis, proliferation, migration, invasion assay, and Western blotting were performed after overexpression or suppression of Brn3a.

Results: The promoter hypermethylation of Brn3a was found in patients with aggressive thyroid cancer and Brn3a was downregulated in tissues of patients with thyroid cancer. In TCGA database, the low-Brn3a-expression group revealed a more aggressive phenotype, including T stage and extrathyroid extension when compared with the high-Brn3a-expression group. Overexpression of Brn3a suppressed cell migration and invasion via regulation of epithelial-mesenchymal transition (EMT)-associated proteins in thyroid cancer cell lines. Brn3a overexpression also downregulated signal transducer and activator of transcription 3 (STAT3) signaling through suppression of tyrosine-protein kinase Met (c-MET). In contrast, knockdown of Brn3a by small interfering ribonucleic acid (siRNA) significantly increased cell migration and invasion through upregulation of c-MET/STAT3. These results imply that Brn3a suppresses tumor metastasis via c-MET/STAT3 inhibition and EMT suppression in thyroid cancer.

Conclusions: Our findings show that Brn3a is a potential tumor suppressor that leads to reduced cancer cell migration and invasion in thyroid cancer. Elucidation of the Brn3a-regulated cancer pathways may therefore provide novel therapeutic strategies to control thyroid cancer metastasis.
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http://dx.doi.org/10.1210/clinem/dgaa316DOI Listing
September 2020

HOXB5 acts as an oncogenic driver in head and neck squamous cell carcinoma via EGFR/Akt/Wnt/β-catenin signaling axis.

Eur J Surg Oncol 2020 06 12;46(6):1066-1073. Epub 2019 Dec 12.

Department of Otolaryngology - Head and Neck Surgery, Research Institute for Medical Sciences, Chungnam National University School of Medicine, Daejeon, Republic of Korea. Electronic address:

Introduction: Identification of therapeutic targets in head and neck squamous cell carcinoma (HNSCC) is essential because most of the patients with advanced HNSCC have a poor prognosis. Homeobox genes constitute a large cluster of transcription factors with important regulatory roles in mammalian embryonic development and cell differentiation. The oncogenic role of homeobox B5 (HOXB5) in HNSCC has not been investigated.

Materials And Methods: We used The Cancer Genome Atlas (TCGA) data to evaluate the correlations between HOXB5 expression and various HNSCC clinicopathological factors. We knocked down HOXB5 expression in HNSCC cell lines and explored the in vitro and in vivo effects on cell proliferation and motility, and HOXB5 signaling.

Results: The Cancer Genome Atlas (TCGA) data shows that HOXB5 is overexpressed in HNSCC compared to normal tissues and significantly associates with tumor stage (P = 0.003), lymph node metastasis (P = 0.031), disease stage (P = 0.002), and angiolymphatic invasion (P = 0.004). Our results also show that HOXB5 expression is up-regulated in HNSCC cell lines, and HOXB5 knockdown significantly reduced cell proliferation and tumor growth in vitro and in vivo. Inhibition of HOXB5 decreases cell migration and invasion via suppression of epithelial-to-mesenchymal transition (EMT)-associated proteins expression. Moreover, HOXB5 directly binds to the promoter region of EGFR and consequently regulates the activity of the Akt/Wnt/β-catenin signaling axis.

Conclusion: HOXB5 may be a novel therapeutic target as an oncogenic driver by regulating EGFR transcription in HNSCC.
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http://dx.doi.org/10.1016/j.ejso.2019.12.009DOI Listing
June 2020

The most reliable time point for intact parathyroid hormone measurement to predict hypoparathyroidism after total thyroidectomy with central neck dissection to treat papillary thyroid carcinoma: a prospective cohort study.

Eur Arch Otorhinolaryngol 2020 Feb 16;277(2):549-558. Epub 2019 Oct 16.

Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Research Institute for Medical Science, Chungnam National University, 640 Daesa-Dong, Chung-Gu, Daejeon, 301-721, Republic of Korea.

Purpose: We assessed the optimal time for intact parathyroid hormone (iPTH) measurement for early detection of post-total thyroidectomy (TT) hypocalcemia in patients with papillary thyroid carcinoma (PTC).

Methods: In this single-center prospective cohort study, 143 patients who underwent TT with central neck dissection with or without lateral neck dissection for PTC were included. Biochemical profiles including iPTH, corrected total calcium, and ionized calcium within 24 h after surgery were analyzed.

Results: The 4-h postoperative iPTH was the most reliable predictor of post-TT transient or permanent hypoparathyroidism (cutoff for hypocalcemia was 3.75 pg/mL, AUC = 0.885, P < 0.001, sensitivity 81.6%, specificity 86.0%; cutoff for permanent hypocalcemia was 2.48 pg/mL, AUC = 0.819, P < 0.001, sensitivity 100%, specificity 57.8% calculated using ROC curves).

Conclusions: The 4-h postoperative iPTH can most accurately predict hypoparathyroidism after TT with central neck dissection to treat PTC and facilitate the early discharge of low-risk postoperative hypoparathyroidism patients and decrease unnecessary overnight observation and calcium supplementation.
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http://dx.doi.org/10.1007/s00405-019-05693-1DOI Listing
February 2020

Association between Circulating Fibroblast Growth Factor 21 and Aggressiveness in Thyroid Cancer.

Cancers (Basel) 2019 Aug 12;11(8). Epub 2019 Aug 12.

Department of Endocrinology and Metabolism, Chungnam National University College of Medicine, Daejeon 35015, Korea.

Fibroblast growth factor 21 (FGF21) plays important roles in regulating glucose, lipid, and energy metabolism; however, its effects in tumors remain poorly understood. To understand the role of FGF21 in regulating tumor aggressiveness in thyroid cancer, serum levels of FGF21 were measured in healthy subjects and patients with papillary thyroid cancer (PTC), and expression levels of FGF21, FGF receptors (FGFRs), and β-klotho (KLB) were investigated in human thyroid tissues. The cell viability, migrating cells, and invading cells were measured in PTC cells after treatment with recombinant FGF21. Higher serum levels of FGF21 were found in patients with thyroid cancer than in control participants, and were significantly associated with body mass index (BMI), fasting glucose levels, triglyceride levels, tumor stage, lymphovascular invasion, and recurrence. Serum FGF21 levels were positively correlated with the BMI in patients with PTC, and significantly associated with recurrence. Recombinant FGF21 led to tumor aggressiveness via activation of the FGFR signaling axis and epithelial-to-mesenchymal transition (EMT) signaling in PTC cells, and AZD4547, an FGFR tyrosine kinase inhibitor, attenuated the effects of FGF21. Hence, FGF21 may be a new biomarker for predicting tumor progression, and targeting FGFR may be a novel therapy for the treatment of obese patients with PTC.
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http://dx.doi.org/10.3390/cancers11081154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721537PMC
August 2019

LAMB3 is associated with disease progression and cisplatin cytotoxic sensitivity in head and neck squamous cell carcinoma.

Eur J Surg Oncol 2019 03 2;45(3):359-365. Epub 2018 Nov 2.

Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea. Electronic address:

Objectives: Laminin subunit beta-3 (LAMB3) is a major component of the basement membrane zone. In our study, we investigated the role of LAMB3 in head and neck squamous cell carcinoma (HNSCC) progression and its clinical implication as a prognostic biomarker.

Materials And Methods: A retrospective analysis of 100 patients with HNSCC who had undergone curative surgery from 1999 to 2011 was performed. We evaluated LAMB3 expression by immunohistochemistry and its associations with clinicopathological characteristics and survival. For functional in vitro analyses, cell proliferation, migration, and invasion and western blot assays were performed following LAMB3 suppression. In addition, the role of LAMB3 in cisplatin-induced cytotoxicity was clarified by measuring cell proliferation.

Results: LAMB3 expression was up-regulated in HNSCC cell lines and patient tissues. High LAMB3 expression was significantly associated with positive lymph node metastasis (odds ratio: 6.316; P < 0.001) and poor prognosis in patients with HNSCC. LAMB3 suppression reduced cell migration/invasion via down-regulation of epithelial-to-mesenchymal transition-associated proteins (Vimentin and Slug). Moreover, LAMB3 suppression increased cisplatin cytotoxicity in HNSCC cells.

Conclusion: Our findings indicate that LAMB3 may be used as a prognostic biomarker in HNSCC and support that LAMB3 silencing could induce the sensitivity of anti-cancer drugs such as cisplatin.
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http://dx.doi.org/10.1016/j.ejso.2018.10.543DOI Listing
March 2019

Clinical significance of extrathyroidal extension according to primary tumor size in papillary thyroid carcinoma.

Eur J Surg Oncol 2018 11 12;44(11):1754-1759. Epub 2018 Jun 12.

Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea. Electronic address:

Background: Extrathyroidal extension (ETE) is a risk factor for poor papillary thyroid carcinoma (PTC) outcomes. However, the clinical significance of ETE according to primary tumor size has not been well-established. The purpose of this study was to compare differences in clinical outcomes, according to the presence and extent of ETE, between different primary tumor size groups.

Methods: In total, 381 patients with PTC underwent total thyroidectomy with or without lymph node (LN) dissection from 2004 to 2010. We divided the patients into two groups according to primary tumor size: ≤ 1 cm or >1 cm. Each group was further divided into subgroups according to the presence of ETE (ETE vs. no ETE) and degree of ETE (microscopic ETE vs. macroscopic ETE). The clinicopathological features and rate of recurrence during follow-up were compared among groups.

Results: Among the PTC patients with primary tumors >1 cm, patients with ETE had a higher recurrence rate than those without ETE, and only macroscopic ETE affected recurrence in patients with PTC > 1 cm (P < 0.05). However, there was no significant difference in recurrence rates between those without ETE and those with microscopic ETE (P = 0.100). When the primary tumor size was less than 1 cm, there were no difference in recurrence rates between the groups with or without ETE, or between the groups with microscopic and macroscopic ETE (P > 0.05).

Conclusions: Our data suggests that the presence and degree of ETE may be associated with PTC outcome based on primary tumor size.
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http://dx.doi.org/10.1016/j.ejso.2018.05.009DOI Listing
November 2018

LAMB3 mediates metastatic tumor behavior in papillary thyroid cancer by regulating c-MET/Akt signals.

Sci Rep 2018 02 9;8(1):2718. Epub 2018 Feb 9.

Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea.

Laminin subunit beta-3 (LAMB3) encodes one of the three subunits of LM-332, a protein of the extracellular matrix secreted by cultured human keratinocytes. While LAMB3 is involved in the invasive and metastatic abilities of several tumor types, including those found in the colon, pancreas, lung, cervix, stomach, and prostate, its mechanism of action in thyroid cancer has not been investigated previously. Our results show that LAMB3 is up-regulated in papillary thyroid cancer, and that its suppression reduces cell migration/invasion via down-regulation of epithelial‒mesenchymal transition-associated proteins (N-cadherin, vimentin, slug) and inhibition of matrix metalloproteinase 9. LAMB3 suppression also significantly decreases Akt phosphorylation and inhibits the transcription of c-MET, reducing its activation. These results suggest that LAMB3 leads to tumor invasion via Akt activation induced by the HGF/c-MET axis in papillary thyroid cancer cells. Our findings reveal a novel mechanism of action for LAMB3 in papillary thyroid cancer cells.
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http://dx.doi.org/10.1038/s41598-018-21216-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807368PMC
February 2018

Relationship Between F-fluorodeoxyglucose Accumulation and the BRAF Mutation in Papillary Thyroid Cancer.

World J Surg 2018 01;42(1):114-122

Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Science, College of Medicine, Chungnam National University, 640 Daesa-Dong, Chung-Gu, Daejeon, 301-721, Republic of Korea.

Background: To determine whether F-fluoro-2-deoxyglucose (F-FDG)-PET/CT is useful for predicting the BRAF mutation status of a primary papillary thyroid carcinoma (PTC).

Methods: A retrospective analysis was performed in 108 patients who underwent F-FDG positron emission tomography-computed tomography (PET/CT) for staging before thyroidectomy and BRAF analysis in biopsy-confirmed PTC. The maximum standardized uptake value (SUV) of the primary tumor was calculated according to FDG accumulation. Univariate and multivariate analyses were performed to assess the association between the SUV and clinicopathological variables.

Results: The BRAF mutation was detected in 71 of 108 (65.7%) patients. In all subjects, the tumor size and BRAF mutation were independently related to the SUV according to multivariate analyses (P = 0.002 and 0.007, respectively). The SUV was significantly higher in tumors with the BRAF mutation than in tumors with wild-type BRAF (10.24 ± 11.89 versus 4.02 ± 3.86; P = 0.007). In the tumor size >1 cm subgroup, the BRAF mutation was the only factor significantly associated with the SUV (P = 0.016). A SUV cutoff level of 4.9 was determined to be significant for predicting the BRAF mutation status (sensitivity 77.4%, specificity 100.0%, area under the curve 0.929; P < 0.0001) according to ROC curve analysis.

Conclusions: The BRAF mutation is independently associated with high F-FDG uptake in PTC, especially in those with a tumor size >1 cm.
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http://dx.doi.org/10.1007/s00268-017-4136-yDOI Listing
January 2018

High Expression of Angiopoietin-1 is Associated with Lymph Node Metastasis and Invasiveness of Papillary Thyroid Carcinoma.

World J Surg 2017 12;41(12):3128-3138

Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Sciences, Chungnam National University School of Medicine, 266 Munhwa-ro, Jung-gu, Daejeon, 301-721, Republic of Korea.

Background: We investigated the expression of angiopoietins in patients with papillary thyroid carcinoma (PTC) and the role of angiopoietins as biomarkers predicting the aggressiveness of PTC.

Methods: Expression of angiopoietins was evaluated by immunohistochemistry of tumor specimens from patients with PTC. We demonstrated potential correlations between expression of angiopoietins and clinicopathologic features.

Results: High expression of Ang-1 was positively correlated with a tumor size >1 cm, capsular invasion, extrathyroid extension, lymphovascular invasion, lymph node metastasis, and recurrence (P < 0.05). Moreover, multivariate analysis revealed that high expression of Ang-1 was an independent risk factor for lymph node metastasis (P < 0.001, odds ratio [OR] = 62.113) and lymphovascular invasion (P = 0.027, OR 4.405). However, there was no significant correlation between Ang-2 and clinicopathologic features.

Conclusions: Our results suggest that Ang-1 can serve as a valuable prognostic biomarker for lymph node metastasis and invasiveness in patients with PTC.
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http://dx.doi.org/10.1007/s00268-017-4111-7DOI Listing
December 2017

Clinical implications of microscopic extrathyroidal extension in patients with papillary thyroid carcinoma.

Oral Oncol 2017 09 20;72:183-187. Epub 2017 Feb 20.

Department of Otorhinolaryngology-Head and Neck Surgery, Research Institute for Medical Sciences, Chungnam National University College of Medicine, Daejeon, Republic of Korea. Electronic address:

Background: Extrathyroidal extension (ETE) is a poor prognostic factor in papillary thyroid carcinoma (PTC). However, the impact of the degree of ETE, especially microscopic ETE, has not been well established. The purpose of present study was to compare differences in clinicopathological characteristics and clinical outcomes according to the presence or extent of ETE.

Methods: Data from 381 patients who underwent total thyroidectomy with/without lymph node (LN) dissection for PTC between 2004 and 2010 were analyzed. Clinicopathological features such as age, gender, LN metastasis, capsular invasion, lymphovascular invasion, and recurrence were compared among three groups divided according to degree of ETE: no ETE (n=144), microscopic ETE (n=191), and macroscopic ETE (n=46).

Results: Tumor size, LN metastasis, lymphovascular invasion, extent of surgery, and administration of postoperative radioactive iodine (RAI) were significantly correlated with degree of ETE. Especially, among the patients with a primary tumor size ≤4cm, the patients with microscopic ETE showed more LN metastasis and lymphovascular invasion than those without ETE, whereas less LN metastasis and lymphovascular invasion than those with macroscopic ETE. In addition, the microscopic ETE group had a significantly lower 5-year recurrence free survival (RFS) than the no-ETE group (92.1% vs. 99.3%, p<0.001) and a significantly higher 5-year RFS than the macroscopic ETE group (92.1% vs. 65.2%, p<0.001).

Conclusions: The degree of ETE is correlated with clinicopathologic features and tumor recurrence. Patients with microscopic ETE have a poorer clinical outcome than those without ETE, but they showed a better outcome than patients with macroscopic ETE.
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http://dx.doi.org/10.1016/j.oraloncology.2017.02.008DOI Listing
September 2017

Clinical implications of the extent of BRAF alleles in patients with papillary thyroid carcinoma.

Oral Oncol 2016 11 19;62:72-77. Epub 2016 Oct 19.

Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University College of Medicine, Daejeon, Republic of Korea. Electronic address:

Objective: There are many conflicting reports about the clinical implications of BRAF in papillary thyroid cancer (PTC). We investigated the associations between the extent of BRAF alleles and both clinico-pathological features and recurrence of PTC.

Materials And Methods: Carcinoma tissues from 60 patients with PTC were genotyped for BRAF using pyrosequencing, and the clinico-pathological factors and disease outcomes of the patients were examined. The associations between the extent of mutant BRAF alleles and both clinico-pathological parameters and recurrence-free survival (RFS) were analyzed.

Results: The BRAF mutation was detected in 66.7% (40/60) of our PTC patients. When we defined four groups on the basis of the extent of BRAF alleles by pyrosequencing-negative (less than 5%), low (5 - less than 15%), intermediate (15 - less than 25%), and high (25% or greater)- the four groups showed statistically significant differences regarding lymph node (LN) metastasis and recurrence (P<0.05). However, age, gender, tumor size, multicentricity, capsular invasion, and lymphovascular invasion were not significantly different among the groups. The 10-year RFS rates in PTC patients with greater than 25% and less than 25% mutated BRAF alleles were 74% and 100%, respectively. This difference was significant (P=0.043).

Conclusions: A high extent more than 25% of BRAF alleles may be associated with disease outcome in PTC patients. We need more data to verify a hypothesis that the extent of BRAF mutations may be clinically informative in the management of PTC, such as by tailoring proper surgical and radioactive iodine treatments and determining appropriate management during follow-up.
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http://dx.doi.org/10.1016/j.oraloncology.2016.10.005DOI Listing
November 2016

Carboxyl-Terminal Modulator Protein Positively Acts as an Oncogenic Driver in Head and Neck Squamous Cell Carcinoma via Regulating Akt phosphorylation.

Sci Rep 2016 06 22;6:28503. Epub 2016 Jun 22.

Department of Otolaryngology-Head and Neck Surgery, Research Institute for Medical Science, Chungnam National University, Daejeon, Republic of Korea.

The exact regulatory mechanisms of carboxyl-terminal modulator protein (CTMP) and its downstream pathways in cancer have been controversial and are not completely understood. Here, we report a new mechanism of regulation of Akt serine/threonine kinase, one of the most important dysregulated signals in head and neck squamous cell carcinoma (HNSCC) by the CTMP pathway and its clinical implications. We find that HNSCC tumor tissues and cell lines had relatively high levels of CTMP expression. Clinical data indicate that CTMP expression was significantly associated with positive lymph node metastasis (OR = 3.8, P = 0.033) and correlated with poor prognosis in patients with HNSCC. CTMP was also positively correlated with Akt/GSK-3β phosphorylation, Snail up-regulation and E-cadherin down-regulation, which lead to increased proliferation and epithelial-to-mesenchymal transition, suggesting that CTMP expression results in enhanced tumorigenic and metastatic properties of HNSCC cells. Moreover, CTMP suppression restores sensitivity to cisplatin chemotherapy. Intriguingly, all the molecular responses to CTMP regulation are identical regardless of p53 status in HNSCC cells. We conclude that CTMP promotes Akt phosphorylation and functions as an oncogenic driver and prognostic marker in HNSCC irrespective of p53.
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http://dx.doi.org/10.1038/srep28503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916413PMC
June 2016

Sugiol inhibits STAT3 activity via regulation of transketolase and ROS-mediated ERK activation in DU145 prostate carcinoma cells.

Biochem Pharmacol 2015 Sep 23;97(1):38-50. Epub 2015 Jul 23.

Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology 125Gwahakro Yoosunggu, Daejeon 305-806, Republic of Korea; Biomolecular Science, University of Science and Technology in Korea, 125 Gwahakro Yoosunggu, Daejeon 305-806, Republic of Korea. Electronic address:

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in various human cancers and has been used as a therapeutic target for tumors. This study screened natural products to identify compounds that inhibit STAT3 activity using a STAT3-dependent luciferase reporter system. Sugiol was identified as a compound that decreased luciferase activity in a dose-dependent manner. Sugiol specifically inhibited STAT3 phosphorylation at Tyr-705 in DU145 prostate cells, and this inhibition was independent of the STAT3 upstream kinase. Sugiol induced cell cycle arrest and decreased the expression levels of STAT3 target genes, such as cyclin D1, cyclin A, and survivin. Notably, we observed that sugiol interacted with transketolase, an enzyme in central metabolism, and increased ROS levels leading to the activation of ERK, which inhibits STAT3 activity. The protein phosphatase MEG2 was also responsible for sugiol-induced STAT3 dephosphorylation. The inhibitory effect of sugiol on cell growth was confirmed using the DU145 mouse xenograft model. We propose that sugiol inhibits STAT3 activity through a mechanism that involves the inhibition of transketolase, which leads to increased ROS levels and MEG2 activation in DU145 cells. Therefore, sugiol is the first compound regulating STAT3 activity via modulation of cancer metabolic pathway and we suggest the use of sugiol as an inhibitor of the STAT3 pathway for the treatment of human solid tumors with activated STAT3.
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http://dx.doi.org/10.1016/j.bcp.2015.06.033DOI Listing
September 2015

Artocarpus altilis (Parkinson) Fosberg Extracts and Geranyl Dihydrochalcone Inhibit STAT3 Activity in Prostate Cancer DU145 Cells.

Phytother Res 2015 May 13;29(5):749-56. Epub 2015 Feb 13.

Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, 125 Gwahakro Yoosunggu, Daejeon, 305-600, Republic of Korea.

Artocarpus altilis (Parkinson) Fosberg has traditionally been used in Indonesia for the treatment of liver cirrhosis, hypertension, and diabetes. In many other countries, it is used for the treatment of malaria, yellow fever, and dengue fever. It has been reported that A. altilis extracts have antiatherosclerotic and cytoprotective effects, but its molecular targets in tumor cells are not yet fully understood. The A. altilis extracts and the partially purified fraction have been shown to inhibit STAT3 activity and the phosphorylation of STAT3 in a dose-dependent manner. To identify the active components, a bioassay-guided isolation of the partially purified fraction resulted in the identification of a geranyl dihydrochalcone, CG901. Its chemical structure was established on the basis of spectroscopic evidence and comparison with published data. The partially purified fraction and the isolated a geranyl dihydrochalcone, CG901, down-regulated the expression of STAT3 target genes, induced apoptosis in DU145 prostate cancer cells via caspase-3 and PARP degradation, and inhibited tumor growth in human prostate tumor (DU145) xenograft initiation model. These results suggest that A. altilis could be a good natural source and that the isolated compound will be a potential lead molecule for developing novel therapeutics against STAT3-related diseases, including cancer and inflammation.
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http://dx.doi.org/10.1002/ptr.5311DOI Listing
May 2015

Ginkgetin inhibits the growth of DU-145 prostate cancer cells through inhibition of signal transducer and activator of transcription 3 activity.

Cancer Sci 2015 Apr 20;106(4):413-20. Epub 2015 Feb 20.

Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea; Korea University of Science and Technology, Daejeon, Korea.

Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in human cancers. Therefore, STAT3 is a therapeutic target of cancer drug discovery. We previously reported that natural products inhibited constitutively activated STAT3 in human prostate tumor cells. We used a dual-luciferase assay to screen 200 natural products isolated from herbal medicines and we identified ginkgetin obtained from the leaves of Ginkgo biloba L. as a STAT3 inhibitor. Ginkgetin inhibited both inducible and constitutively activated STAT3 and blocked the nuclear translocation of p-STAT3 in DU-145 prostate cancer cells. Furthermore, ginkgetin selectively inhibited the growth of prostate tumor cells stimulated with activated STAT3. Ginkgetin induced STAT3 dephosphorylation at Try705 and inhibited its localization to the nucleus, leading to the inhibition of expression of STAT3 target genes such as cell survival-related genes (cyclin D1 and survivin) and anti-apoptotic proteins (Bcl-2 and Bcl-xL). Therefore, ginkgetin inhibited the growth of STAT3-activated tumor cells. We also found that ginkgetin inhibited tumor growth in xenografted nude mice and downregulated p-STAT3(Tyr705) and survivin in tumor tissues. This is the first report that ginkgetin exerts antitumor activity by inhibiting STAT3. Therefore, ginkgetin is a good STAT3 inhibitor and may be a useful lead molecule for development of a therapeutic STAT3 inhibitor.
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http://dx.doi.org/10.1111/cas.12608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409885PMC
April 2015

Inhibition of STAT3 activation by KT-18618 via the disruption of the interaction between JAK3 and STAT3.

Biochem Pharmacol 2014 May 4;89(1):62-73. Epub 2014 Mar 4.

Laboratory of Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Daejeon 305-806, Republic of Korea; University of Science and Technology in Korea, 125 Gwahakro, Daejeon 305-806, Republic of Korea. Electronic address:

The constitutive activation of STAT3 in human cancers causes the abnormal proliferation and survival of cancer cells, and thus, STAT3 is a therapeutic target of antitumor drugs. We screened a small-molecule library of 8600 synthetic compounds from the "Korea Chemical Bank" to identify inhibit STAT3 activity using a cell-based luciferase assay system. KT-18618 ((Z)-N-(4-chlorophenyl)-N-methyl-2-[1,3,3,3,-tetrafluoro-2-(thiophen-2-yl)prop-1-enyloxy]-acetamide) was selected as a novel inhibitor of the JAK/STAT3 pathway. KT-18618 inhibited STAT3 phosphorylation and the expression of STAT3-regulated genes. The inhibition of STAT3 phosphorylation led to the apoptosis of MDA-MB-468 cells. We postulated that the inhibition of the JAK family of proteins or c-Src inhibited STAT3 phosphorylation. Interestingly, the phosphorylation of these kinases was only mildly inhibited, but the phosphorylation of STAT3 was completely inhibited. This result implies that the inhibition of STAT3 phosphorylation by KT-18618 is an independent event that occurs through the phosphorylation of upstream kinases. Co-immunoprecipitation experiments revealed that KT-18618 inhibited the JAK3-STAT3 interaction. Moreover, JAK3 molecules were captured by biotinylated KT-18618, implying that KT-18618 bound to JAK3 molecules. Additionally, 1μM KT-18618 inhibited JAK3 kinase activity by approximately 28% in an in vitro kinase assay. From these results, we suggest that KT-18618 binds to JAK3 molecules and disrupts the JAK3-STAT3 interaction, which leads to the inhibition of STAT3 phosphorylation. KT-18618 is the first inhibitor of the JAK3-STAT3 interaction.
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http://dx.doi.org/10.1016/j.bcp.2014.02.017DOI Listing
May 2014

Cosmomycin C inhibits signal transducer and activator of transcription 3 (STAT3) pathways in MDA-MB-468 breast cancer cell.

Bioorg Med Chem 2011 Dec 17;19(24):7582-9. Epub 2011 Oct 17.

Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahakro, Yoosung, Daejeon 305-806, Republic of Korea.

The signal transducer and activator of transcription 3 (STAT3) is constitutively activated in cancer cells. Therefore, blocking the aberrant activity of STAT3 in tumor cells is a validated therapeutic strategy. To discover novel inhibitors of STAT3 activity, we screened against microbial natural products using a dual-luciferase assay. Using the microbial metabolome library, we identified cosmomycin C (CosC), which was isolated from the mycelium extract of Streptomyces sp. KCTC19769, as a STAT3 pathway inhibitor. CosC inhibited STAT3 (Tyr705) phosphorylation and subsequent nuclear translocation in MDA-MB-468 breast cancer cells. CosC-mediated inhibition of STAT3 signaling pathway was confirmed by suppressed expression of STAT3 downstream target proteins including cyclin D1, Bcl-xL, survivin, Mcl-1, and VEGF in CosC-treated MDA-MB-468 cells. Flow cytometry showed that CosC caused accumulation in the G(0)-G(1) phase of the cell cycle and induced apoptosis via PARP cleavage and caspase-3 activation. Based on these findings, CosC may be a potential candidate for modulation of STAT3 pathway.
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http://dx.doi.org/10.1016/j.bmc.2011.10.025DOI Listing
December 2011

Down-regulation of AMP-activated protein kinase sensitizes DU145 carcinoma to Fas-induced apoptosis via c-FLIP degradation.

Exp Cell Res 2009 Aug 25;315(14):2433-41. Epub 2009 May 25.

Department of Biochemistry and Molecular Biology, Medical Research Center and Biomedical Science Institute, Kyung Hee University School of Medicine, 1 Hoegi-dong, Tongdaemun-gu, Seoul 130-701, Republic of Korea.

The death receptor Fas (APO-1/CD95) induces apoptosis in many tissues upon cross-linking by its ligand (FasL), but a number of cancer cells exhibit resistance to such apoptosis. Indeed, resistance to apoptosis seems to be one of the hallmarks of cancer, and therefore, it is clinically important to understand the underlying mechanisms by which cancer cells acquire such resistance. In the present study, we demonstrate that Fas signaling in DU145 human prostate cancer cells leads to rapid activation of AMP-activated protein kinase (AMPK), which plays a major role in adaptive responses to ATP-depleting conditions; prostate cancer is resistant to Fas-mediated apoptosis despite high levels of Fas surface expression and no mutation in the Fas gene. We further demonstrate that inhibition of AMPK sensitizes DU145 cells to Fas-induced apoptosis via enhancement of ubiquitination and consequent proteasome degradation of the apoptosis inhibitory protein c-FLIP. These findings thus reveal a novel anticancer property of AMPK inhibition and support the synergistic application of AMPK inhibition in cancer therapy to overcome Fas resistance.
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http://dx.doi.org/10.1016/j.yexcr.2009.05.018DOI Listing
August 2009

Reactive oxygen species stabilize hypoxia-inducible factor-1 alpha protein and stimulate transcriptional activity via AMP-activated protein kinase in DU145 human prostate cancer cells.

Carcinogenesis 2008 Apr 6;29(4):713-21. Epub 2008 Feb 6.

Department of Biochemistry and Molecular Biology, Kyung Hee University School of Medicine, Seoul 130-701, Korea.

Hypoxia-inducible factor (HIF-1) plays a central role in the cellular adaptive response to hypoxic conditions, which are closely related to pathophysiological conditions, such as cancer. Although reactive oxygen species (ROS) have been implicated in the regulation of hypoxic and non-hypoxic induction of HIF-1 under various conditions, the role of ROS is quite controversial, and the mechanism underlying the HIF-1 regulation by ROS is not completely understood yet. Here, we investigated the biochemical mechanism for the ROS-induced HIF-1 by revealing a novel role of adenosine monophosphate-activated protein kinase (AMPK) and the upstream signal components. AMPK plays an essential role as energy-sensor under adenosine triphosphate-deprived conditions. Here we report that ROS induced by a direct application of H(2)O(2) and menadione to DU145 human prostate carcinoma resulted in accumulation of HIF-1alpha protein by attenuation of its degradation and activation of its transcriptional activity in an AMPK-dependent manner. By way of contrast, AMPK was required only for the transcriptional activity of HIF-1 under hypoxic condition, revealing a differential role of AMPK in these two stimuli. Furthermore, our data show that inhibition of AMPK enhances HIF-1alpha ubiquitination under ROS condition. Finally, we show that the regulation of HIF-1 by AMPK in response to ROS is under the control of c-Jun N-terminal kinase and Janus kinase 2 pathways. Collectively, our findings identify AMPK as a key determinant of HIF-1 functions in response to ROS and its possible role in the sophisticated HIF-1 regulatory mechanisms.
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http://dx.doi.org/10.1093/carcin/bgn032DOI Listing
April 2008

Antidiabetes and antiobesity effect of cryptotanshinone via activation of AMP-activated protein kinase.

Mol Pharmacol 2007 Jul 11;72(1):62-72. Epub 2007 Apr 11.

Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species, Kyung Hee University School of Medicine, Seoul, Korea.

Metabolic disorders, including type 2 diabetes and obesity, represent major health risks in industrialized countries. AMP-activated protein kinase (AMPK) has become the focus of a great deal of attention as a novel therapeutic target for the treatment of metabolic syndromes, because AMPK has been demonstrated to mediate, at least in part, the effects of a number of physiological and pharmacological factors that exert beneficial effects on these disorders. Thus, the identification of a compound that activates the AMPK pathway would contribute significantly to the treatment and management of such syndromes. In service of this goal, we have screened a variety of naturally occurring compounds and have identified one compound, cryptotanshinone, as a novel AMPK pathway activator. Cryptotanshinone was originally isolated from the dried roots of Salvia militorrhiza, an herb that is used extensively in Asian medicine and that is known to exert beneficial effects on the circulatory system. For the first time, in the present study, we have described the potent antidiabetic and antiobesity effects of cryptotanshinone, both in vitro and in vivo. Our findings suggest that the activation of the AMPK pathway might contribute to the development of novel therapeutic approaches for the treatment of metabolic disorders such as type 2 diabetes and obesity.
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http://dx.doi.org/10.1124/mol.107.034447DOI Listing
July 2007

AMP-activated protein kinase activity is required for vanadate-induced hypoxia-inducible factor 1alpha expression in DU145 cells.

Carcinogenesis 2004 Dec 5;25(12):2497-507. Epub 2004 Aug 5.

Department of Biochemistry and Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species, Kyung Hee University College of Medicine, Seoul 130-701, Korea.

Hypoxia-inducible factor 1 (HIF-1), a pivotal transcription factor composed of HIF-1alpha and HIF-1beta subunits, plays a major role in tumor progression by activating a number of genes critically involved in adaptation to hypoxia. HIF-1 is also induced by several carcinogenic metals. Vanadate, an environmental toxic metal, is considered as a potent inducer of tumors in animals and is reported to activate HIF-1 activity. However, the involved mechanisms are poorly understood. In the present study, we have examined the biochemical mechanisms of the vanadate-induced HIF-1 activation in cancer cells by primarily focusing on the role of AMP-activated protein kinase (AMPK), which plays an essential role as an energy sensor under ATP-deprived conditions. We demonstrate that AMPK was rapidly activated in response to vanadate in DU145 human prostate carcinoma, and that its activation preceded HIF-1alpha expression. Under this condition, inhibition of AMPK by a pharmacological and molecular approach dramatically abolished the vanadate-induced HIF-1alpha expression as well as HIF-1-mediated physiological responses. Phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin signaling was also involved in vanadate-induced HIF-1alpha expression, but it was independent of AMPK signaling pathway. Moreover, we demonstrate a role of reactive oxygen species as an upstream signal for these two pathways. These results suggest that AMPK is a novel and critical component of HIF-1 regulation, further implying its involvement in vanadate-induced carcinogenesis.
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http://dx.doi.org/10.1093/carcin/bgh253DOI Listing
December 2004

AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells.

J Biol Chem 2003 Oct 4;278(41):39653-61. Epub 2003 Aug 4.

Department of Molecular Biology, Medical Research Center for Bioreaction to Reactive Oxygen Species, Kyung Hee University College of Medicine, Seoul, Korea.

AMP-activated protein kinase (AMPK) functions as an energy sensor to provide metabolic adaptations under the ATP-deprived conditions such as hypoxia. In the present study, we considered a role of AMPK in the adaptive response to hypoxia by examining whether AMPK is involved in the regulation of hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor that is critical for hypoxic induction of physiologically important genes. We demonstrate that hypoxia or CoCl2 rapidly activated AMPK in DU145 human prostate cancer cells, and its activation preceded the induction of HIF-1 alpha expression. Under these conditions, blockade of AMPK activity by a pharmacological or molecular approach significantly attenuated hypoxia-induced responses such as HIF-1 target gene expression, secretion of vascular endothelial growth factor, glucose uptake, and HIF-1-dependent reporter gene expression, indicating that AMPK is critical for the HIF-1 transcriptional activity and its target gene expression. Its functional requirement for HIF-1 activity was also demonstrated in several different cancer cell lines, but AMPK activation alone was not sufficient to stimulate the HIF-1 transcriptional activity. We further present data showing that AMPK transmits a positive signal for HIF-1 activity via a signaling pathway that is independent of phosphatidylinositol 3-kinase/AKT and several mitogen-activated protein kinases. Taken together, our results suggest that AMPK is a novel and critical component of HIF-1 regulation, implying its new roles in oxygen-regulated cellular phenomena.
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http://dx.doi.org/10.1074/jbc.M306104200DOI Listing
October 2003