Abstract:
:Environmental or occupational exposure to low doses of arsenic induces a series of health problems including cancer. The molecular events in arsenic-induced carcinogenicity remain to be defined. In the NuLi-1 immortalized human lung epithelial cell line with p53 and pRb deficiency, exposure to low doses of arsenic trioxide for 72 h promoted cell proliferation and upregulated the gene transcription levels of FOXM1, CDC6, CDC25A, and cyclin D1, which are both critical cell cycle regulatory genes and proto-oncogenes. Continuous in vitro exposure to 1 µM arsenic trioxide for 34 wks induced malignant cell transformation, as evidenced by enhanced anchorage-independent cell growth. The expression of FOXM1, CDC6, CDC25A, and Cyclin D1 was dynamically elevated at the gene transcription and protein levels in the process of cell transformation. The carcinogenic ability of transformed cell colonies coincides with the expression levels of FOXM1 in in vitro anchorage-independent growth assays and in vivo tumor xenograft formation assays. In reverse, the knockdown of FOXM1 in lung adenocarcinoma A549 cells or arsenic-transformed NuLi-1 cells significantly decreased anchorage-independent cell growth and tumor xenograft formation. The transformed NuLi-1 cells showed genomic instability in the form of copy number variation (CNV) at chromosome 1, 5, 6, 18, and 20, but not loss of heterozygosity (LOH). These results showed for the first time that chronic exposure to low doses of arsenic trioxide promoted lung carcinogenicity, in part by aberrantly upregulating FOXM1 and its associated oncogenes, when the tumor suppressor genes p53 and pRb were inactivated.
journal_name
Mol Carcinogjournal_title
Molecular carcinogenesisauthors
Liu Y,Hock JM,Van Beneden RJ,Li Xdoi
10.1002/mc.21989subject
Has Abstractpub_date
2014-05-01 00:00:00pages
380-91issue
5eissn
0899-1987issn
1098-2744journal_volume
53pub_type
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