CREB-TARGET GENES IN MALIGNANT MESOTHELIOMA

$6,811P20FY2009RRNIH

University Of Vermont & St Agric College, Burlington VT

Investigators

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Malignant mesotheliomas (MMs) are aggressive neoplasms that are derived from the surface serosal cells of the pleural and peritoneal cavities. MM is associated with asbestos exposure however, little is known about the crucial cellular mechanisms contributing to the development and chemoresistance of MM. cAMP response element binding protein (CREB) is a transcription factor that rgulates a variety of cellular functions. CREB-dependent gene expression is also linked to various functions like growth/survival, migration/invasion, angiogenesis and drug resistance. The role of CREB has been studied in a few cancers but its role in MM is completely unknown. Data from our laboratory show increased activation of CREB and CREB-regulated genes in human mesothelial cells after asbestos exposure as well increased endogenous activation of CREB in 5 human MM lines and in tissue arrays from 3 MM patients. We hypothesized that CREB activation leads to expression of CREB-regulated genes involved in various tumorigenesis and drug resistance process of MM. In the present proposal we studied by microarray analysis (U133A2 Affymetrix chip and GeneSifter program to analyze data) common CREB-regulated genes after transfecting two different MM cell lines (Hmeso and PPMMill) with sh CREB or negative control. This study revealed a set of CREB-regulated genes involved in various tumorigenec processes in Hmeso (167 increased and 279 decreased more than 2 fold) and PPMMill (1555 increased and 2144 decreased more than 2 fold) mesothelioma cell lines. Functional relevance of identified genes in two MM cell lines will be validated and explored in a larger study. Identified genes could possibly act as potential target for MM treatment either alone or in combination with chemotherapeutic drugs.

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