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Sue-Hwa Lin

Publications and source records attributed to Sue-Hwa Lin.

30 records · Page 2Linked to original sources
PubMed2004

CEACAM1 modulates epidermal growth factor receptor--mediated cell proliferation.

Phosphorylation of the cell adhesion protein CEACAM1 increases insulin sensitivity and decreases insulin-dependent mitogenesis in vivo. Here we show that CEACAM1 is a substrate of the EGFR and that upon being phosphorylated, CEACAM1 reduces EGFR-mediated growth of transfected Cos-7 and MCF-7 cells in response to EGF. Using transgenic mice overexpressing a phosphorylation-defective CEACAM1 mutant in liver (L-SACC1), we show that the effect of CEACAM1 on EGF-dependent cell proliferation is mediated by its ability to bind to and sequester Shc, thus uncoupling EGFR signaling from the ras/MAPK pathway. In L-SACC1 mice, we also show that impaired CEACAM1 phosphorylation leads to ligand-independent increase of EGFR-mediated cell proliferation. This appears to be secondary to visceral obesity and the metabolic syndrome, with increased levels of output of free fatty acids and heparin-binding EGF-like growth factor from the adipose tissue of the mice. Thus, L-SACC1 mice provide a model for the mechanistic link between increased cell proliferation in states of impaired metabolism and visceral obesity.

Animals↗
PubMed2003

Role for NudC, a dynein-associated nuclear movement protein, in mitosis and cytokinesis.

NudC, a nuclear movement protein that associates with dynein, was originally cloned as a mitogen-inducible early growth response gene. NudC forms a biochemical complex with components of the dynein/dynactin complex and is suggested to play a role in translocation of nuclei in proliferating neuronal progenitors as well as in migrating neurons in culture. Here, we show that NudC plays multiple roles in mitosis and cytokinesis in cultured mammalian cells. Altering NudC levels by either small interfering RNA-mediated gene silencing or adenovirus-mediated overexpression resulted in multinucleated cells and cells with persistent intercellular connections and disorganized midzone and midbody matrix. These phenotypes suggest a failure in cytokinesis in NudC altered cells. Further, a key mitotic enzyme, polo-like kinase, is mislocalized from the centrosomes and the midbody in NudC altered cells. Gene silencing of nud-1, the Caenorhabditis elegans ortholog of NudC, led to a loss of midzone microtubules and the rapid regression of the cleavage furrow, which resulted in one-celled embryos containing two nuclei. The loss of midzone microtubule organization owing to silencing of the NudC/nud-1 gene in two systems, coupled with the loss of Plk1 from mitotic structures in mammalian cells, provide clues to the cytokinesis defect and the multinucleation phenotype. Our findings suggest that NudC functions in mitosis and cytokinesis, in part by regulating microtubule organization at the midzone and midbody.

Active Transport, Cell Nucleus↗
PubMed2003

Antitumor activity of the 16-kDa prolactin fragment in prostate cancer.

The 16-kDa prolactin (PRL), derived from the proteolytic cleavage of wild-type 23-kDa PRL, has been shown to have antiangiogenic activity. Such an antiangiogenic activity may have an effect on tumor growth in vivo. Here we examined the effect of 23-kDa and 16-kDa PRL on tumor growth, and the potential of using recombinant 16-kDa human PRL for prostate cancer therapy. The effects of 23-kDa PRL and 16-kDa PRL on the tumorigenicity of prostate cancer cells in vivo were studied. Using an adenovirus transfer vector to achieve high efficiency 23-kDa and 16-kDa PRL transfection in DU145 and PC-3 human prostate carcinoma cell lines, we demonstrated that expression of 16-kDa PRL in the prostate cancer cells markedly reduced their ability to form tumors in a xenograft animal model. These studies established that the 16-kDa PRL has antitumor activity in vivo, presumably as a result of its antiangiogenic effect. Interestingly, 23-kDa PRL showed a weak and transient suppression of prostate tumor growth. The weak antitumor activity of 23-kDa PRL may be because of the production of 16-kDa PRL from 23-kDa PRL by the tumor cells. Thus, the apparent effect of 23-kDa PRL on the growth of DU145 and PC-3 cells in vivo may result from the combined effects of 23-kDa PRL and 16-kDa PRL. These results suggest that the 16-kDa PRL has potential as a treatment agent in prostate cancer.

Adenoviridae↗
PubMed2003

Expression and purification of the angiogenesis inhibitor 16-kDa prolactin fragment from insect cells.

The 16-kDa fragment of prolactin (16-kDa PRL), derived from proteolytic cleavage of 23-kDa PRL, was shown to have antiangiogenic activity. Previous studies have shown that recombinant 16-kDa PRL produced from bacteria often contained endotoxins, which are cytotoxic to endothelial cells, and varied in its biological activity due to changes in its refolding from inclusion bodies. These problems limited the use of recombinant 16-kDa PRL. To improve the generation of recombinant 16-kDa PRL, we expressed 16-kDa PRL in Sf9 insect cells using a baculoviral expression system. The signal sequence of the human PRL gene and codons for seven histidines were added to the N- and C-termini, respectively, of the 16-kDa PRL cDNA construct. Recombinant 16-kDa PRL was detected in both the cell pellet and the medium. About 0.28 mg purified protein was isolated from the cell pellet of 4 x 10(7) infected cells using nickel affinity chromatography. Sixteen kilodalton PRL was posttranslationally modified with apparent molecular weights of 16 and 18 kDa on SDS-PAGE. The level of 18-kDa protein was significantly reduced after digestion with peptidyl-N-glycosidase, suggesting that the heterogeneity was due to glycosylation of 16-kDa PRL. N-terminal sequence analysis confirmed the fact that both proteins were human 16-kDa PRL and the signal sequences were cleaved at the same position as that of human PRL. Consistent with its role as an angiogenesis inhibitor, purified recombinant 16-kDa PRL inhibits the proliferation of endothelial cells with a potency similar to that previously reported for the protein generated in Escherichia coli. This 16-kDa PRL expressed in Sf9 cells is a useful reagent for functional studies and for the purification and identification of its receptor.

Angiogenesis Inhibitors↗
PubMed2002

Hp95 promotes anoikis and inhibits tumorigenicity of HeLa cells.

p95 is a putative signal transduction protein of approximately 95 kDa that contains multiple tyrosine residues that are conserved from yeast to human, a Src phosphorylation consensus sequence and a proline-rich C-terminus that binds SH3-domains. Previous studies have established that mammalian p95 is physically associated with proteins that regulate apoptotic induction and cell transformation; however, it is unclear whether p95 is a positive or negative regulator in these processes. Moreover, a p95 partner protein has been localized at both focal adhesions and actin-cytoskeletons in rat astrocytes. However, there is no evidence that mammalian p95 has roles in regulating cell adhesion or morphology. In this study, we examined the effects of p95 on the anchorage-independent growth and tumorigenicity of malignant HeLa cells, and on the growth and morphology of non-transformed NIH3T3 cells. In HeLa cells, p95 overexpression promoted detachment-induced apoptosis (anoikis), inhibited detachment of viable cells from substratum and reduced tumorigenicity. In NIH3T3 cells, p95 overexpression promoted flat cell morphology and slowed cell proliferation, whereas p95 downregulation had opposite effects. These findings indicate that the mammalian p95 is a positive regulator in apoptotic signaling and a negative regulator in cell transformation. They also suggest that p95 has roles in regulating cell adhesion and morphology.

3T3 Cells↗
PubMed2002

Inhibition of prostate tumor angiogenesis by the tumor suppressor CEACAM1.

We have previously shown that CEACAM1, a cell-adhesion molecule, acts as a tumor suppressor in prostate carcinoma. Expression of CEACAM1 in prostate cancer cells suppresses their growth in vivo. However, CEACAM1 has no effect on the growth of prostate cancer cells in vitro. This difference suggests that the antitumor effect of CEACAM1 may be due to inhibition of tumor angiogenesis, perhaps by increased secretion of antiangiogenic molecules from the cells. In this study, we have demonstrated that expression of CEACAM1 in DU145 prostate cancer cells induced the production of a factor or factors that specifically blocked the growth of endothelial but not epithelial cells. Conditioned medium from the CEACAM1-expressing cells but not control luciferase-expressing cells inhibited endothelial cell migration up a gradient of stimulatory vascular endothelial growth factor in vitro and inhibited corneal neovascularization induced by basic fibroblast growth factor in vivo. Moreover, conditioned medium from CEACAM1-expressing cells induced endothelial cell apoptosis in vitro. Only medium conditioned by CEACAM1 mutants that were able to suppress tumor growth in vivo could cause endothelial cell apoptosis. These observations suggest that CEACAM1-mediated tumor suppression in vivo is, at least in part, due to the ability of CEACAM1 to inhibit tumor angiogenesis.

Antigens, CD↗
PubMed2002

Prostate carcinoma with testicular or penile metastases. Clinical, pathologic, and immunohistochemical features.

BACKGROUND: Despite the proximity, prostate carcinoma seldom metastasizes to the penis or testis. METHODS: In the current study, the authors retrospectively examined the clinical history of 12 patients with prostate carcinoma and testicular or penile metastases. Pathologic review and immunohistochemical staining were performed on tumors from eight of these patients. RESULTS: Patients with prostate carcinoma and testicular or penile metastasis responded to androgen ablative therapy (median duration, 33 months). They were predisposed to developing persistent or recurrent urinary symptoms and visceral metastases. Six of 9 evaluable patients had elevated serum carcinoembryonic antigen levels (> 6 ng/mL), whereas 2 of 10 patients had low or undetectable serum prostate specific antigen levels (< 4 ng/mL). In seven of the eight patients for whom specimens were available, the tumors were found to contain histologic features that were compatible with a diagnosis of ductal or endometrioid adenocarcinoma of the prostate. CONCLUSIONS: Patients with prostate carcinoma and testicular or penile metastases have unique clinical and pathologic characteristics. Many of these patients' tumors are compatible with a subtype of prostate carcinoma known as ductal adenocarcinoma. Further studies need to be performed to elucidate the biologic basis of the various histologic subtypes of prostate carcinoma.

Aged↗
PubMed2002

Ectopic expression of FGF-3 results in abnormal prostate and Wolffian duct development.

To evaluate the effects of FGF-3 expression in the prostate and male reproductive tract, we employed a bitransgenic system to target FGF-3 to these organs. We present a first study that ectopic FGF-3 expression resulted in exuberant hyperplasia of all bigenic prostatic lobes typified by epithelial stratification, cribiform structures and papillary tufts. These cells displayed increased nuclear-to-cytoplasmic ratios and bromodeoxyuridine (BrdU) proliferative index but retained relatively uniform nuclear androgen receptor (AR) and the tumor suppressor C-CAM1 staining. Furthermore, the dysmorphogenic prostatic cells also resembled PIN (prostatic intraepithelial neoplasia)-like lesions but did not appear to have invaded the basal lamina. In addition to these phenotypes, profound disorders of the bigenic Wolffian duct derivatives were observed. The bigenic ampullary glands and vas deferens were extremely cystic, hypertrophic and hyperplastic; the enlarged epididymi showed a reduction of spermatozoa and the seminal vesicles exhibited a dramatic reduction of seminal secretions. Because of these severe abnormalities, these infertile males presented with diaphragmatic hernias, hemoperitoneum and many secondary abnormalities at sacrifice. Taken together, we show that ectopic FGF-3 expression severely perturbs normal prostate development and our system should be useful for the analyses of early changes in prostatic hyperplasia.

Animals↗
PubMed2002

Stem-cell origin of metastasis and heterogeneity in solid tumours.

An explanation for the inherently metastatic and heterogeneous nature of cancers may be their derivation from distinct stem cells. The type of stem cell from which a neoplasm arises determines both the metastatic potential and the phenotypic diversity of that neoplasm. Hence, tumours originating from an early stem cell or its progenitor cells metastasise readily and have a more heterogeneous phenotype, whereas tumours originating from a later stem cell or its progenitor cells have limited metastatic potential and a more homogeneous phenotype. Further investigation of the role of stem cells in the development of cancer may lead to the discovery of novel diagnostic tools, prognostic markers, and therapeutic targets in the battle against cancer.

Biomarkers, Tumor↗
PubMed2002

Enhanced suppression of prostate tumor growth by combining C-CAM1 gene therapy and angiogenesis inhibitor TNP-470.

We have previously shown that C-CAM1-based gene therapy effectively suppressed prostate tumor growth in nude mice xenograft models. In this study, we examined the effects of combining C-CAM1-based therapy and TNP-470, a potent angiogenesis inhibitor, on prostate cancer in a xenografted tumor model. The direct cytotoxic effects of Ad-C-CAM1 (recombinant adenovirus containing C-CAM1 cDNA) and TNP-470 on DU145 cells in vitro were determined by microculture tetrazolium assay. The in vivo antitumor effects of either agent alone were studied in a DU145 xenografted tumor model. Cells were infected with Ad-C-CAM1 or the control virus at multiplicities of infection (m.o.i.) of 5 or 10 and then inoculated onto nude mice 48 h later. TNP-470 (0, 17 or 35 mg/kg) was given 15, 17 and 19 days after inoculation. Combined treatments in vivo were carried out to determine whether there were synergistic antitumor effects. Both Ad-C-CAM1 and the control virus were minimally toxic to DU145 in vitro. There was evident dose-dependent suppression of xenografted tumor growth by either Ad-C-CAM1 or TNP-470. By the median-effect analysis, combination of the two agents generated strong synergistic antitumor effects as shown by marked tumor suppression as compared to either treatment alone. The novel strategy may have clinical implications for the treatment of prostate cancer.

Adenosine Triphosphatases↗
PubMed2002

Biological significance of c-met over expression in papillary renal cell carcinoma.

PURPOSE: Hereditary papillary renal cell carcinoma is associated with mutations of the c-met proto-oncogene. Similar aberrations have been described at a molecular level in up to 13% of sporadic papillary renal cell carcinomas. We assessed c-met expression in papillary renal cell carcinomas and evaluated the prognostic significance of c-met expression in patients with this tumor. MATERIALS AND METHODS: We performed immunohistochemical testing to identify c-met expression in archival specimens of 55 papillary renal cell carcinomas in 51 patients. Only 1 patient reported a family history of renal malignancy. RESULTS: We identified c-met protein expression in the cytoplasm and cell membrane of 80% and 56% of these tumors, respectively. c-met expression significantly correlated with higher stage tumors (p = 0.004) but it was not associated with Fuhrman nuclear grade (p = 0.157). A trend toward a higher overall survival rate was noted in patients in whom tumors did not express c-met but this association failed to achieve statistical significance (p = 0.07). CONCLUSIONS: Our study indicates that c-met over expression may be associated with an aggressive phenotype in these tumors.

Adult↗