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1.
Br J Cancer ; 113(6): 970-8, 2015 Sep 15.
Article in English | MEDLINE | ID: mdl-26325105

ABSTRACT

BACKGROUND: The transforming growth factor-beta (TGF- ß) pathway has been implicated in proliferation, migration and invasion of various cancers. Endoglin is a TGF-ß accessory receptor that modulates signalling. We identified Endoglin as an epigenetically silenced tumour-suppressor gene in lung cancer by means of a genome-wide screening approach, then sought to characterise its effect on lung cancer progression. METHODS: Methylation microarray and RNA sequencing were carried out on lung cancer cell lines. Epigenetic silencing of Endoglin was confirmed by methylation and expression analyses. An expression vector and a 20-gene expression panel were used to evaluate Endoglin function. Pyrosequencing was carried out on two independent cohorts comprising 112 and 202 NSCLC cases, respectively, and the impact of Endoglin methylation on overall survival (OS) was evaluated. RESULTS: Methylation in the promoter region resulted in silencing of Endoglin, which could be reactivated by demethylation. Increased invasion coupled with altered EMT marker expression was observed in cell lines with an epithelial-like, but not those with a mesenchymal-like, profile when Endoglin was absent. Methylation was associated with decreased OS in stage I but not in stages II-III disease. CONCLUSIONS: We show that Endoglin is a common target of epigenetic silencing in lung cancer. We reveal a link between Endoglin silencing and EMT progression that might be associated with decreased survival in stage I disease.


Subject(s)
Antigens, CD/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Gene Silencing , Genes, Tumor Suppressor , Lung Neoplasms/genetics , Receptors, Cell Surface/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Disease Progression , Down-Regulation , Endoglin , Genome-Wide Association Study , Humans , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Methylation , Promoter Regions, Genetic , Protein Array Analysis , Sequence Analysis, DNA/methods
2.
Oncogene ; 30(32): 3513-21, 2011 Aug 11.
Article in English | MEDLINE | ID: mdl-21423205

ABSTRACT

We performed a kinome-wide siRNA screen and identified 70 kinases altering cell migration in A549 lung cancer cells. In particular, ribosomal S6 kinase 1 (RSK1) silencing increased, whereas RSK2 and RSK4 downregulation inhibited cell motility. In a secondary collagen-based three-dimensional invasion screen, 38 of our hits cross-validated, including RSK1 and RSK4. In two further lung cancer cell lines, RSK1 but not RSK4 silencing showed identical modulation of cell motility. We therefore selected RSK1 for further investigation. Bioinformatic analysis followed by co-immunoprecipitation-based validation revealed that the actin regulators VASP and Mena interact with RSK1. Moreover, RSK1 phosphorylated VASP on T278, a site regulating its binding to actin. In addition, silencing of RSK1 enhanced the metastatic potential of these cells in vivo using a zebrafish model. Finally, we investigated the relevance of this finding in human lung cancer samples. In isogenically matched tissue, RSK1 was reduced in metastatic versus primary lung cancer lesions. Moreover, patients with RSK1-negative lung tumours showed increased number of metastases. Our results suggest that the findings of our high-throughput in vitro screen can reliably identify relevant clinical targets and as a proof of principle, RSK1 may provide a biomarker for metastasis in lung cancer patients.


Subject(s)
Lung Neoplasms/genetics , RNA Interference , RNA, Small Interfering/genetics , Ribosomal Protein S6 Kinases, 90-kDa/genetics , Animals , Binding Sites , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , Cell Line, Tumor , Cell Movement/genetics , Embryo, Nonmammalian/embryology , Embryo, Nonmammalian/metabolism , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Microfilament Proteins/genetics , Microfilament Proteins/metabolism , Microscopy, Fluorescence , Neoplasm Metastasis , Neoplasm Transplantation , Phosphoproteins/genetics , Phosphoproteins/metabolism , Phosphorylation , Protein Binding , Reverse Transcriptase Polymerase Chain Reaction , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Threonine/genetics , Threonine/metabolism , Transplantation, Heterologous , Zebrafish/embryology
3.
J Clin Pathol ; 58(9): 962-7, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16126878

ABSTRACT

BACKGROUND: Recent reports have divided diffuse large B cell lymphoma (DLBCL) into germinal centre B cell-like and activated B cell-like subgroups with implicated differences in prognosis. AIMS: To delineate the germinal centre B cell derivation group from an Asian series of DLBCLs. METHODS: Fifty four cases were analysed by polymerase chain reaction to detect the t(14;18) translocation and immunohistochemistry for BCL2, CD10, BCL6, and E2F1 expression. RESULTS: Eighteen of 54 cases had bcl2 gene rearrangement, 36 of 52 expressed BCL2, 29 of 52 expressed BCL6, 20 of 53 expressed CD10, and 18 of 53 expressed E2F1. There was a significant association between bcl2 gene rearrangement and the expression of both BCL2 and CD10. Using the minimally acceptable criteria of t(14;18) rearrangement and/or CD10 expression, 26 of 54 cases were probably germinal centre derived, in agreement with other reports. A higher proportion of cases had t(14;18) translocation, suggesting that they may be derived from transformed follicular lymphomas. E2F1 positivity did not correlate with the known germinal centre markers, even though it has recently been suggested that it may be a new GC marker. CONCLUSIONS: It may be possible to stratify patients for treatment using markers for specific lineages of B cell differentiation.


Subject(s)
Germinal Center/pathology , Lymphoma, B-Cell/pathology , Lymphoma, Large B-Cell, Diffuse/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Asian People/genetics , Child , Chromosomes, Human, Pair 14/genetics , Chromosomes, Human, Pair 18/genetics , Female , Gene Rearrangement, B-Lymphocyte , Genes, bcl-2/genetics , Humans , Immunophenotyping , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/immunology , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/immunology , Male , Middle Aged , Polymerase Chain Reaction/methods , Translocation, Genetic
4.
Cancer Nurs ; 24(1): 68-75, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11219425

ABSTRACT

Cervical cancer remains a significant cause of mortality and morbidity in Chinese women, despite the efficacy of the screening procedure for the disease. This article focuses on specific gender and culturally related experiences of Chinese women presenting for Papancolaou (Pap) tests. The first phase of a descriptive exploratory study involved the administration of a questionnaire to a total population of female Hong Kong Chinese clerical and technical staff working in academic departments of a tertiary institution. The second phase consisted of in-depth semistructured interviews with a purposive sample of women to explore experiences of Pap smear screening. Of these women, 68.2% associated pain with a Pap smear. In addition, 78.6% of the women associated a Pap smear with embarrassment. Older women were more likely to experience pain and embarrassment during the procedure. In the qualitative data, women's personal images and experiences reflected four subthemes including pain, sexual connotations of the procedure, vulnerability, and diminished embarrassment after childbirth. The second substantive theme, characteristics of the practitioner, highlighted the importance of procedural, interpersonal, and culturally sensitive skills, particularly in respect to information-giving and interaction with women. The conclusion outlines the nursing implications for Chinese women presenting for Pap smears in terms of cultural sensitivity as a means of enhancing attendance patterns.


Subject(s)
Culture , Health Knowledge, Attitudes, Practice , Papanicolaou Test , Vaginal Smears/psychology , Adult , Female , Hong Kong , Humans , Middle Aged , Pain/etiology , Patient Acceptance of Health Care , Professional-Patient Relations , Vaginal Smears/adverse effects
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