Biomedical subjects

Samuel C Mok

Publications and source records attributed to Samuel C Mok.

49 records · Page 3Linked to original sources

PubMed2003

Osteopontin is down-regulated in hydatidiform mole.

OBJECTIVE: Osteopontin (OPN) is a glycoprotein of the extracellular matrix that can bind to different types of receptors including integrins and CD44 receptors. Multiple binding affinity enables OPN to play a role in many physiological and pathological processes. OPN contributes to tumorigenesis in several types of cancers. OPN is also expressed by the endometrium and by trophoblast cells of the chorionic villus in human placenta, where OPN may regulate implantation and placentation in early pregnancies by promoting cell-cell interactions, adhesion, spreading, and migration of trophoblast. Our purpose was to determine the expression of OPN mRNA and protein in hydatidiform mole and in normal placenta of comparable gestational age. METHODS: A total of 13 fresh tissues from complete hydatidiform moles, 2 from partial hydatidiform moles, and 9 from normal placentas were analyzed by performing quantitative real-time PCR on microdissected trophoblast cells and immunohistochemistry on frozen sections of tissue. RESULTS: Our results showed significantly lower expression of OPN mRNA and protein in hydatidiform mole, and in particular complete mole (P = 0.001 by real-time PCR and P < 0.001 by immunohistochemistry) as compared to nermal placenta. CONCLUSION: Although precise molecular mechanisms of gestational trophoblastic diseases have not yet been determined, down-regulation of osteopontin may play an important role in the pathogenesis of molar pregnancy.

Dissection↗

PubMed2003

New technologies for the identification of markers for early detection of ovarian cancer.

PURPOSE OF REVIEW: The ovarian cancer screening regimens in current use fail to identify disease at an early curable stage. RECENT FINDINGS: New technologies are emerging that facilitate the identification of diagnostic tumor markers. In particular, high throughput techniques using microarray technology and proteomic screening have enriched the study of protein expression by ovarian cancer cells. SUMMARY: Further evaluation of serum proteins associated with ovarian cancer holds promise for the development of a tumor marker panel that could aid in the early diagnosis of ovarian cancer, and save lives.

Biomarkers, Tumor↗

PubMed2002

BRCA1 supports XIST RNA concentration on the inactive X chromosome.

BRCA1, a breast and ovarian tumor suppressor, colocalizes with markers of the inactive X chromosome (Xi) on Xi in female somatic cells and associates with XIST RNA, as detected by chromatin immunoprecipitation. Breast and ovarian carcinoma cells lacking BRCA1 show evidence of defects in Xi chromatin structure. Reconstitution of BRCA1-deficient cells with wt BRCA1 led to the appearance of focal XIST RNA staining without altering XIST abundance. Inhibiting BRCA1 synthesis in a suitable reporter line led to increased expression of an otherwise silenced Xi-located GFP transgene. These observations suggest that loss of BRCA1 in female cells may lead to Xi perturbation and destabilization of its silenced state.

Animals↗

PubMed2002

Genomic and expression analysis of the 12p11-p12 amplicon using EST arrays identifies two novel amplified and overexpressed genes.

We performed parallel array comparative genomic hybridization and array expression analysis of the 12p11-p12 amplicon in human testicular seminomas and an ovarian carcinoma cell line using an expressed sequence tags (ESTs) array spotted with 8254 ESTs. The data were normalized using a robust statistical modeling and the significance inferred from the local SD. We identified two ESTs within the chromosomal amplicon that were amplified and overexpressed in > or =75-100 percent of analyzed tumors with the 12p11-p12 amplicon. These sequences, belonging to coding regions of two novel genes designated here as GCT1 and GCT2, were broadly expressed in a panel of human tissues, including testis and ovary. GCT1 and GCT2 were overexpressed in 92 and 71 percent, respectively, of a panel of seminomas tested. Combined array comparative genomic hybridization and array expression analysis is a valid approach for gene discovery in large chromosomal amplicons.

Aged↗

PubMed2002

Polymorphisms of the estrogen-metabolizing genes CYP17 and catechol-O-methyltransferase and risk of epithelial ovarian cancer.

Because some studies have linked polymorphic variants of the estrogen-metabolizing genes CYP17 and catechol O-methyl transferase (COMT) with risk for hormonally related cancers, we sought to determine whether selected polymorphisms of these genes differed between women with and without ovarian cancer. From a population-based study of ovarian cancer, we analyzed DNA from a total of 480 cases and controls. PCR amplification was performed using primers that amplify restriction sites for MspAI (A2 polymorphism-CYP17) and NlaIII (Val/Met polymorphism-COMT). Digestion of the PCR products was performed. Genotypes identified by gel electrophoresis were assigned as homozygous wild type (WW), heterozygous variant (Wv), and homozygous variant (vv). Frequencies were compared using chi(2) or Fisher's exact tests. Logistic regression was used to calculate crude and adjusted relative risks (RRs) for ovarian cancer associated with possession of any variant allele overall, and within demographic, weight, and smoking history categories, and by histological subtype of ovarian cancer. A portion (68.9%) of cases either carried or was homozygous for the A2 variant of CYP17 compared with 53.9% of controls, for a RR (and 95% confidence interval) of 1.86 (1.26, 2.75; P = 0.003), adjusted for age, parity, oral contraceptive use, site of study, and family history of breast or ovarian cancer. The increased risk was most apparent for women >50 and women with invasive serous cancers. A portion (71.9%) of cases either carried or was homozygous for the Val/Met variant of COMT, compared with 76.9% of controls (P = 0.27). Although the inverse association of ovarian cancer with possession of a Val/Met variant was not significant overall, it was for mucinous tumors of the ovary, with an adjusted RR of 0.28 (0.13, 0.61; P = 0.0012). Possession of the A2 variant of CYP17 appears to increase risk for ovarian cancer, whereas possession of the Val/Met variant of COMT decreases the risk for mucinous tumors. Confirmation in other populations and further exploration of potential pathogenetic mechanisms will be necessary.

Alleles↗

PubMed2002

Reproductive hormone-induced, STAT3-mediated interleukin 6 action in normal and malignant human ovarian surface epithelial cells.

BACKGROUND: Reproductive hormones are associated with risk for epithelial ovarian cancer. To determine the effect of such hormones on the activation of interleukin 6 (IL-6)/STAT3 (signal transducer and activator of transcription-3) signaling, which may be involved in ovarian cancer, we investigated the status of STAT3, IL-6, and its receptor in immortalized human ovarian surface epithelial (HOSE) and ovarian cancer (OVCA) cell lines. METHODS: Two immortalized HOSE cell lines and two OVCA cell lines were cultured with gonadotropins, sex steroid hormones, and/or IL-6, alone or with specific inhibitors or IL-6-neutralizing antibodies. Expression of IL-6, the IL-6 receptor alpha chain (IL-6Ralpha), and phosphorylated and unphosphorylated STAT3 messenger RNAs (mRNAs) and proteins in all cells was determined. Cell proliferation and soft-agar colony formation were assessed. STAT3 activity was investigated in OVCA cells transfected with a dominant negative STAT3 (Dn-STAT3), wild-type STAT3, or an empty control vector. All statistical tests were two-sided. RESULTS: Levels of IL-6 mRNA and protein increased in all cells treated with follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17beta-estradiol, or estrone but increased only in OVCA cells treated with testosterone and 5alpha-dihydrotestosterone. For all lines, IL-6 antibodies partially inhibited hormone-stimulated cell proliferation but completely inhibited IL-6-enhanced cell proliferation. IL-6 induced STAT3 phosphorylation and activation in HOSE cells; STAT3 was constitutively activated in OVCA cells. Higher levels of IL-6Ralpha and STAT3 transcription factors were observed in OVCA cells than in HOSE cells. After transfection, Dn-STAT3 suppressed endogenous STAT3 and inhibited all forms of IL-6-stimulated OVCA cell proliferation (OVCA 429 cells, P<.001; OVCA 432 cells, P<.006), whereas wild-type STAT3 enhanced HOSE cell proliferation (wild-type STAT3 at 0.5 microg/mL in HOSE 306 cells, P<.002; STAT3 at 1.0 microg/mL in HOSE 306 or both concentrations of wild-type STAT3 in HOSE 642 cells, P<.001). CONCLUSIONS: The IL-6/STAT3 signaling pathway may mediate FSH-, LH-, and estrogen-stimulated HOSE cell proliferation. Increased IL-6Ralpha expression and constitutive STAT3 activation may be associated with ovarian cancer.

Adult↗

PubMed2002

Osteopontin as a potential diagnostic biomarker for ovarian cancer.

CONTEXT: Development of new biomarkers for ovarian cancer is needed for early detection and disease monitoring. Analyses involving complementary DNA (cDNA) microarray data can be used to identify up-regulated genes in cancer cells, whose products may then be further validated as potential biomarkers. OBJECTIVE: To describe validation studies of an up-regulated gene known as osteopontin, previously identified using a cDNA microarray system. DESIGN, SETTING, AND PARTICIPANTS: Experimental and cross-sectional studies were conducted involving ovarian cancer and healthy human ovarian surface epithelial cell lines and cultures, archival paraffin-embedded ovarian tissue collected between June 1992 and June 2001, and fresh tissue and preoperative plasma from 144 patients evaluated for a pelvic mass between June 1992 and June 2001 in gynecologic oncology services at 2 US academic institutions. Plasma samples from 107 women selected from an epidemiologic study of ovarian cancer initiated between May 1992 and March 1997 were used as healthy controls. MAIN OUTCOME MEASURES: Relative messenger RNA expression in cancer cells and fresh ovarian tissue, measured by real-time polymerase chain reaction as 2(-DeltaDeltaCT)(a quantitative value representing the amount of osteopontin expression); osteopontin production, localized and scored in ovarian healthy and tumor tissue with immunohistochemical studies; and amount of osteopontin in patient vs control plasma, measured using an enzyme-linked immunoassay. RESULTS: The geometric mean for 2(-DeltaDeltaCT)for osteopontin expression in 5 healthy ovarian epithelial cell cultures was 4.1 compared with 270.4 in 14 ovarian cancer cell lines (P =.03). The geometric mean 2(-DeltaDeltaCT)for osteopontin expression in tissue from 2 healthy ovarian epithelial samples was 9.0 compared with 164.0 in 27 microdissected ovarian tumor tissue samples (P =.06). Immunolocalization of osteopontin showed that tissue samples from 61 patients with invasive ovarian cancer and 29 patients with borderline ovarian tumors expressed higher levels of osteopontin than tissue samples from 6 patients with benign tumors and samples of healthy ovarian epithelium from 3 patients (P =.03). Osteopontin levels in plasma were significantly higher (P<.001) in 51 patients with epithelial ovarian cancer (486.5 ng/mL) compared with those of 107 healthy controls (147.1 ng/mL), 46 patients with benign ovarian disease (254.4 ng/mL), and 47 patients with other gynecologic cancers (260.9 ng/mL). CONCLUSIONS: Our findings provide evidence for an association between levels of a biomarker, osteopontin, and ovarian cancer and suggest that future research assessing its clinical usefulness would be worthwhile.

Biomarkers, Tumor↗

PubMed2002

Multicolor spectral karyotyping of serous ovarian adenocarcinoma.

We applied multicolor spectral karyotyping (SKY) to decipher the chromosomal complexity of a panel of seven cell lines and four primary tumors derived from patients with high-grade serous adenocarcinoma of the ovary. By this method we identified a total of 188 unbalanced translocations, nine reciprocal translocations [t(2;15)(q13;q23), t(7;17) (q32;q21), t(8;22)(p11;q11), t(8;22) (q24;q13), t(10;19) (q24;q13.2), t(11;19) (q13;p11), t(12;21)(q13;q22),t(18;20) (q?11;q?11), t(18;22)(q?11;q?13)], 6 isochromosomes [i(1q), i(7q), i(8q), i(9p), i(17q), i(21q)], and 23 deletions. By detailed mapping of rearrangement breakpoints, it was possible to identify several recurring breakpoint clusters at chromosomal bands 1p36, 2p11, 2p23, 3p21, 3q21, 4p11, 6q11, 8p11, 9q34, 10p11, 11p11, 11q13, 12p13, 12q13, 17q21, 18p11, 18q11, 20q11, and 21q22. Recurrent interstitial deletion of chromosomal bands 8p11, 11p11, and 12q13 and a recurrent unbalanced translocation--der(6)t(6;8)(q11;q11)-were also identified. In addition, a homogeneously staining region localized in one cell line to 11q13 was found using SKY to be derived from genetic material originating from chromosome 12. Subsequent comparative genomic hybridization (CGH) studies on this tumor revealed the amplification of DNA sequences derived from the short arm of chromosome 12 at the 12p11.2 region. These studies demonstrate the power of SKY, CGH, and G-banding to resolve the full spectrum of chromosomal rearrangements in serous ovarian adenocarcinoma.

Adenocarcinoma, Papillary↗

PubMed2002

Down-regulation of DOC-2 in colorectal cancer points to its role as a tumor suppressor in this malignancy.

PURPOSE: Colorectal cancer is the second most common cause of cancer death and the fourth most prevalent carcinoma in the Western world. Loss of tumor-suppressor gene function in colon cancer leads to ineffective negative growth regulation that is normally exerted by growth-suppressing factors. DOC-2/hDAB2 is a newly identified candidate tumor-suppressor gene in ovarian cancer and choriocarcinoma. In these tumors it negatively influences mitogenic signal transduction of growth factors and blocks ras activity. In the present study we sought to determine the role of DOC-2 in colorectal cancer. METHODS: DOC-2 expression was analyzed by Northern blot analysis, hybridization, and immunohistochemistry in 27 primary and metastatic colorectal cancers and in 15 normal colon tissues in correlation with clinicopathologic data. RESULTS: Northern blot analysis demonstrated a decrease of DOC-2 messenger RNA levels in primary and metastatic colorectal cancers compared with normal controls. In normal colorectal tissues, DOC-2 immunoreactivity was strongly present on the surface columnar epithelial cells. In contrast, DOC-2 immunoreactivity was weak to moderate in the epithelium of colorectal cancers, and the intensity of the signals in colorectal cancer was greatly decreased compared with the normal colorectal tissues. In addition, DOC-2 immunoreactivity in lymph node and liver metastasis was weak to absent in the cancer cells and significantly decreased compared with their primary tumors. CONCLUSIONS: The expression of DOC-2 is down-regulated in primary tumors and metastases of colorectal cancer, which suggests that DOC-2 functions as a tumor suppressor in this malignancy.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Recent advances in molecular biology of gestational trophoblastic diseases. A review.

Gestational trophoblastic diseases are interrelated conditions characterized by abnormal growth of chorionic tissues with various propensities for local invasion and metastasis. Complete mole is a unique conception in that all nuclear DNA is paternally derived and all cytoplasmic DNA is maternally derived. In contrast, partial mole generally has a triploid karyotype, where the extra haploid set of chromosomes is paternally derived: Gestational trophoblastic diseases are characterized by altered expression of several growth regulatory factors and oncogenes. While differences in expression of oncoproteins may be important to the development of gestational trophoblastic disease, the precise molecular changes that are critical to pathogenesis remain unknown.

Disease Progression↗

PubMed2002

Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from high-risk women.

PURPOSE: The purpose of this research was to examine the DNA methylation profiles of primary sporadic ovarian cancers and ovarian tissues from high-risk women. EXPERIMENTAL DESIGN: We analyzed the DNA methylation status of nine cancer-related genes in 49 primary ovarian tumors, 39 nonmalignant ovarian tissues obtained from 16 women with no known risk and from 23 high-risk women with a strong family history of breast and/or ovarian cancer or BRCA1 germ-line mutations, and 11 ovarian cancer cell lines, by methylation-specific PCR. RESULTS: Our findings are as follows: (a) methylation rates of four of nine genes, RASSF1A (41%), HIC1 (35%), E-cadherin (29%), and APC (18%) were significantly higher in tumors compared with controls. At least one of the four genes was methylated in 76% of the tumors; (b) a low frequency of methylation was present in nonmalignant tissues; (c) no significant differences in methylation frequencies were seen between the nonmalignant ovarian tissues from women at high-risk and those with no known risk of developing ovarian cancer; (d) methylation of the BRCA1 gene was found in 10% of sporadic tumors but in none of the samples from women with a germ-line BRCA1 mutation; and (e) ovarian cancer cell lines showed a similar frequency of methylation to ovarian tumors except for the HIC1 gene. CONCLUSIONS: Our results suggest that aberrant methylation of specific genes, including two not described previously, may be important in ovarian cancer pathogenesis but not in ovaries at risk for cancer development.

DNA↗

PubMed2002

Relationship of XIST expression and responses of ovarian cancer to chemotherapy.

Expression profiling to characterize cancer pharmacology has become a new approach to discover novel molecular targets for prognostic markers and cancer therapy. In a study to compare the global RNA expression profiles between primary and recurrent ovarian tumors from the same patient, we have identified XIST (inactive X chromosome-specific transcripts) as the most differentially expressed gene that was down-regulated in the recurrent tumor. XIST encodes a spliced noncoding polyadenylated transcript that is unique in being expressed exclusively from the inactive X chromosome and is involved in the X-inactivation process. Subsequent characterization of XIST expression in a panel of female cancer cell lines showed that the expression level of XIST correlates significantly with Taxol sensitivity. The clinical relevance of this observation is demonstrated by the strong association between XIST RNA levels and disease-free periods of ovarian cancer patients in a group of 21 ovarian cancer cases with Taxol in the therapeutic regiments. Cytogenetic studies on ovarian cancer cell lines indicated that loss of inactive X chromosome is one mechanism for the loss of XIST transcripts in the cell lines. Our data suggest that XIST expression may be a potential marker for chemotherapeutic responses in ovarian cancer.

Antineoplastic Agents, Phytogenic↗

PubMedDate not supplied

Expression of cytokines and receptors in normal, immortalized, and malignant ovarian epithelial cell lines.

BACKGROUND: Ovarian carcinoma originates from the epithelial cells on the surface of the ovary. This study evaluates cytokine production by these cells. MATERIALS AND METHODS: Normal human ovary surface epithelial cells (HOSE cells), immortalized HOSE cells and ovarian cancer cells were used for the study of cytokines. RESULTS: Eight of 14 cytokines were increased in > or = 3 ovarian cancer cell lines compared with normal HOSE cells. Three cytokines were increased 5-fold in the immortalized HOSE cell line and in multiple ovarian cancer cell lines. Cytokine receptor expression revealed that 7 of 8 ovarian cancer cell lines had > or = 1 autocrine loop. Anti-EGFR antibody failed to inhibit growth of ovarian cancer cells which expressed multiple cytokine receptors. CONCLUSION: Ovarian cancer cells produce more cytokines than normal HOSE cells. Immortalized HOSE cells display a cytokine profile similar to the cancer cells. Finally, multiple autocrine loops in ovarian cancer may limit the therapeutic usefulness of single cytokine receptor blockade.

Antibodies↗