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Cho, Hanbyoul,Kim, Jae-Hoon Taylor Francis 2009 Biomarkers Vol.14 No.3
<P>Simple, non-aversive methods to identify cervical neoplasia are needed. The purpose of this study was to investigate the clinical value of differential white blood cell (WBC) counts as a biomarker for cervical neoplasia. We performed a retrospective review of laboratory results in 407 cervical cancers, 495 cervical intraepithelial neoplasias (CIN) and 916 healthy controls. Because pretreatment neutrophil and monocyte counts showed the potential as a biomarker, we combined these parameters and designated this combined marker MNM (multiplication of neutrophil and monocyte counts). MNM showed a sensitivity of 53.1% and a specificity of 78.1%, which are much higher than those of SCC-Ag. On Cox multivariate analysis, MNM positivity (hazard ratio = 2.82, p = 0.042), stage and tumour size were independent predictors of poor prognosis. Our findings suggest that pretreatment MNM could be a candidate as a simple and cost-effective biomarker in cervical cancer.</P>
Cho, HanByoul,Kim, Jae-Hoon Williams Wilkins Co 2009 The Journal of histochemistry and cytochemistry Vol.57 No.5
<P>We recently identified lipocalin2 (LCN2) as being upregulated in ovarian cancer cell lines. The purpose of this study was to validate LCN2 upregulation in ovarian cancers and to investigate its potential as a serum biomarker. We assayed LCN2 expression in ovarian cancers using real-time PCR and IHC. To evaluate the potential of LCN2 as a biomarker, we measured serum LCN2 levels in 54 ovarian cancers, 15 borderline and 53 benign ovarian tumors, and 90 healthy controls. SYBR green PCR and IHC showed LCN2 overexpression in ovarian cancers. LCN2 immunoreactivity was significantly associated with tumor differentiation (p=0.009), as well-differentiated tumors showed the highest LCN2 expression. Serum LCN2 level in ovarian cancer was significantly higher than in the other study groups (p<0.001), and in accordance with IHC results, it also correlated with tumor differentiation, with well-differentiated tumors having the highest value. The sensitivity and specificity of LCN2 in detecting ovarian cancer was 72.2% and 50.4%, respectively. By Cox univariate analysis, LCN2 positivity was an independent prognostic factor for overall survival (hazard ratio = 1.47, p=0.012). In conclusion, LCN2 expressions are upregulated and related to tumor differentiation in ovarian cancers and should be included in future research assessing potential biomarkers for ovarian cancer.</P>
Diagnostic and prognostic impact of osteopontin expression in endometrial cancer.
Cho, HanByoul,Kang, Eun Suk,Kim, Young Tae,Kim, Jae-Hoon Marcel Dekker 2009 Cancer investigation Vol.27 No.3
<P>The role of osteopontin as a biomarker in endometrial cancer has not been conclusively established. We evaluated the expression and potential of osteopontin as a biomarker for endometrial cancer. Real-time polymerase chain reaction and immunohistochemistry revealed osteopontin overexpression in endometrial cancer. The plasma osteopontin level in endometrial cancer was significantly higher than in healthy controls (P< 0.001). In FIGO stage I endometrial cancer, osteopontin correctly identified 18 of 29 cases (62.1%) that were not detected by CA125. By Cox multivariate analysis, osteopontin positivity was an independent prognostic factor for disease-free survival (hazard ratio = 3.18, P= 0.035).</P>
Cho, Hanbyoul,Lim, Beom Jin,Kang, Eun Suk,Choi, Joong Sub,Kim, Jae-Hoon Tohoku University Medical Press 2009 The Tohoku journal of experimental medicine Vol.218 No.2
<P>Ovarian cancer is a leading cause of death among gynecological malignancies. Established cancer cell lines are useful tools for clinical and basic researches. We have therefore established a new human ovarian cancer cell line, YDOV-151, derived from the mucinous cystadenocarcinoma and characterized it by the microarray analyses. A mucinous origin of the YDOV-151 was evident from light microscopy, and its epithelial-like character was confirmed with electron microscopy. No pathogenic mutations were found in the BRCA1 and BRCA2 genes. The subcutaneous transplantation of YDOV-151 cells into nude mice successfully induced the tumor mass after 3 weeks. cDNA microarray analysis revealed 1,926 genes (> 2-fold differences, <I>P</I> < 0.05) that distinguished the YDOV-151 from human ovarian surface epithelial (HOSE) cells. To identify candidate biomarkers, we selected five genes (SFN, RGC32, CDCA7, LAMP3, and SLCO4A1), each of which was up-regulated (> 7-fold) in YDOV-151 and had an available antibody assay for further validation. In SYBR Green real-time PCR, the relative expression levels of RGC32 (651-fold), LAMP3 (1,930-fold), and SLCO4A1 (20,598-fold) were significantly higher in YDOV-151 than in HOSEs (<I>P</I> < 0.001). RGC32 may be involved in cell cycle regulation, LAMP3 may promote metastasis, and SLCO4A1 is a member of anion-transporting polypeptides. The newly established ovarian cancer cell line, YDOV-151, would be a useful model for elucidating the biology and the pathogenesis of mucinous cystadenocarcinoma. In addition, the identification and validation of up-regulated genes may provide a genetic approach for identifying biomarkers in ovarian cancer.</P>
Cho, HanByoul,Kim, Mi Kyung,Lee, Jae Kwan,Son, Sung Kyong,Lee, Kwang-Beom,Lee, Jong-Min,Lee, Jung Pil,Hur, Soo Young,Kim, Jae-Hoon Walter de Gruyter GmbH 2009 Clinical chemistry and laboratory medicine Vol.47 No.8
<P>Although there have been some epidemiological studies on the effects of diet and nutritional status on cervical carcinogenesis, evidence for a protective effect of antioxidant micronutrients against cervical neoplasia is insufficient. The relationship between serum antioxidant micronutrients and sociodemographic factors and the risk of cervical neoplasia was investigated in this multi-center, case-control study.</P>
CDK7 is a reliable prognostic factor and novel therapeutic target in epithelial ovarian cancer
Kim, Jihye,Cho, Young-Jae,Ryu, Ji-Yoon,Hwang, Ilseon,Han, Hee Dong,Ahn, Hyung Jun,Kim, Woo Young,Cho, Hanbyoul,Chung, Joon-Yong,Hewitt, Stephen M.,Kim, Jae-Hoon,Kim, Byoung-Gie,Bae, Duk-Soo,Choi, Chel Elsevier 2020 Gynecologic oncology Vol.156 No.1
<P><B>Abstract</B></P> <P><B>Objective</B></P> <P>Cyclin-dependent kinase 7 (CDK7) engages tumor growth by acting as a direct link between the regulation of transcription and the cell cycle. Here, we investigated the clinical significance of CDK7 expression and its potential as a therapeutic target in epithelial ovarian cancer (EOC).</P> <P><B>Methods</B></P> <P>CDK7 expression was examined in 436 ovarian tissues including normal to metastatic ovarian tumors using immunohistochemistry, and its clinical implications were analyzed. Furthermore, we performed <I>in vitro</I> and <I>in vivo</I> experiments using CDK7 siRNA or a covalent CDK7 inhibitor (THZ1) to elucidate the effect of CDK7 inhibition on tumorigenesis in EOC cells.</P> <P><B>Results</B></P> <P>The patient incidence of high CDK7 expression (CDK7<SUP>High</SUP>) gradually increased from normal ovarian epithelium to EOC (<I>P</I> < 0.001). Moreover, CDK7<SUP>High</SUP> was associated with an advanced stage and high-grade histology (<I>P</I> = 0.035 and <I>P</I> = 0.011, respectively) in EOC patients and had an independent prognostic significance in EOC recurrence (<I>P</I> = 0.034). CDK7 inhibition with siRNA or THZ1 decreased cell proliferation and migration, and increased apoptosis in EOC cells, and this anti-cancer mechanism is caused by G0/G1 cell cycle arrest. In <I>in vivo</I> therapeutic experiments using cell-line xenograft and PDX models, CDK7 inhibition significantly decreased the tumor weight, which was mediated by cell proliferation and apoptosis.</P> <P><B>Conclusion</B></P> <P>Mechanistic interrogation of CDK7 revealed that it is significantly associated with an aggressive phenotype of EOC, and it has independent prognostic power for EOC recurrence. Furthermore, CDK7 may be a potential therapeutic target for patients with EOC, whether platinum sensitive or resistant.</P> <P><B>Highlights</B></P> <P> <UL> <LI> CDK7 inhibition has an anti-cancer effect on platinum-sensitive EOC. </LI> <LI> CDK7 inhibition could induce responsiveness to platinum chemotherapy in platinum-resistant EOC. </LI> <LI> CDK7 overexpression had independent negative prognostic value for disease recurrence of EOC. </LI> <LI> CDK7 might play a critical role in EOC tumorigenesis, and it also serves as a possible therapeutic target in EOC. </LI> </UL> </P>
Downregulation of ERp57 expression is associated with poor prognosis in early-stage cervical cancer
Chung, Hyunsoo,Cho, Hanbyoul,Perry, Candice,Song, Jaekyung,Ylaya, Kris,Lee, Heejeong,Kim, Jae-Hoon Informa UK Ltd. 2013 Biomarkers Vol.18 No.7
<P><I>Objective</I>: We investigated the clinical significance of ERp57 in the progression of cervical cancer.</P><P><I>Methods</I>: mRNA and protein expression of ERp57 in cervical neoplasias were examined.</P><P><I>Results</I>: ERp57 mRNA expression was significantly decreased in cervical cancers. Immunohistochemistry revealed that ERp57 expression in 123 cervical cancers was down-regulated compared to cervical intraepithelial neoplasias or normal tissues (<I>p</I> < 0.001). Low ERp57 expression was significantly associated with worse overall survival (HR = 12.19, <I>p</I> = 0.018).</P><P><I>Conclusions</I>: Low ERp57 expression independently predicts a poor outcome for patients with cervical cancer, supporting the notion that ERp57 may be a promising novel cancer target.</P>
Targeting Cyclin D-CDK4/6 Sensitizes Immune-Refractory Cancer by Blocking the SCP3–NANOG Axis
Oh, Se Jin,Cho, Hanbyoul,Kim, Suhyun,Noh, Kyung Hee,Song, Kwon-Ho,Lee, Hyo-Jung,Woo, Seon Rang,Kim, Suyeon,Choi, Chel Hun,Chung, Joon-Yong,Hewitt, Stephen M.,Kim, Jae-Hoon,Baek, Seungki,Lee, Kyung-Mi American Association for Cancer Research 2018 Cancer Research Vol.78 No.10
<P>These findings reveal cyclin D1-CDK4/6 inhibition as an effective strategy for controlling SCP3<SUP>high</SUP> immune-refractroy cancer.</P><P>Immunoediting caused by antitumor immunity drives tumor cells to acquire refractory phenotypes. We demonstrated previously that tumor antigen–specific T cells edit these cells such that they become resistant to CTL killing and enrich NANOG<SUP>high</SUP> cancer stem cell-like cells. In this study, we show that synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, is overexpressed in immunoedited cells and upregulates NANOG by hyperactivating the cyclin D1–CDK4/6 axis. The SCP3–cyclin D1–CDK4/6 axis was preserved across various types of human cancer and correlated negatively with progression-free survival of cervical cancer patients. Targeting CDK4/6 with the inhibitor palbociclib reversed multiaggressive phenotypes of SCP3<SUP>high</SUP> immunoedited tumor cells and led to long-term control of the disease. Collectively, our findings establish a firm molecular link of multiaggressiveness among SCP3, NANOG, cyclin D1, and CDK4/6 and identify CDK4/6 inhibitors as actionable drugs for controlling SCP3<SUP>high</SUP> immune-refractory cancer.</P><P><B>Significance:</B> These findings reveal cyclin D1-CDK4/6 inhibition as an effective strategy for controlling SCP3<SUP>high</SUP> immune-refractroy cancer. <I>Cancer Res; 78(10); 2638–53. ©2018 AACR</I>.</P>