Annie N Y Cheung

The University of Hong Kong, Hong Kong, Hong Kong

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Publications (202)839.44 Total impact

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    ABSTRACT: Human placental trophoblasts can be considered pseudomalignant, with tightly controlled proliferation, apoptosis, and invasiveness. Gestational trophoblastic disease (GTD) represents a family of heterogeneous trophoblastic lesions with aberrant apoptotic and proliferative activities and dysregulation of cell signaling pathways. We characterize the oncogenic effects of factor that binds to the inducer of short transcripts of HIV-1 [FBI-1, alias POZ and Krüppel erythroid myeloid ontogenic factor (POKEMON)/ZBTB7A] in GTD and its role in promoting cell aggressiveness in vitro and tumor growth in vivo. IHC studies showed increased nuclear expression of FBI-1, including hydatidiform moles, choriocarcinoma (CCA), and placental site trophoblastic tumor, in GTD. In JAR and JEG-3 CCA cells, ectopic FBI-1 expression opposed apoptosis through repression of proapoptotic genes (eg, BAK1, FAS, and CASP8). FBI-1 overexpression also promoted Akt activation, as indicated by Akt-pS473 phosphorylation. FBI-1 overexpression promoted mobility and invasiveness of JEG-3 and JAR, but not in the presence of the phosphoinositide 3-kinase inhibitor LY294002. These findings suggest that FBI-1 could promote cell migration and invasion via phosphoinositide 3-kinase/Akt signaling. In vivo, nude mice injected with CCA cells with stable FBI-1 knockdown demonstrated reduced tumor growth compared with that in control groups. These findings suggest that FBI-1 is clinically associated with the progression of, and may be a therapeutic target in, GTD, owing to its diverse oncogenic effects on dysregulated trophoblasts. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
    American Journal Of Pathology 07/2015; 185(7). DOI:10.1016/j.ajpath.2015.03.011 · 4.59 Impact Factor
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    ABSTRACT: p21-activated kinases (Paks) are serine/threonine protein kinases involved in biological events linked to malignant tumor progression. In this study, expression of Pak1, p-Pak2 Ser20, Pak4, pPak4 Ser474 in 21 normal endometrium, 16 hyperplastic endometrium without atypia, 17 atypical complex hyperplasia and 67 endometrial cancers was assessed by immunohistochemistry and correlated with clinicopathological parameters. We also accessed the proliferative role and downstream targets of Pak1 in endometrial cancer. Pak1 was expressed in cytoplasm whereas Pak4 and p-Pak4 were expressed in both cytoplasm and nucleus of endometrial tissues. In normal endometrium, significantly higher Pak1 (P = 0.028) and cytoplasmic p-Pak2 (P = 0.048) expression was detected in proliferative endometrium than secretory endometrium. Pak1, cytoplasmic and nuclear Pak4 and nuclear p-Pak4 was significantly overexpressed in endometrial cancer when compared to atrophic endometrium (all P<0.05). Moreover, type I endometrioid carcinomas showed significantly higher Pak1 expression than type II non-endometrioid carcinomas (P<0.001). On the other hand, Pak1, Pak4 and p-Pak4 expression negatively correlated with histological grade (all P<0.05) while p-Pak2 and cytoplasmic Pak4 expression inversely correlated with myometrial invasion (all P<0.05). Furthermore, patients with endometrial cancers with lower cytoplasmic Pak4 expression showed poorer survival (P = 0.026). Multivariate analysis showed cytoplasmic Pak4 is an independent prognostic factor. Functionally, knockdown of Pak1, but not Pak4, in endometrial cancer cell line led to reduced cell proliferation along with reduced cyclin D1, estrogen receptor (ERα) and progestogen receptor (PR) expression. Significant correlation between Pak1 and PR expression was also detected in clinical samples. Our findings suggest that Pak1 and cytoplasmic p-Pak2 may promote cell proliferation in normal endometrium during menstral cycle. Pak1, cytoplasmic and nuclear Pak4 and nuclear p-Pak4 are involved in the pathogenesis of endometrial cancer especially in postmenopausal women. Pak1 promote endometrial cancer cell proliferation, particular in type I endometrioid carcinoma. Cytoplasmic Pak4 can be potential prognostic marker in endometrial cancer.
    PLoS ONE 07/2015; 10(7):e0133467. DOI:10.1371/journal.pone.0133467 · 3.23 Impact Factor
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    ABSTRACT: Objective: To study the effect of human chorionic gonadotropin (hCG) on Olfactomedin-1 (Olfm1) expression and spheroid attachment in human Fallopian tube epithelial cells in vitro. Design: Experimental study Setting: Reproductive biology laboratory Patient(s): Healthy non-pregnant women Intervention(s): No patient interventions Main Outcome Measure(s): Luteinizing hormone/chorionic gonadotropin receptor (LHCGR) and Olfm1 expression in Fallopian tube epithelium cell line (OE-E6/E7 cells). OE-E6/E7 cells treated with hCG, U0126 Erk inhibitor or XAV939 Wnt/β-catenin inhibitor were analyzed by Western blotting, RT-PCR, and in vitro spheroid attachment assay. Result(s): hCG increased spheroid attachment on OE-E6/E7 cells through down-regulation of Olfm1 and activation of Wnt and MAPK signaling pathways. U0126 down-regulated both MAPK and Wnt/β-catenin signaling pathways and up-regulated Olfm1 expression. XAV939 down-regulated only the Wnt/β-catenin-signaling pathway but up-regulated Olfm1 expression. Conclusion(s): hCG activated both Erk and Wnt/β-catenin signaling pathways and enhanced spheroid attachment on Fallopian tube epithelial cells through down-regulation of Olfm1 expression. Key Words: Olfactomedin-1; Fallopian tube; tubal ectopic pregnancy; Wnt-signaling; MAPK signaling
    Fertility and sterility 05/2015; 104(2). DOI:10.1016/j.fertnstert.2015.04.030 · 4.59 Impact Factor
  • Diana Lim · Philip P C Ip · Annie N.Y. Cheung · Takako Kiyokawa · Esther Oliva
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    ABSTRACT: Accurate distinction of clear cell carcinoma (CCC) from endometrioid carcinoma (EC) has important clinical implications, but, not infrequently, EC demonstrates clear cell change (EC-CC), mimicking CCC. We examined whether a panel of immunomarkers can help distinguish between these tumors. Sixty-four CCCs (40 ovarian and 24 uterine), 34 ECs (21 ovarian and 13 uterine), and 34 EC-CCs (6 ovarian and 28 uterine) were stained for HNF1β, BAF250a, Napsin A, ER, and PR. Intensity and extent of immunoreactivity was assessed. Fifty-seven of 64 (89%) CCCs, 14/34 (41%) EC-CCs, and 16/34 (47%) ECs expressed HNF1β, and 56/64 (88%) CCCs, 4/34 (12%) EC-CCs, and 1/34 (3%) ECs stained for Napsin A. Most CCCs demonstrated at least moderate and diffuse staining for both markers, whereas only focal and weak expression was identified in most EC-CC/EC. Compared to HNF1β, Napsin A showed increased specificity (93.0% vs. 55.9%, P<0.0001) and similar sensitivity (87.5% vs. 89.1%) in distinguishing CCC from EC-CC/EC. Thirteen of 64 (20%) CCCs, 6/34 (18%) EC-CCs, and 2/34 (6%) ECs showed loss of BAF250a. ER was expressed by 10/64 (16%) CCCs, 30/34 (88%) EC-CCs, and 33/34 (97%) ECs, whereas PR positivity was identified in 9/64 (14%) CCCs, 26/34 (77%) EC-CCs, and 33/34 (97%) ECs. The majority of EC and EC-CC demonstrated diffuse staining for ER/PR, whereas most CCCs showed very focal positivity. There is a statistically significant difference in HNF1β, Napsin A, ER, and PR immunoexpression between CCC and EC/EC-CC, with Napsin A being a more specific marker for CCC than HNF1β. Overall, the immunoprofile of EC-CC is more comparable to that of EC than CCC. The use of a panel of immunostains can help distinguish EC-CC from CCC.
    The American journal of surgical pathology 04/2015; Publish Ahead of Print(8). DOI:10.1097/PAS.0000000000000436 · 5.15 Impact Factor
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    ABSTRACT: E2 protein binding to the four E2 binding sites (E2BSs) at the long control region of Human Papillomavirus (HPV) 16/18 genome may exert either transcriptional activation/repression on E6 and E7 oncoproteins. Methylation status at the E2BSs may affect the relative binding of E2 protein to them. In this study, methylation percentage at E2BS 1, 2 (promoter-proximal), and 4 (promoter-distal) were assessed by pyrosequencing and compared among HPV 16/18-positive cervical cancer, high-grade, and low-grade Cervical Intraepithelial Neoplasia, Atypical Squamous Cells of Undetermined Significance, and normal cervical epithelium. HPV 16 E2BS1&2 were more methylated than HPV 16 E2BS4 in cervical cancer whereas in cervical premalignant lesions and normal epithelium, HPV 16 E2BS1&2 were less methylated than HPV 16 E2BS4. HPV 18 E2BS1&2 remained more methylated than E2BS4 in all histological groups. HPV 16 E2BS1&2 methylation increased from high-grade lesions to cervical cancer (P < 0.001). HPV 16 E2BS4 methylation increased from low-grade to high-grade premalignant lesions (P = 0.041). Both HPV 18 E2BS1&2 and E2BS4 methylation increased from low-grade to high-grade Cervical Intraepithelial Neoplasia (P = 0.019 and 0.001 respectively) and further increased form high-grade lesions to cervical cancer (P < 0.001 and 0.005 respectively). Conclusively, HPV 16 E2BS1&2 (for transcriptional repression of E6/E7 oncoproteins) became more heavily methylated than E2BS4 (for transcriptional activation of E6/E7) in cervical cancer, favouring the differential binding of E2 protein to E2BS4. Increasing methylation at HPV 16/18 E2BSs are potentially useful adjunctive molecular markers for predicting progression from low-grade to high-grade cervical premalignant lesions and from high-grade lesions to cervical cancer. J. Med. Virol. © 2015 Wiley Periodicals, Inc.
    Journal of Medical Virology 02/2015; 87(6). DOI:10.1002/jmv.24129 · 2.35 Impact Factor
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    ABSTRACT: Deregulation of FOXM1 has been documented in various cancers. The aim of this study was to evaluate the role of FOXM1 in ovarian cancer tumorigenesis and paclitaxel resistance. Expression of FOXM1 was examined in 119 clinical samples by immunohistochemistry and correlated with clinicopathological parameters. Effects of FOXM1 knockdown on ovarian cancer cell migration, invasion and mitotic catastrophe were also studied. qPCR and ChIP-qPCR were used to establish KIF2C as a novel FOXM1 target gene implicated in chemoresistance. High nuclear FOXM1 expression in ovarian cancer patient samples was significantly associated with advanced stages (P = 0.035), shorter overall (P = 0.019) and disease-free (P = 0.014) survival. Multivariate analysis confirmed FOXM1 expression as an independent prognostic factor for ovarian cancer. FOXM1 knockdown significantly inhibited migration and invasion of ovarian cancer cells and enhanced paclitaxel-mediated cell death and mitotic catastrophe in a p53-independent manner. Bioinformatics analysis suggested a number of potential transcription targets of FOXM1. One of the potential targets, KIF2C, exhibited similar expression pattern to FOXM1 in chemosensitive and chemoresistant cells in response to paclitaxel treatment. FOXM1 could be detected at the promoter of KIF2C and FOXM1 silencing significantly down-regulated KIF2C. Our findings suggest that FOXM1 is associated with poor patient outcome and contributes to paclitaxel resistance by blocking mitotic catastrophe. KIF2C is identified as a novel FOXM1 transcriptional target that may be implicated in the acquisition of chemoresistance. FOXM1 should be further investigated as a potential prognostic marker and therapeutic target for ovarian cancer.
    PLoS ONE 11/2014; 9(11):e113478. DOI:10.1371/journal.pone.0113478 · 3.23 Impact Factor
  • Annie N Y Cheung
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    ABSTRACT: Extensive use of ultrasound in early pregnancy has given rise to increased diagnostic dilemma, particularly the differential diagnosis of early complete mole, partial mole and abnormal nonmolar villous lesions. The rare entities of placental mesenchymal dysplasia, twin pregnancy with one complete mole further pose problems. Overdiagnosis of hydatidiform mole in ectopic pregnancy should also be avoided.Molecular cytogenetic studies, besides enhancing our understanding of pathogenesis, also facilitate diagnosis and management. Laboratory techniques including microsatellite analysis, flow cytometry, in situ hybridization, sequencing, comparative genomic hybridization, and imprinting gene studies have been applied. Vast majority of complete moles are diploid and purely androgenic while most partial moles are triploid having excessive paternal genome with maternal contribution. Adjunct techniques, such as p57kip2 immunohistochemistry as well as ploidy and microsatellite analysis, have become more commonly applied to facilitate diagnosis of GTD. Molecular cytogenetic studies are also useful in distinguishing gestational and non-gestational trophoblastic choriocarcinoma with implication on chemotherapy regimes.However, we should understand clearly the diagnostic pattern and limitation of such tests to avoid misinterpretation. The basic prerequisite of processing adequate or all evacuated material for histopathological evaluation as well as correlation with clinical, radiological and biochemical findings remains the most important diagnostic approach.
    Pathology 10/2014; 46 Suppl 2:S17-S18. DOI:10.1097/01.PAT.0000454108.65695.6b · 2.19 Impact Factor
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    ABSTRACT: The kinesin protein Kif7 has been recognized as an integral component of hedgehog signalling. Aberrant activation of hedgehog signalling has been implicated in many human solid tumours. Gestational trophoblastic disease includes frankly malignant choriocarcinoma and potentially malignant hydatidiform mole. Here we investigated the hedgehog signalling components expression profiles in gestational trophoblastic disease. Downregulation of Gli1, Gli2, Gli3 and Kif7 was demonstrated in clinical samples of choriocarcinoma and hydatidiform moles as well as choriocarcinoma cell lines when compared with normal placentas. Ectopic expression of Kif7 in two choriocarcinoma cell lines JAR and JEG-3 led to a decrease in cell growth and increase in apoptosis demonstrated by MTT and TUNEL assays, respectively. Overexpression of Kif7 also led to suppressed cell migration through transwell assay. In contrast, knocking down Kif7 in HTR-8/SVneo, an immortalized trophoblast cell line, increased cell number over time and increased the migratory ability of the cells. Taken together, Kif7 may contribute to pathogenesis of gestational trophoblastic disease through enhancing survival and promoting dissemination of trophoblasts.
    PLoS ONE 09/2014; 9(9):e108248. DOI:10.1371/journal.pone.0108248 · 3.23 Impact Factor
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    ABSTRACT: Human papillomaviruses (HPV) is the principal etiological agent of cervical cancer. However, exposure to the high risk type-HPV alone is insufficient for tumor formation, and additional factors are required for the HPV infected cells to become tumorigenic. Dysregulated microRNAs expression is frequently observed in cancer but their roles in the formation of cervical cancer have not been fully revealed. In this study, we compared the expression of miR-135a in laser capture microdissected cervical specimens and confirmed over-expression of the microRNA in malignant cervical squamous cell carcinoma when compared to precancerous lesions. Transient force-expression of miR-135a induced growth in low density culture, anchorage independent growth, proliferation and invasion of a HPV-16 E6/E7 immortalized cervical epithelial cell-line, NC104-E6/E7. The observed effects were due to the inhibitory action of miR-135a on its direct target SIAH1 leading to up-regulation of ß-catenin/TCF signaling. MiR-135a force-expression enhanced the growth of HeLa- and NC104-E6/E7-derived tumor in vivo. The effect of miR-135a could be partially nullified by SIAH1 force-expression. More importantly, the expression of SIAH1 and ß-catenin correlated with that of miR-135a in pre-cancerous and cancerous lesions of cervical biopsies. By comparing the tumorigenic activities of miR-135a in E6/E7 positive/negative cell lines and in NC104-E6/E7 with or without E6/E7 knockdown, we demonstrated that HPV E6/E7 proteins are prerequisite for miR-135a as a oncomiR. Taken together, miR-135a/SIAH1/ß-catenin signaling is important in the transformation and progression of cervical carcinoma.
    Carcinogenesis 02/2014; 35(9). DOI:10.1093/carcin/bgu032 · 5.33 Impact Factor
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    ABSTRACT: Stress adaptation has profound consequences for malignant progression and the response to therapy. BRCA1 is an important modulator of cellular stress, but our understanding of its mechanisms of action remains incomplete. Here we identify autophagy as an essential mechanism protecting BRCA1 deficient cancer cells from metabolic stress and allow their survival, which may underlie its significant cancer-promoting properties. We showed that targeted inhibition of endogenous BRCA1 using small interfering RNA caused significant autophagy in response to serum starvation and endoplasmic reticulum stress, whereas overexpression of BRCA1 did not, confirming that the effect was BRCA1 specific. We demonstrated that Beclin 1 was activated in BRCA1 deficient cells, suggesting involvement of a canonical pathway. Importantly, BRCA1 deficient cells were highly dependent on autophagy for survival, and rapidly underwent cell death upon disruption of autophagy. Notably, this dependence on protective autophagy extended to their tissue of origin, as ovarian surface epithelial cells from women testing positive for BRCA1 mutations, in contrast to those with no mutations, robustly induced autophagy to mitigate the stress and promote their survival. These findings highlight a novel role for BRCA1 in protective autophagy, which may make its essential contribution to tumorigenesis and prognosis.
    Cancer letters 12/2013; 346(1). DOI:10.1016/j.canlet.2013.12.026 · 5.62 Impact Factor
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    ABSTRACT: Gestational choriocarcinoma is a malignant tumour derived from placental trophoblast and the most aggressive member of gestational trophoblastic disease (GTD). Apoptotic stimulating protein of p53-2 (ASPP2) is a member of ASPP family that transactivates p53 and thereby functions as a tumour suppressor. In this study, the expression profile of ASPP2 in choriocarcinoma was examined in comparison with normal placentas and hydatidiform moles, the latter being a type of GTD that carries malignant potential. Downregulation of ASPP2 mRNA and protein was demonstrated in choriocarcinoma by quantitative PCR and immunohistochemistry. ASPP2-transfected choriocarcinoma cells (JEG-3 and JAR) showed an increase in apoptosis and a decrease in cell migration as detected by TUNEL and wound healing assays, respectively, illustrating the complex action of ASPP2 on cell functions other than programmed cell death. Activated Src is known to be important in tumour progression. Transfection of ASPP2 but not ASPP1, another tumour suppressive ASPP, was found to be related to subsequent decreased Src-pY416 phosphorylation, suggesting an inactivating effect of ASPP2 on Src. Moreover, this ASPP2-mediated inactivation of Src could be abolished by RNA interference with Csk, a kinase that can inhibit Src activation. Our findings suggested that the ability of ASPP2 to attenuate Src activation was specific to ASPP2 in a Csk dependent manner. Taken together, we demonstrated a loss of tumour suppressive ASPP2 in choriocarcinoma with effects on cell migration as well as apoptosis. We also unveiled a possible mechanistic link between ASPP2 and Csk/Src signaling pathway, implicating the multiple cellular functions of ASPP2.
    Carcinogenesis 05/2013; 71(8 Supplement). DOI:10.1093/carcin/bgt161 · 5.33 Impact Factor
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    ABSTRACT: OBJECTIVE: To study adrenomedullin (ADM) expression and its relation to ciliary beat frequency (CBF) in the nasal mucociliated epithelium in tubal ectopic pregnancy (tEP). DESIGN: Experimental study. SETTING: University teaching hospital. PATIENT(S): Women with tEP and normal intrauterine pregnancy matched for age and gestational age were recruited. Healthy nonpregnant women were also recruited as nonpregnant controls. INTERVENTION(S): Nasal epithelial brushing. MAIN OUTCOME MEASURE(S): Adrenomedullin expression in nasal epithelium (measured by real-time reverse transcription-polymerase chain reaction, plasma ADM concentration (measured by ELISA), and CBF (measured by photometric method). RESULT(S): We have demonstrated a similar decrease in ADM expression and CBF in the nasal mucociliated epithelium, as well as in plasma ADM concentration, in women with tEP compared with normal pregnant women. Adrenomedullin up-regulates nasal CBF via the ADM receptor, as in the oviduct. There is significant correlation between nasal and oviductal CBF. CONCLUSION(S): Nasal epithelium ADM and CBF, as well as plasma ADM, are possible predictors of women at risk of tEP.
    Fertility and sterility 05/2013; 100(2). DOI:10.1016/j.fertnstert.2013.04.007 · 4.59 Impact Factor
  • Chun-Wing Yeung · Annie N. Y. Cheung
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    ABSTRACT: Quantitative and qualitative human chorionic gonadotrophin (hCG) assays are widely used to detect pregnancy state and abnormal trophoblastic lesions. At least five different forms of hCG have been characterized and different trophoblastic diseases produce different forms of hCG in varying proportions. Because of the difference in antibody specificity in various commercial automated immunoassays of HCG, discordant results may be obtained by laboratories using different hCG assays, with a falsely low or negative result obtained if the assay does not recognize the hCG variants produced from the trophoblastic tissue. On the other hand, significantly elevated hCG concentration can paradoxically lead to false-negative results in two-site immunometric assay due to high-dose hook effect. Clinicians managing patients with trophoblastic lesions should be aware of these limitations of current hCG assays and clinical laboratories should have measures to avoid analytical false negative hCG results.
    03/2013; DOI:10.1007/s13669-013-0067-2
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    ABSTRACT: Recent evidence has suggested that AMPK activators may be applied as therapeutic drugs in suppressing cancer cell growth. However, the molecular mechanism of their suppressive function in cancer cells is still unclear. Here we show that AMPK activators impair cervical cancer cell growth through the reduction of DVL3, a positive regulator in Wnt/β-catenin signaling and an oncogenic player in cervical cancer tumorigenesis. By western blot and immunohistochemical analyses, we demonstrated that DVL3 was frequently upregulated and significantly associated with elevated β-catenin (P = 0.009) and CyclinD1 (P = 0.009) expressions in cervical cancer. Enforced expression of DVL3 elevated β-catenin and augmented cervical cancer cell growth, verifying that DVL3-mediated Wnt/β-catenin activation is involved in cervical cancer oncogenesis. On the other aspect, we noted that the cervical cancer cell growth was remarkably suppressed by AMPK activators and such cell growth inhibition was in concomitant with the reduction of DVL3 protein level in dose- and time-dependent manners. Besides, impaired mTOR signaling activity also reduced DVL3 expression. In contrast, co-treatment with Compound C (AMPK inhibitor) could significantly abrogate metformin induced DVL3 reduction. In addition, co-treatment with AM114 or MG132 (proteosomal inhibitors) could partially restore DVL3 expression under the treatment of metformin. Further in vivo ubiquitination assay revealed that metformin could reduce DVL3 by ubiquitin/proteasomal degradation. To our knowledge, this is the first report showing the probable molecular mechanisms of that the AMPK activators suppress cervical cancer cell growth by impairing DVL3 protein synthesis via AMPK/mTOR signaling and/or partially promoting the proteasomal degradation of DVL3.
    PLoS ONE 01/2013; 8(1):e53597. DOI:10.1371/journal.pone.0053597 · 3.23 Impact Factor
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    ABSTRACT: The female reproductive system is a complex system. Epithelia of the female reproductive system including the ovaries, the oviduct, and the uterus are important sites for follicular development, ovulation, fertilization, implantation, and embryo development. They are also able to synthesize and secrete various hormones, growth factors, and cytokines, which are essential to women's health, sexuality, and reproduction. Conversely, their dysfunction has been implicated in disorders such as infertility, endometriosis, and many other gynecological diseases, as well as cancer. In this chapter, we describe detailed procedures for establishing and maintaining primary cultures of human ovarian surface epithelium, oviductal epithelium, and endometrium. We also provide protocols for cell immortalization, clonal isolation, and in coculture with stromal cells. These cultures can be useful models for investigating the molecular and cellular functions of these epithelia in both normal and pathological states.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 945:347-63. DOI:10.1007/978-1-62703-125-7_21 · 1.29 Impact Factor
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    ABSTRACT: Despite being an essential vitamin, folate has been implicated to enhance tumor growth, as evidenced by reports on overexpression of folate receptor alpha (FRα) in carcinomas. The role of another folate transporter, reduced folate carrier (RFC), is largely unknown. This study investigated the roles of folate, FRα and RFC in ovarian cancers. We demonstrated FRα mRNA and protein overexpression and reduced RFC expression in association with FRα gene amplification and RFC promoter hypermethylation, respectively. FRα overexpression was associated with tumor progression while RFC expression incurred a favorable clinical outcome. Such reciprocal expression pattern was also observed in ovarian cancer cell lines. Folate was shown to promote cancer cell proliferation, migration and invasion in vitro, and down-regulate E-cadherin expression. This effect was blocked after either stable knockdown of FRα or ectopic overexpression of RFC. This hitherto unreported phenomenon suggests that, RFC can serve as a balancing partner of FRα and confer a protective effect in patients with high FRα-expressing ovarian carcinomas, as evidenced by their prolonged overall and disease-free survivals. In conclusion, we report on the paradoxical impact of FRα (putative oncogenic) and RFC (putative tumor suppressive) in human malignancies. FRα and RFC may potentially be explored as therapeutic target or prognostic marker respectively. We recommend caution and additional research on folate supplements in cancer patients.
    PLoS ONE 11/2012; 7(11):e47201. DOI:10.1371/journal.pone.0047201 · 3.23 Impact Factor
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    ABSTRACT: Gene expression profiling aimed at classifying and prognosing breast cancer has yielded signatures with little if any concordance. However, expression arrays used in these studies do not discriminate alternate RNA splice isoforms that vary widely in cancer and might resolve this problem. In this study, we profiled splice isoforms in a panel of tamoxifen-sensitive and resistant cell lines, defining a novel variant (BQ323636.1) of the nuclear receptor co-repressor 2 (NCOR2) that was associated with tamoxifen resistance. Over-expression of this variant in a tamoxifen-sensitive cell line induced its resistance to tamoxifen. We confirmed our initial findings from cell lines in 77 breast tumors from a Chinese cohort, where BQ323636.1 expression was higher in tamoxifen-resistant patients than tamoxifen-sensitive patients. For patients who were ER-positive and had received tamoxifen treatment, higher BQ323636.1 expression level correlated with distant metastasis. High expression level of BQ323636.1 was found to be associated with poorer overall and disease-free survival for patients who had received tamoxifen treatment. Notably, higher BQ323636.1 vs. NCOR2 wild type ratio was also associated with negative ER and PR status, and triple-negative status (ER-/PR-/HER2- receptor status). Mechanistic investigations showed that under conditions of tamoxifen exposure BQ323636.1 suppressed the transcriptional activity of ERα, exhibiting promoter regulating functions. Our findings highlight a novel splice variant of the ERα co-repressor NCOR2 as a candidate biomarker in breast cancer that not only predicts tamoxifen response but might be targeted to overcome tamoxifen resistance.
    Cancer Research 11/2012; 73(1). DOI:10.1158/0008-5472.CAN-12-2241 · 9.33 Impact Factor
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    ABSTRACT: In recent years, much attention has been paid to the concept of cancer stem cells (CSC) and self-renewal related pathways in cancer biology. This review outlines the dysregulated stemness-related genes or transcription factors in gynecological cancers. Hedgehog (Hh) and Notch signaling are important pathways in tissue pattern programming and cell fate determination during embryonic development. Hyperactivation of these two pathways was frequently observed in gynecological malignancies such as ovarian, endometrial and cervical cancers. In contrast, the expression profiles of pluripotency-regulating core transcriptional circuitry: Nanog, Oct4 and Sox2 appear heterogeneous. Among these transcription factors, overexpression of Nanog was found to exert a prominent effect in gynecological tumorigenesis, while dysregulations of Oct4 and Sox2 may vary in a context dependent manner. On the other hand, the isolation of putative CSC illustrates a hierarchy model of tumor heterogeneity, in which only a subset of cells among biologically distinct populations can initiate tumor growth. Re-activation of these pluripotent transcription factors (Nanog, Oct4 and/or Sox2) in association with distinct tumorigenic properties could be found in clones isolated from gynecological tumors using various approaches. Recent understanding on the roles of Hh and Notch signaling in enhancing CSC survival may help to better understand the mechanism of carcinogenesis and identify new pharmaceutical targets for gynecological malignancies.
    Histology and histopathology 09/2012; 27(9):1121-30. · 2.10 Impact Factor
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    ABSTRACT: In recent years, much attention has been paid to the concept of cancer stem cells (CSC) and selfrenewal related pathways in cancer biology. This review outlines the dysregulated stemness-related genes or transcription factors in gynecological cancers. Hedgehog (Hh) and Notch signaling are important pathways in tissue pattern programming and cell fate determination during embryonic development. Hyperactivation of these two pathways was frequently observed in gynecological malignancies such as ovarian, endometrial and cervical cancers. In contrast, the expression profiles of pluripotency-regulating core transcriptional circuitry: Nanog, Oct4 and Sox2 appear heterogeneous. Among these transcription factors, overexpression of Nanog was found to exert a prominent effect in gynecological tumorigenesis, while dysregulations of Oct4 and Sox2 may vary in a context dependent manner. On the other hand, the isolation of putative CSC illustrates a hierarchy model of tumor heterogeneity, in which only a subset of cells among biologically distinct populations can initiate tumor growth. Re-activation of these pluripotent transcription factors (Nanog, Oct4 and/or Sox2) in association with distinct tumorigenic properties could be found in clones isolated from gynecological tumors using various approaches. Recent understanding on the roles of Hh and Notch signaling in enhancing CSC survival may help to better understand the mechanism of carcinogenesis and identify new pharmaceutical targets for gynecological malignancies.
    Histology and histopathology 09/2012; 27(9):1121-1130. · 2.10 Impact Factor
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    ABSTRACT: Paired-like homeodomain 2 (PITX2) is a bicoid homeodomain transcription factor which plays an essential role in maintaining embryonic left-right asymmetry during vertebrate embryogenesis. However, emerging evidence suggests that the aberrant upregulation of PITX2 may be associated with tumor progression, yet the functional role that PITX2 plays in tumorigenesis remains unknown. Using real-time quantitative RT-PCR (Q-PCR), Western blot and immunohistochemical (IHC) analyses, we demonstrated that PITX2 was frequently overexpressed in ovarian cancer samples and cell lines. Clinicopathological correlation showed that the upregulated PITX2 was significantly associated with high-grade (P = 0.023) and clear cell subtype (P = 0.011) using Q-PCR and high-grade (P<0.001) ovarian cancer by IHC analysis. Functionally, enforced expression of PITX2 could promote ovarian cancer cell proliferation, anchorage-independent growth ability, migration/invasion and tumor growth in xenograft model mice. Moreover, enforced expression of PITX2 elevated the cell cycle regulatory proteins such as Cyclin-D1 and C-myc. Conversely, RNAi mediated knockdown of PITX2 in PITX2-high expressing ovarian cancer cells had the opposite effect. Our findings suggest that the increased expression PITX2 is involved in ovarian cancer progression through promoting cell growth and cell migration/invasion. Thus, targeting PITX2 may serve as a potential therapeutic modality in the management of high-grade ovarian tumor.
    PLoS ONE 05/2012; 7(5):e37076. DOI:10.1371/journal.pone.0037076 · 3.23 Impact Factor

Publication Stats

4k Citations
839.44 Total Impact Points


  • 1990–2015
    • The University of Hong Kong
      • • Department of Pathology
      • • Department of Obstetrics and Gynaecology
      Hong Kong, Hong Kong
  • 1991–2014
    • Queen Mary Hospital
      Hong Kong, Hong Kong
  • 2002–2010
    • Lands Department of The Government of the Hong Kong Special Administrative Region
      Hong Kong, Hong Kong
  • 2006
    • The Chinese University of Hong Kong
      Hong Kong, Hong Kong
    • Hong Kong SAR Government
      Hong Kong, Hong Kong
    • Kwong Wah Hospital
      Hong Kong, Hong Kong
  • 2005
    • Zhengzhou University
      Cheng, Henan Sheng, China
  • 1995
    • Stanford University
      • Department of Obstetrics and Gynecology
      Palo Alto, California, United States
  • 1994
    • Harvard Medical School
      • Department of Pathology
      Boston, MA, United States