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Jeung, Eui-Bae,Park, Se-Hyung,Leung, Peter C.K.,Yang, Hoe-Saeng,Sim, Jae-Chul,Kim, Kyung-Tai,Choi, Kyung-Chul 대한부인종양 콜포스코피학회 2003 Journal of Gynecologic Oncology Vol.14 No.4
Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases which are activated in response to a diverse array of extracellular stimuli, and mediate signal transduction from the cell surface to the nucleus. The chemotherapeutic agents, growth factors and reproductive hormones have been demonstrated to activate MAPKs, suggesting that the MAPK signaling pathway plays an important role in the regulation of proliferation, apoptosis, survival and differentiation in response to these external stimuli in ovarian cancer. In addition to MAPKs as an oncogenic pathway, phosphatidylinositol 3-kinase (PI3K) plays a role in a various range of important cellular processes associated with malignant characterestics including cell growth, survival and migration, which is a member of lipid kinases subfamily that phosphorylates and dephosphorylates the 3-position of the inositol ring of phosphoinositides in a membrane. In this review, recent results of the MAPK and PI3K signaling cascades by external stimuli, and potential roles of these oncogenic pathways as an oncogenic pathway are summarized in epithelial ovarian cancer.
Kim, Ki-Yon,Kim, Seung U,Leung, Peter C K,Jeung, Eui-Bae,Choi, Kyung-Chul Japanese Cancer Association 2010 CANCER SCIENCE Vol.101 No.4
<P>Recent studies have shown that genetically engineered stem cells (GESTECs) to produce suicide enzymes that convert non-toxic prodrugs to toxic metabolites selectively migrate toward tumor sites and reduce tumor growth. In the present study, we evaluated whether these GESTECs were capable of migrating to human ovarian cancer cells and examined the potential therapeutic efficacy of the gene-directed enzyme prodrug therapy against ovarian cancer cells in vitro. The expression of cytosine deaminase (CD) or carboxyl esterase (CE) mRNA of GESTECs was confirmed by RT-PCR. A modified transwell migration assay was performed to determine the migratory capacity of GESTECs to ovarian cancer cells. GESTECs (HB1.F3.CD or HB1.F3.CE cells) engineered to express a suicide gene (CD or CE) selectively migrated toward ovarian cancer cells. A [(3)H] thymidine incorporation assay was conducted to measure the proliferative index. Treatment of human epithelial ovarian cancer cell line (SKOV-3, an ovarian adenocarcinoma derived from the ascites of an ovarian cancer patient) with the prodrugs 5-fluorocytosine (5-FC) or camptothecin-11 (CPT-11) in the presence of HB1.F3.CD or HB1.F3.CE cells resulted in the inhibition of ovarian cancer cell growth. Based on the data presented herein, we suggest that GESTECs expressing CD/CE may have a potent advantage to selectively treat ovarian cancers. (Cancer Sci 2010; 101: 955-962).</P>
Oh, Hoon Kyu,Choi, Youn Seok,Yang, Yeong-In,Kim, Ji-Hyun,Leung, Peter C K,Choi, Jung-Hye Published for the European Society for Human Repro 2013 Molecular human reproduction Vol.19 No.3
<P>Leptin acts as a potential growth stimulator in several normal and neoplastic cells. Recent studies have shown the presence of increased levels of leptin in the peritoneal fluid of patients with endometriosis, implicating leptin in the pathogenesis of endometriosis. However, the specific function of leptin in the induction of mitogenesis in endometriosis is not known. This study investigated the expression of the leptin receptor (ObR) in endometrioma tissues and immortalized endometriotic cells, and the effect of leptin on cell growth. ObR expression was higher in endometriomas than in the normal endometrium, and it was detected in 74% of epithelial and 30% of stromal endometrioma tissues. In addition, human endometriotic epithelial cells (11Z and 12Z) showed a high level of ObR when compared with endometrial cells and endometriotic stromal cells (22B). Furthermore, leptin treatment stimulated the growth of 11Z and 12Z cells, but not that of 22B cells. Knockdown of the ObR in 11Z and 12Z cells impaired the ability of leptin to induce cell growth. Leptin induced the activation of Janus Kinases 2 (JAK2), signal transducers and activators of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK) in endometriotic epithelial cells. Moreover, pretreatment with the JAK2/STAT3 inhibitor AG490 and the ERK inhibitor PD98059 significantly inhibited leptin-induced cell growth. The present results show that the ObR is induced in endometriosis, and that leptin stimulates the growth of endometriotic epithelial cells through the JAK2/STAT3 and ERK pathways.</P>
Choi, Jung-Hye,Chen, Chien-Lin,Poon, Song Ling,Wang, Hsin-Shih,Leung, Peter C K Published for the Society of Endocrinology by the 2009 Endocrine-related cancer Vol.16 No.1
<P>In addition to their critical roles in folliculogenesis and ovarian granulosa cell steroidogenesis, gonadotropins have been implicated as potential risk factors in ovarian epithelial carcinomas, most of which are derived from ovarian surface epithelium (OSE). However, the molecular mechanism underlying the effects of FSH and LH in OSE and its neoplastic counterpart is not well understood. We previously demonstrated that gonadotropins promote the growth of OSE cells by regulating the levels of epidermal growth factor receptor (EGFR) via the activation of ERK1/2 and PI3K pathways in immortalized human OSE (IOSE) cells. In this study, we investigated whether cAMP and its novel binding target, named exchange protein activated by cAMP (Epac), are involved in the gonadotropin-induced EGFR expression in OSE cells. Gonadotropins elevated intracellular cAMP levels in both IOSE and granulosa cells, and this increase was attenuated by SQ22536, an inhibitor of adenylyl cyclase (AC). The activation of the ERK1/2 and Akt pathways as well as the expression of EGFR was stimulated by reagents that elevate intracellular cAMP levels, via cAMP analog 8-bromo-cAMP and AC activator forskolin. A similar increase was observed when the cells were treated with a novel cAMP analog, 8-(4-chlorophenylthio)-2'-O-methyl adenosine-3',5'-cyclic monophosphate (8-CPT-2ME-cAMP), which activates Epac specifically but not PKA. Moreover, the gonadotropin-induced EGFR expression and ERK1/2 and Akt activation were abolished by overexpression of dominant negative Epac. Taken together, these results indicate that the AC/cAMP/Epac signaling pathway may mediate the up-regulation of EGFR by gonadotropins via ERK1/2 and Akt activation.</P>
Lee, Hye-Rim,Jeung, Eui-Bae,Cho, Myung-Haing,Kim, Tae-Hee,Leung, Peter C K,Choi, Kyung-Chul Blackwell Publishing Ltd 2013 Journal of cellular and molecular medicine Vol.17 No.1
<P>Endocrine-disrupting chemicals (EDCs) are natural or synthetic compounds present in the environment which can interfere with hormone synthesis and normal physiological functions of male and female reproductive organs. Most EDCs tend to bind to steroid hormone receptors including the oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR). As EDCs disrupt the actions of endogenous hormones, they may induce abnormal reproduction, stimulation of cancer growth, dysfunction of neuronal and immune system. Although EDCs represent a significant public health concern, there are no standard methods to determine effect of EDCs on human beings. The mechanisms underlying adverse actions of EDC exposure are not clearly understood. In this review, we highlighted the toxicology of EDCs and its effect on human health, including reproductive development in males and females as shown in <I>in vitro</I> and <I>in vivo</I> models. In addition, this review brings attention to the toxicity of EDCs <I>via</I> interaction of genomic and non-genomic signalling pathways through hormone receptors.</P>