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        KSR1 is coordinately regulated with Notch signaling and oxidative phosphorylation in thyroid cancer

        Lee, Jandee,Seol, Mi-Youn,Jeong, Seonhyang,Kwon, Hyeong Ju,Lee, Cho Rok,Ku, Cheol Ryong,Kang, Sang-Wook,Jeong, Jong Ju,Shin, Dong Yeob,Nam, Kee-Hyun,Lee, Eun Jig,Chung, Woong Youn,Jo, Young Suk Journal of Endocrinology (Ltd. by Guarantee) 2015 Journal of molecular endocrinology Vol.54 No.2

        <P>Kinase suppressor of RAS1 (KSR1) is a scaffold protein implicated in RAS-mediated RAF activation. However, the molecular function of KSR in papillary thyroid cancer (PTC) is unknown. Thus, this study aimed to characterize the role of KSR1 in patients with PTC. qRT-PCR and immunohistochemistry (IHC) revealed inter-tumor heterogeneities in the expression of KSR1 in PTC tissues. Interestingly, BRAFV600E-positive PTC showed higher <I>KSR1</I> mRNA expression than BRAFV600E-negative PTC (<I>P</I><0.001). Gene Set Enrichment Analysis (GSEA) using public repositories showed that high KSR1 expression coordinately upregulated Notch signaling (nominal <I>P</I>=0.019, false discovery rate (FDR) <I>q</I>-value=0.165); this finding was supported by GeneNetwork analysis, indicating that <I>KSR1</I> expression is positively correlated with <I>NOTCH1</I> expression (<I>ρ</I>=0.677, <I>P</I>=6.15×10<SUP>−9</SUP>). siRNA against KSR1 (siKSR1) significantly decreased ERK phosphorylation induced by BRAFV600E, resulting in reduced expression of <I>NOTCH1</I> and <I>HES1</I>, targets of Notch signaling. GSEA revealed that high KSR1 expression was also associated with downregulation of genes related to oxidative phosphorylation (OxPhos). Consistent with this, electron microscopy showed that PTCs with high KSR1 expression exhibited structural defects of the mitochondrial cristae. Furthermore, siKSR1-transfected BCPAP and 8505C cells generated fewer colonies in colony-forming assays. In addition, GSEA showed that high expression of KSR2 and connector enhancer of KSR1 (CNKSR1) also coordinately upregulated Notch signaling (KSR2: nominal <I>P</I>=0.0097, FDR <I>q</I>-value=0.154 and CNKSR1: nominal <I>P</I><0.0001, FDR <I>q</I>-value=0.00554), and high CNKSR2 was associated with downregulation of the OxPhos gene set (nominal <I>P</I><0.0001, FDR <I>q</I>-value <0.0001). In conclusion, KSR1 is coordinately regulated with Notch signaling and OxPhos in PTC, because its scaffold function might be required to sustain the proliferative signaling and metabolic remodeling associated with this type of cancer.</P>

      • KCI등재
      • 신장이식후 발생한 유두상 갑상선암

        이잔디(Jandee Lee),홍 협(Hyeop Hong),정종주(Jong Ju Jeong),남기현(Kee-Hyun Nam),정웅윤(Woong Youn Chung),소의영(Euy-Young Soh),박정수(Cheong Soo Park) 대한두경부종양학회 2008 대한두경부 종양학회지 Vol.24 No.1

        Purpose :The chronic use of immunosuppressive therapy in transplant recipients can increase the long-term risk of carcinoma. The aim of this study was to determine the incidence, biological behaviors, and treatment outcomes in PTC(papillary thyroid carcinoma) in renal allograft recipients. Material and Methods :The present study examined the incidence and biological behavior of PTCs in RA recipients. A total of 1,739 RA patients treated between January 1986 and December 1999 were followed-up for a median 137(84-238) months. During the follow-up period, 129(7.4%) recipients were identified as having posttransplant malignancies. Of those, 12(0.7%) had PTCs, and these comprised six male and six female patients with a median age of 41(23-57) years. Results :Nine cases(incidentalomas) were diagnosed based on ultrasonography(US) screening. Eight of those nine were TNM stage I, and two of the three clinical carcinomas were TNM stage IVa. During a median follow-up of 94(18-159) months, two(16.7%) PTC patients developed loco-regional recurrence, but no patients showed distant metastasis. Posttransplant PTC showed no gender bias, and was often associated with aggressive lymphatic metastasis. However, most incidentalomas showed a favorable treatment outcome. Conclusion :In conclusion, routine surveillance of the thyroid gland using US screening is recommended to ensure early detection, treatment and favorable prognosis in RA patients with PTC.

      • SCISCIESCOPUS

        Aberrant Expression of COT Is Related to Recurrence of Papillary Thyroid Cancer

        Lee, Jandee,Jeong, Seonhyang,Park, Jae Hyun,Lee, Cho Rok,Ku, Cheol Ryong,Kang, Sang-Wook,Jeong, Jong Ju,Nam, Kee-Hyun,Shin, Dong Yeob,Lee, Eun Jig,Chung, Woong Youn,Jo, Young Suk Williams & Wilkins Co 2015 Medicine Vol.94 No.6

        <▼1><P>Supplemental Digital Content is available in the text</P></▼1><▼2><P><B>Abstract</B></P><P>Aberrant expression of Cancer Osaka Thyroid Oncogene mitogen-activated protein kinase kinase kinase 8 (COT) (MAP3K8) is a driver of resistance to B-RAF inhibition. However, the de novo expression and clinical implications of COT in papillary thyroid cancer (PTC) have not been investigated.</P><P>The aim of this study is to investigate the expression of A-, B-, C-RAF, and COT in PTC (n = 167) and analyze the clinical implications of aberrant expression of these genes.</P><P>Quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC) were performed on primary thyroid cancers. Expression of COT was compared with clinicopathological characteristics including recurrence-free survival. Datasets from public repository (NCBI) were subjected to Gene Set Enrichment Analysis (GSEA).</P><P>qPCR data showed that the relative mRNA expression of <I>A-</I>, <I>B-</I>, <I>C-RAF</I> and <I>COT</I> of PTC were higher than normal tissues (all <I>P</I> < 0.01). In addition, the expression of COT mRNA in PTC showed positive correlation with A- (<I>r</I> = 0.4083, <I>P</I> < 0.001), B- (<I>r</I> = 0.2773, <I>P</I> = 0.0003), and C-RAF (<I>r</I> = 0.5954, <I>P</I> < 0.001). The mRNA expressions of A-, B,- and C-RAF were also correlated with each other (all <I>P</I> < 0.001). In IHC, the staining intensities of B-RAF and COT were higher in PTC than in normal tissue (<I>P</I> < 0.001). Interestingly, moderate-to-strong staining intensities of B-RAF and COT were more frequent in B-RAF<SUP>V600E</SUP>-positive PTC (<I>P</I> < 0.001, <I>P</I> = 0.013, respectively). In addition, aberrant expression of COT was related to old age at initial diagnosis (<I>P</I> = 0.045) and higher recurrence rate (<I>P</I> = 0.025). In multivariate analysis, tumor recurrence was persistently associated with moderate-to-strong staining of COT after adjusting for age, sex, extrathyroidal extension, multifocality, T-stage, N-stage, TNM stage, and B-RAF<SUP>V600E</SUP> mutation (odds ratio, 4.662; 95% confidence interval 1.066 − 21.609; <I>P</I> = 0.045). Moreover, moderate-to-strong COT expression in PTC was associated with shorter recurrence-free survival (mean follow-up duration, 14.2 ± 4.1 years; <I>P</I> = 0.0403). GSEA indicated that gene sets related to B-RAF-RAS (<I>P</I> < 0.0001, false discovery rate [FDR] <I>q</I>-value = 0.000) and thyroid differentiation (<I>P</I> = 0.048, FDR <I>q</I>-value = 0.05) scores were enriched in lower COT expression group and gene sets such as T-cell receptor signaling pathway and Toll-like receptor signaling pathway are coordinately upregulated in higher COT expression group (both, <I>P</I> < 0.0001, FDR <I>q</I>-value = 0.000).</P><P>Aberrant expression of A-, B-, and C-RAF, and COT is frequent in PTC; increased expression of COT is correlated with recurrence of PTC.</P></▼2>

      • KCI등재후보
      • 미세 유두 갑상선암의 크기에 따른 임상상 및 단기간 치료 결과

        이잔디(Jandee Lee),오동규(Dong-Kyu oh),임승수(Seung Soo Lim),남기현(Kee-Hyun Nam),정웅윤(Woong Youn Chung),소의영(Euy Yong Soh),박정수(Cheong Soo Park) 대한두경부종양학회 2008 대한두경부 종양학회지 Vol.24 No.1

        Purpose :The incidence of papillary thyroid microcarcinoma(PTMC) has increased due to the widespread use of high resolution ultrasonography and fine-needle aspiration biopsy. However, the clinical and biologic behaviors of PTMC is debatable. The aim of this study was to describe clinicopathologic features of PTMC and to suggest whether tumor size(5mm) might prove the useful parameter for determining the surgical strat-egy in PTMC. Material and Methods :From Jan. 2000 to Dec. 2005, 1355 of 2678 patients with papillary thyroid car-cinoma were identified as having PTMC, based on tumor size≤10mm(50.6%). Among patients with PTMC, we further separated tumors<5mm(minute group:group M) from those 5 to 10mm(tiny group:group T). We compared the clinicopathological characteristics and the TNM stagings between two groups. Results :There were 114(8.4%) men and 1241(91.6%) women with a median age of 47 years(range;13-79). During a mean follow-up of 47.3(range;22-93), 13 patients(1.0%) developed locoregional recur-rences and 3 patients(0.2%) showed distant metastases at initial presentation. Statistical analysis revealed that the presence of extracapsular invasion(p<0.0001), invasion to adjacent structure(p<0.0001), multifocality(p< 0.0001), central lymph node metastasis(p<0.0001), and lateral lymph node metastasis(p<0.0001) were all significantly higher in tiny group(tumor≥5mm). Furthermore, minute group demonstrated a significantly lower tumor stage(AJCC TNM classification) compared with tiny group(p<0.0001). Conclusion :Patients with PTMC have a favorable treatment outcomes, although the distinction needs to be made with reference to the clinicopathologic behaviors. It would be reasonable to consider that tumor size(5mm) would be useful parameter for the treatment strategy of PTMC.

      • KCI등재

        유두 미세 갑상선암

        이잔디(Jandee Lee),윤지섭(Ji Sup Yun),남기현(Kee-Hyun Nam),정웅윤(Woong Youn Chung),소의영(Euy-Young Soh),박정수(Cheong Soo Park) 대한외과학회 2007 Annals of Surgical Treatment and Research(ASRT) Vol.72 No.4

        Purpose: The clinical importance of papillary microcarcinoma (PTMC) is debatable. Because PTMC is being diagnosed with increasing frequency, it is important to describe the clinical and histological characteristics that confer aggressive behavior to this cancer. This study was carried out to evaluate the clinical and histological characteristics of PTMC and to determine an appropriate treatment strategy for such cases. Methods: From Jan. 2000 to Dec. 2005, 1,255 patients with small papillary carcinoma, which measured less than 2.0 ㎝ in its greater dimension, underwent total thyroidectomy at our institution. Among these patients, 633 (50.4%) had a thyorid carcinoma less than or equal to 1 ㎝ in diameter (Group A). The clinicopathologic features and treatment outcome of these patients were evaluated and compared with the remaining 622 cases (49.6%) (Group B). Results: For the patients with PTMC (Group A), there were 70 men and 563 women with a median age of 44 years (range; 12∼86). During a mean follow-up of 32.5±18.2 months, 6 patients (0.9%) developed locoregional recurrences and 3 patients (0.5%) showed distant metastases. There was no disease-related mortality in both groups. The disease of group B was more likely to show extracapsular invasion (P<0.001), invasion to adjacent structures (P<0.001), and lateral neck node metastasis (P<0.001) than that of group A. However, there were no significant differences in multifocality (P=0.189), bilaterality (P=0.203), the locoregional recurrence rate (P=0.065) and the distant metastasis rate (P=0.325) between the two groups. On multivariate analysis, locoregional recurrent disease was associated with central lymph node metastases (P=0.033) and lateral neck node metastases (P=0.022). Conclusion: Despite PTMC having less aggressive clinicopathologic parameters as compared with clinical cancer (>1 ㎝), some PTMCs show aggressive clinical behavior and locoregional recurrence. The treatment of PTMC should be individualized based on its tumor risk profiles and the clinical presentations. Moreover, performing close follow-up is essential, especially for those patients who present with cervicolateral lymph node metastases.

      • KCI등재

        여포상 갑상선 암

        이잔디(Jandee Lee),윤지섭(Ji Sup Yun),정종주(Jong Ju Jeong),남기현(Kee-Hyun Nam),정웅윤(Wong-Youn Chung),소의영(Euy-Young Soh),박정수(Cheong Soo Park) 대한외과학회 2008 Annals of Surgical Treatment and Research(ASRT) Vol.74 No.1

        Purpose: Follicular thyroid carcinoma (FTC) is a relatively rare form of thyroid carcinoma that often presents at a more advanced stage of disease with a higher incidence of distant metastases because of its propensity for vascular invasion. However, FTC and papillary thyroid carcinoma (PTC) have similar prognoses when they are matched for age and stage. Therefore, this study was conducted to evaluate the useful prognostic factors and determine the optimal management of FTC. Methods: This study was conducted on 216 patients with FTC who underwent thyroidectomy at our institutions between April 1986 and August 2006. The patients included 174 women and 42 men with a mean age of 41 (4∼87) years, and patients underwent follow-up evaluation for a mean period of 114 (6∼253) months. The potential risk factors for treatment outcome were calculated using multivariate analysis, and the prognostic accuracy of UICC/AJCC pTNM staging, AMES, AGES, MACIS, and Degroot classification for predicting survival were compared. Results: During the follow-up period, 13 (6.0%) patients developed locoregional recurrences and 8 patients (3.7%) showed distant metastases. In addition, cause specific mortality was seen in 8 patients (3.7%). The overall survival and cause-specific survival (CSS) rates at 10 years were 95.4% and 89.3%, respectively, and these cases were accurately predicted by the AMES and pTNM staging systems. The Cox proportional hazards revealed that gender (P=0.015), angioinvasion (P=0.013), invasion to adjacent structure (P=0.003), widely invasive carcinoma (P=0.028), and distant metastases at the time of presentation (P<0.001) were independent prognostic factors for survival. Conclusion: The extent of surgery in cases of FTC should be individualized based on the clinicopathologic findings; Conservative surgery should be adequate for cases of minimally invasive FTC without angioinvasion, however total or near-total thyroidectomy should be conducted in cases of widely invasive and minimally invasive FTC with angioinvasion.

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