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Whole genome expression signature of SWCNT and MWCNT vs. asbestos subchronic exposures to human pleural mesothelial cells

ABSTRACT: Malignant mesothelioma is one of the most aggressive forms of cancer known. Recent studies have shown that carbon nanotubes (CNTs) are biopersistent and induce mesothelioma in animals, but the underlying mechanisms are not known. Here, we investigate the effect of long-term exposure to CNTs on the aggressive behaviors of human pleural mesothelial cells, the primary cellular target of human lung mesothelioma. We show that sub-chronic exposure (4 month) to single- and multi-walled CNTs induced proliferation, migration and invasion of the cells similar to that observed in asbestos-exposed cells. An up-regulation of several key genes known to be important in cell invasion, notably matrix metalloproteinase-2 (MMP-2), was observed in the exposed mesothelial cells as determined by real-time PCR. Western blot and enzyme activity assays confirmed the increased expression and activity of MMP-2. Whole genome expression microarray analysis further indicated the importance of MMP-2 in the invasion gene signaling network of the exposed cells. Knockdown of MMP-2 in CNT and asbestos-exposed cells by shRNA-mediated gene silencing effectively inhibited the aggressive phenotypes. This study provides new evidence for CNT-induced cell invasion and indicates the role of MMP-2 in the process.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48855 | GEO | 2015/11/23

SECONDARY ACCESSION(S): PRJNA212005

REPOSITORIES: GEO

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Project description:Recent in vivo studies reported that inhaled carbon nanotube distribute in the alveolar region resulting in an acute inflammation, progressive fibrotic response and particle accumulation at the bronchoalveolar junction with low clearance. With similar biopersistence and shape as asbestos, a known lung carcinogen, growing concern has arisen for elevated risk of carbon nanotube-induced lung carcinogenesis; however few studies have evaluated long-term human health risks associated with chronic pulmonary carbon nanotube exposures compared to asbestos. To address this knowledge gap, we conducted subchronic in vitro exposures of dispersed single walled carbon nanotube, multi-walled carbon nanotube and crocidolite asbestos to human small airway epithelial cells to assess their neoplastic transformation potential. Subchronic single-, multi-walled carbon nanotube and asbestos exposures caused human lung cell neoplastic transformation exhibited by increased proliferation, anchorage-independent growth, invasion and angiogenesis. Whole genome profiling and protein expression analyses showed that carbon nanotube-induced transformation mechanism(s) was largely different from asbestos-related inflammatory signaling, suggesting specific carbon nanotube-induced carcinogenic potential. This study provides novel carbon nanotube and asbestos toxicogenomic information for risk assessment and an in vitro model to evaluate transformation potential of carbon nanotubes and other nanoparticles. Whole genome expression profiling was conducted on human immortalized small airway epithelial cells (SAEC-hTERT) following 6 month in vitro chronic exposure to six separate treatments to assess differences in carbon nanotube (CNT) vs. asbestos potential tumorigenesis signaling. Dispersed single wall CNT (D-SWCNT), multi-wall CNT (D-MWCNT), ultrafine carbon black (D-UFCB), crocidolite asbestos (ASB) and saline (SAL) exposed cells were compared to SurvantaM-BM-. dispersant (DISP) passage control cells. Each treatment possessed 3 biological cDNA replicates. One technical replicate was performed per biological sample.

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Whole genome expression signature of SWCNT and MWCNT vs. asbestos subchronic exposures to human pleural mesothelial cells

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