Abstract
Arsenic is a well-documented human carcinogen. The present study explored the role of the onco-miR, miR-21 and its target protein, programmed cell death 4 (PDCD4) in arsenic induced malignant cell transformation and tumorigenesis. Our results showed that treatment of human bronchial epithelial (BEAS-2B) cells with arsenic induces ROS through p47phox, one of the NOX subunits that is the key source of arsenic-induced ROS. Arsenic exposure induced an upregulation of miR-21 expression associated with inhibition of PDCD4, and caused malignant cell transformation and tumorigenesis of BEAS-2B cells. Indispensably, STAT3 transcriptional activation by IL-6 is crucial for the arsenic induced miR-21 increase. Upregulated miR-21 levels and suppressed PDCD4 expression was also observed in xenograft tumors generated with chronic arsenic exposed BEAS-2B cells. Stable shut down of miR-21, p47phox or STAT3 and overexpression of PDCD4 or catalase in BEAS-2B cells markedly inhibited the arsenic induced malignant transformation and tumorigenesis. Similarly, silencing of miR-21 or STAT3 and forced expression of PDCD4 in arsenic transformed cells (AsT) also inhibited cell proliferation and tumorigenesis. Furthermore, arsenic suppressed the downstream protein E-cadherin expression and induced β-catenin/TCF-dependent transcription of uPAR and c-Myc. These results indicate that the ROS-STAT3-miR-21-PDCD4 signaling axis plays an important role in arsenic -induced carcinogenesis.
Highlights
R Arsenic is a well-documented human carcinogen
We found that chronic arsenic exposure increased miR-21 levels and was associated with inhibition of programmed cell death 4 (PDCD4) expression and malignant cell transformation
R nic treatment in a dose-dependent manner. These results indicate that PDCD4 suppression increases uPAR and c-Myc expressions, and activates β-catenin/TCF4 complex binding to the uPAR and c-Myc promoters during chronic arsenic exposure
Summary
Arsenic induces human cancers including lung cancer[42] and can affect the expression of certain miRNAs43,44. Arsenic treatment robustly increased miR-21 levels with an associated decrease in PDCD4 expression in BEAS-2B cells. Upregulation of miR-21 and inhibition of PDCD4 by chronic arsenic treatment induced malignant transformation and tumorigenesis of BEAS-2B cells. Stable knockdown of p47phox and overexpression of catalase in BEAS-2B cells markedly suppressed the arsenic-induced miR-21 up-regulation and PDCD4 inhibition, and Rthereby prevented malignant transformation and tumorigenesis. R In summary, we found that chronic arsenic exposure to BEAS-2B cells increases miR-21 levels with an associated inhibition of PDCD4 expression, and causes malignant transformation and tumorigenesis (Fig. 10F). Our findings demonstrate an active involvement of a ROS-STAT3-miR-21-PDCD4 signaling axis in arsenic-induced malignant cell transformation and tumorigenesis
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