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Alice S T Wong

Publications and source records attributed to Alice S T Wong.

13 recordsLinked to original sources
PubMed2007

Role of endocrine and growth factors on the ovarian surface epithelium.

Epithelial ovarian cancer is a highly fatal disease for which prevention strategies have been limited; in part because of our poor understanding of the underlying biology of its precursor, the ovarian surface epithelium (OSE). The OSE is a single layer of flat-to-cuboidal mesothelial cells that covers the surface of the ovary. Despite its inconspicuous appearance in vivo, it is believed that OSE cells actively participate in the cyclical ovulatory rupture and repair process. The continuous rupture of the OSE at ovulation and the subsequent proliferation to repair the wound renders the cells susceptible to genetic damage and malignant transformation. As the ovary is a rich source of multiple hormones, and normal OSE and ovarian carcinomas secrete and have receptors for hormones, growth factors and cytokines, these factors are strong candidates to regulate normal OSE physiology and the transformation and progression of ovarian cancers. In particular, alterations of hormone/growth factor production and receptor expression are common in ovarian tumors. This review summarizes the current knowledge in the field of endocrinology and its relationship to the biology and pathology of the OSE.

Animals↗
PubMed2006

Gonadotropin-releasing hormone promotes ovarian cancer cell invasiveness through c-Jun NH2-terminal kinase-mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9.

Gonadotropin-releasing hormone (GnRH) receptor is present in 80% of ovarian cancer, and numerous studies have provided evidence for a role of GnRH in cell proliferation. In this study, the effect of GnRH on the invasion potential of ovarian cancer cells was investigated. In vitro migration and cell invasion assays with the ovarian cancer cell lines Caov-3 and OVCAR-3 revealed the biphasic nature of GnRH; low concentrations of GnRH agonist (GnRHa) increased the cell motility and invasiveness of these cells, but at increased concentrations, the stimulatory effect was insignificant. Reverse transcription-PCR, Western blot, and gelatin zymography showed that the expression of metastasis-related proteinases, matrix metalloproteinase (MMP)-2 and MMP-9, was up-regulated and activated by GnRHa. Moreover, we observed that GnRHa was able to transactivate the MMP-2 and MMP-9 promoters. The invasive/migratory phenotype activated by GnRHa can be blocked by specific inhibitors or neutralizing antibodies to MMP-2 and MMP-9. Knockdown of the GnRH receptor using small interfering RNA significantly inhibited the GnRH-induced MMP activation, invasion, and migration. In addition, we showed that the c-Jun NH(2)-terminal kinase, but not extracellular signal-regulated kinase 1/2 or p38 mitogen-activated protein kinase, signaling pathway was critical for GnRH-mediated up-regulation of MMP, cell invasion, and motility. These results indicate for the first time an expanded role for GnRH in other aspects of ovarian tumor progression, such as metastasis, via activation of MMP and the subsequent increase in cell migration and invasion.

Cell Line, Tumor↗
PubMed2006

Ginsenoside-Rg1 induces vascular endothelial growth factor expression through the glucocorticoid receptor-related phosphatidylinositol 3-kinase/Akt and beta-catenin/T-cell factor-dependent pathway in human endothelial cells.

Ginsenoside-Rg1, the most prevalent active constituent of ginseng, is a potent proangiogenic factor of vascular endothelial cells. This suggests that Rg1 may be a new modality for angiotherapy. Rg1 can activate the glucocorticoid receptor (GR). However, the regulatory steps downstream from GR that promote Rg1-induced angiogenesis have not been elucidated. Here we showed for the first time that Rg1 was a potent stimulator of vascular endothelial growth factor (VEGF) expression in human umbilical vein endothelial cells, and importantly this induction was mediated through a phosphatidylinositol 3-kinase (PI3K)/Akt and beta-catenin/T-cell factor-dependent pathway via the GR. Rg1 stimulation resulted in an increase in the level of beta-catenin, culminating its nuclear accumulation, and subsequent activation of VEGF expression. Transfection of a stable form of beta-catenin (S37A) or the use of a glycogen synthase kinase 3beta inhibitor to stabilize beta-catenin induced VEGF synthesis, whereas small interfering RNA-mediated down-regulation of beta-catenin did not, confirming that the effect was beta-catenin-specific. Using a luciferase reporter gene assay, we observed that Rg1 increased T-cell factor/lymphoid enhancer factor transcriptional activity. These events were mediated via a PI3K-dependent phosphorylation of the inhibitory Ser9 residue of glycogen synthase kinase 3beta. In addition, the GR antagonist RU486 was able to inhibit Rg1-induced PI3K/Akt and beta-catenin activation. These findings provide new insights into the mechanism responsible for Rg1 functions.

Animals↗
PubMed2006

Gonadotropin-induced apoptosis in human ovarian surface epithelial cells is associated with cyclooxygenase-2 up-regulation via the beta-catenin/T-cell factor signaling pathway.

Gonadotropins play a prominent role in ovarian function and pathology. We have shown that treatment with gonadotropins (FSH and LH/human chorionic gonadotropin) reduces the amount of N-cadherin with a concomitant induction of apoptosis in human ovarian surface epithelial (OSE) cells, but precise molecular mechanisms remain to be elucidated. Here, we demonstrated activation of beta-catenin/T-cell factor (TCF) signaling by gonadotropins. We further showed that ectopic expression of N-cadherin was sufficient to recruit beta-catenin to the plasma membrane, thereby blocking beta-catenin/TCF-mediated transactivation in gonadotropin-treated cells. Transfection with beta-catenin small interfering RNA or expression of dominant negative TCF inhibited apoptosis, whereas expression of dominant stable beta-catenin (S37A) caused significant apoptosis, thus supporting a proapoptotic role for beta-catenin/TCF in human OSE. In addition, we showed that gonadotropins enhanced beta-catenin/TCF transcriptional activity through inactivation of glycogen synthase kinase-3beta in a phosphatidylinositol 3-kinase/Akt-dependent manner, indicating cross talk between the phosphatidylinositol 3-kinase/Akt and beta-catenin signaling pathways through glycogen synthase kinase-3beta. Furthermore, gonadotropins increased cyclooxygenase-2 (COX-2) expression via the beta-catenin/TCF pathway. COX-2 also played a role in gonadotropin-induced apoptosis, as treatment with the COX-2-specific inhibitor NS-398 or COX-2 small interfering RNA blocked gonadotropin-dependent apoptotic activity. These findings suggest that the participation of beta-catenin in adhesion and signaling may represent a novel mechanism through which gonadotropins may regulate the cellular fate of human OSE.

Apoptosis↗
PubMed2006

Pigment epithelium-derived factor is estrogen sensitive and inhibits the growth of human ovarian cancer and ovarian surface epithelial cells.

Epithelial ovarian carcinoma is the most lethal gynecological cancer. However, little is known about the molecular mechanisms underlying the disease development and progression. In this study, we found that the expression of pigment epithelium-derived factor (PEDF) was greatly reduced in ovarian tumors and in ovarian cancer cell lines when compared with their normal precursor, ovarian surface epithelium (OSE). In addition, we showed that exogenous PEDF inhibited the growth of cultured human OSE as well as ovarian cancer cell lines, whereas targeted inhibition of endogenous PEDF using small interfering RNA or neutralizing PEDF antibody promoted the growth of these cells, confirming that the growth-inhibitory effect was PEDF specific. We also report for the first time that estrogen is an important upstream regulator of PEDF in human OSE. Treatment of the cultured cells with 17 beta-estradiol (E2) inhibited the expression of PEDF protein and mRNA in a dose- and time-dependent manner, which could be reversed by the specific estrogen receptor antagonist, ICI 182,780, indicating that the regulation was estrogen receptor-mediated. We further showed that this down-regulation of PEDF gene transcription was a direct, primary effect of E2. E2 promoted OSE and ovarian cancer cell growth, whereas simultaneous treatment with E2 and PEDF abrogated the estrogenic growth stimulation of these cells. This study is the first to demonstrate a role of PEDF in OSE biology and ovarian cancer and suggests that the loss of PEDF may e of relevance in carcinogenesis.

Antibodies↗
PubMed2006

Activation of p70S6K induces expression of matrix metalloproteinase 9 associated with hepatocyte growth factor-mediated invasion in human ovarian cancer cells.

The expression of hepatocyte growth factor (HGF) receptor, encoded by the Met oncogene, is elevated in ovarian and a variety of cancers. Here we show that human ovarian cancer cells with high Met expression were more sensitive to the cell motility and invasion effect of HGF. Met down-regulation by small interfering RNAs or K252a resulted in reduced migration in response to HGF. The invasive/migratory phenotype activated by HGF can be blocked by specific inhibitors of the phosphatidylinositol-3-kinase (PI3K) cascade, inhibitor of p70(S6K), and also the expression of a dominant-negative Akt, demonstrating that HGF transmits the motogenic signal through PI3K and Akt to p70(S6K). A significant role for p70(S6K) in cell invasion is further supported by the observation that expression of constitutively active forms of p70(S6K) is sufficient to induce invasive and migratory phenotypes in ovarian cancer cells. Importantly, activation of p70(S6K) stimulated expression and proteolytic activity of matrix metalloproteinase (MMP)-9 and cellular invasion, whereas it had little effect on MMP-2, suggesting for the first time that MMP-9 up-regulation by p70(S6K) as a key step for HGF-induced invasion and migration. These data suggest that interfering p70(S6K) may provide a novel means of controlling tumor cell invasiveness.

Acetylcysteine↗
PubMed2005

Gonadotropins regulate N-cadherin-mediated human ovarian surface epithelial cell survival at both post-translational and transcriptional levels through a cyclic AMP/protein kinase A pathway.

Gonadotropins are the major regulators of ovarian function and may be involved in the etiology of ovarian cancer. In this study, we report a new mechanism whereby gonadotropins regulate the survival of human ovarian surface epithelium (OSE), the tissue of origin of epithelial ovarian carcinomas. Our results indicate that disruption of N-cadherin-mediated cell-cell adhesion is an important molecular event in the apoptosis of human OSE. Treatment with surge serum concentrations of gonadotropins reduced the amount of N-cadherin with a concomitant induction of apoptosis, and this effect was mediated by a cAMP/protein kinase A pathway but not the ERK1/2 and protein kinase C cascades. We further demonstrated that activation of the gonadotropins/cAMP signaling pathway in human OSE led to a rapid down-regulation of N-cadherin protein level followed by a reduction at the level of N-cadherin mRNA, indicating that expression of N-cadherin was regulated by post-translational and transcriptional mechanisms. The former mechanism was mediated by increased turnover of N-cadherin protein and could be reversed by inhibition of proteasomal or matrix metalloproteinase (MMP-2) activity. On the other hand, at the transcriptional level, the addition of actinomycin D abolished the cAMP-mediated decrease in N-cadherin mRNA but did not change its stability. Inhibition of protein kinase A or expressing a dominant negative mutant of cAMP-response element-binding protein blocked this decrease of N-cadherin mRNA. Together, the combined operation of post-translational and transcriptional mechanisms suggests that regulation of N-cadherin is a crucial event and emphasizes the important role that N-cadherin has in controlling the survival capability of human OSE.

Annexin A5↗
PubMed2005

Proteomic analysis of a preneoplastic phenotype in ovarian surface epithelial cells derived from prophylactic oophorectomies.

OBJECTIVE: To study the pattern of protein expression associated with a predisposition to develop ovarian cancer. METHODS: Prophylactic oophorectomy is used to prevent ovarian carcinoma in high-risk populations who have a strong family history of breast/ovarian cancer. In ovarian specimens of these women, the ovarian surface epithelium (OSE), which is tissue of origin of epithelial ovarian cancer, often shows altered morphology, growth patterns and differentiation features that are believed to be preneoplastic. This study has used a proteomic approach, based on two-dimensional gel electrophoresis and mass spectrometry, to compare the protein profiles of OSE from women with a history of familial ovarian cancer (FH-OSE), i.e., at least two first-degree relatives with such cancer and/or testing positive for BRCA1 mutations, to those without such history (NFH-OSE). RESULTS: Of >1500 protein spots, there were 8 proteins whose levels were significantly altered in FH-OSE. Three were known ovarian tumor associated proteins, others were novel changes. A number of the alterations seen were accompanied with protein modifications and have not been previously reported. There was a predominance of sequences related to the stress response pathway. Differential expression of selected genes was confirmed by Western blotting and real-time reverse transcription polymerase chain reaction. CONCLUSIONS: Our findings define the OSE phenotype of women at a high risk of developing ovarian cancer. Protein alterations seen in these tissues may represent an early, irreversible, non-mutational step in ovarian epithelial neoplastic progression and may be potential early and sensitive markers for the evaluation of cancer risk.

Adult↗
PubMed2004

Progressive changes in Met-dependent signaling in a human ovarian surface epithelial model of malignant transformation.

We used an experimental in vitro model of human ovarian surface epithelium (OSE), the tissue of origin of >90% of ovarian cancers, to more precisely define the contribution of hepatocyte growth factor (HGF) to various OSE phenotypes at different stages of neoplastic progression. Neoplastic transformation of OSE in cultures was achieved by multiple genetic manipulations, resulting in the nontumorigenic line IOSE-29, the tumorigenic IOSE-Ov29, and the tumor-derived, more highly malignant IOSE-Ov29/T4. We demonstrate here that, compared to IOSE-29, IOSE-Ov29 and IOSE-Ov29/T4 exhibited higher levels of the HGF receptor Met and an increasing duration of ERK1/2 activation with malignant progression, in conjunction with other neoplastic properties. HGF activated Met signaling in all lines but elicited different responses: HGF induced cell dispersion (scattering) and collagen gel invasion in IOSE-Ov29 and IOSE-Ov29/T4 but did not alter the growth pattern of IOSE-29. Inhibition with PD98059 and LY294002 independently prevented HGF-induced invasive growth. Furthermore, our results show that HGF-induced invasion can be mediated through a rapamycin-sensitive p70 S6K cascade, which demonstrates that p70S6K can regulate cell motility in addition to its well-established role in protein synthesis. Taken together, our data correlate specific responses to HGF-mediated signaling with specific signaling pathways and with progressive neoplastic changes.

Carcinoma↗
PubMed2004

Epithelio-mesenchymal transition in a neoplastic ovarian epithelial hybrid cell line.

A hybrid cell line, IOSE-Ov29, was created through fusion of cells from the human ovarian adenocarcinoma line OVCAR3 and the non-tumorigenic SV40 Tag-transfected human ovarian surface epithelial line IOSE-29. OVCAR3 cells exhibit a differentiated epithelial phenotype, whereas line IOSE-29 expresses mesenchymal characteristics that were acquired in culture by epithelio-mesenchymal transition. Microsatellite analysis, comparative genomic hybridization (CGH), and MFISH showed the genotype of the IOSE-Ov29 cells to contain components of both parent cell lines, but to be predominantly OVCAR3 derived. IOSE-Ov29 resembled OVCAR3 and differed from IOSE-29 as shown by its unlimited life span, tumorigenicity, epithelial morphology, keratin, occludin, E-cadherin and CA125 expression, increased expression of kinases of the PI3K pathway, and loss of cGMP-dependent protein kinase expression. IOSE-29-derived properties included SV40 Tag expression, growth inhibition by activin, collagen type III secretion, increased adhesion and spreading on tissue culture plastic, and increased growth rate. Proliferation of all three lines was stimulated by FSH and ATP and inhibited by GnRH I and GnRH II. Interestingly, IOSE-Ov29 was more anchorage independent than either parent line and was the only line that invaded Matrigel in Boyden chambers and formed invasive branches in collagen gels. The results indicate that IOSE-Ov29 is an IOSE-29/OVCAR3 hybrid, which differs from both parent lines genetically and phenotypically. Unexpectedly, fusion with the non-tumorigenic IOSE-29 cells enhanced malignancy-associated characteristics of OVCAR3, presumably as a result of the expression of IOSE-29-derived mesenchymal properties that are usually acquired by carcinoma cells through epithelio-mesenchymal transition during metastatic progression.

Adenocarcinoma↗
PubMed2003

Ovarian surface epithelium: family history and early events in ovarian cancer.

Ovarian cancer is the most common cause of death from gynecological cancers in the Western world. There are many genetic and environmental factors which can influence a woman's risk of getting ovarian cancer. A strong family history of breast or ovarian cancer is definitely one of the most important and best-defined epidemiological risk factors. This review evaluates current knowledge of hereditary ovarian cancer. Histologic, cytologic and molecular studies on the ovarian surface epithelium (OSE), which is the origin of ovarian epithelial carcinomas, from women with a strong family history for ovarian carcinomas or with a mutation in one of the two known cancer susceptibility genes - BRCA1 and BRCA2, provide a background to facilitate understanding of the early changes in ovarian carcinogenesis. This overview is followed by a discussion of recent hypotheses and research on two questions. First, is there a mutational hotspot of BRCA mutation for ovarian cancer? Second, why do mutations in BRCA1 and BRCA2, which are ubiquitously expressed genes that participate in general cellular activities, lead preferentially to breast and ovarian cancer?

Animals↗
PubMed2003

Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin.

Loss of E-cadherin expression or function in tumors leads to a more invasive phenotype. In this study, we investigated whether the invasion suppressor activity of E-cadherin is mediated directly by tighter physical cell adhesion, indirectly by sequestering beta-catenin and thus antagonizing beta-catenin/T cell factor (TCF) signaling, or by other signaling pathways. To distinguish mechanisms, we expressed wild-type E-cadherin and various E-cadherin mutants in invasive E-cadherin-negative human breast (MDA-MB-231) and prostate (TSU-Pr1) epithelial carcinoma cell lines using a tetracycline-inducible system. Our data confirm that E-cadherin inhibits human mammary and prostate tumor cell invasion. We find that adhesion is neither necessary nor sufficient for suppressing cancer invasion. Rather, the invasion suppressor signal is mediated through the beta-catenin-binding domain of the E-cadherin cytoplasmic tail but not through the p120ctn-binding domain. beta-catenin depletion also results in invasion suppression. However, alteration in the beta-catenin/TCF transcriptional regulation of target genes is not required for the invasion suppressor activity of E-cadherin, suggesting the involvement of other beta-catenin-binding proteins.

Breast Neoplasms↗