help button home button Am J Pathol Epitomics, Inc.
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Originally published online as doi:10.2353/ajpath.2009.080721 on February 13, 2009

Published online before print February 13, 2009
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental Material
Right arrow All Versions of this Article:
ajpath.2009.080721v1
174/3/762    most recent
Right arrow Purchase Article
Right arrow View Shopping Cart
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Romagnoli, S.
Right arrow Articles by Bosari, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Romagnoli, S.
Right arrow Articles by Bosari, S.
(American Journal of Pathology. 2009;174:762-770.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080721

Identification of Potential Therapeutic Targets in Malignant Mesothelioma Using Cell-Cycle Gene Expression Analysis

Solange Romagnoli*, Ester Fasoli*, Valentina Vaira*, Monica Falleni*, Caterina Pellegrini*, Anna Catania{dagger}, Massimo Roncalli{ddagger}, Antonio Marchetti§, Luigi Santambrogio, Guido Coggi* and Silvano Bosari*

From the Department of Medicine, Surgery, and Dentistry,* Division of Pathology, the University of Milan Medical School, AOS Paolo and Fondazione Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena, Milan; the Center for Preclinical Investigation,{dagger} Fondazione Ospedale Maggiore Policlinico Mangiagalli e Regina Elena, Milan; the Department of Pathology,{ddagger} University of Milan, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Clinico Humanitas, Milan; and the Clinical Research Center,§ Center of Excellence on Aging, University Foundation, Chieti; the Department of Surgery, Thoracic Unit, the University of Milan Medical School, Fondazione Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena, Milan, Italy

Cell-cycle defects are responsible for cancer onset and growth. We studied the expression profile of 60 genes involved in cell cycle in a series of malignant mesotheliomas (MMs), normal pleural tissues, and MM cell cultures using a quantitative polymerase chain reaction-based, low-density array. Nine genes were significantly deregulated in MMs compared with normal controls. Seven genes were overexpressed in MMs, including the following: CDKN2C, cdc6, cyclin H, cyclin B1, CDC2, FoxM1, and Chk1, whereas Ube1L and cyclin D2 were underexpressed. Chk1 is a principal mediator of cell-cycle checkpoints in response to genotoxic stress. We confirmed the overexpression of Chk1 in an independent set of 87 MMs by immunohistochemistry using tissue microarrays. To determine whether Chk1 down-regulation would affect cell-cycle control and cell survival, we transfected either control or Chk1 siRNA into two mesothelioma cell lines and a nontumorigenic (Met5a) cell line. Results showed that Chk1 knockdown increased the apoptotic fraction of MM cells and induced an S phase block in Met5a cells. Furthermore, Chk1 silencing sensitized p53-null MM cells to both an S phase block and apoptosis in the presence of doxorubicin. Our results indicate that cell-cycle gene expression analysis by quantitative polymerase chain reaction can identify potential targets for novel therapies. Chk1 knockdown could provide a novel therapeutic approach to arrest cell-cycle progression in MM cells, thus increasing the rate of cell death.






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2009 by the American Society for Investigative Pathology.