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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
MicroRNA-155 regulates arsenite-induced malignant transformation by targeting Nrf2-mediated oxidative damage in human
Chengzhi Chen1, Xuejun Jiang2, Shiyan Gu3
1Department of Occupational and Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China; Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing Medical University, Chongqing, People's Republic of China.
Abstract:
Arsenite is a well-documented human lung carcinogen but the detailed mechanisms of carcinogenesis remain unclear. In this study, human bronchial epithelial (16-HBE) cells were continuously exposed to 2.5μM arsenite for about 13 weeks to induce the phenotypes of malignant transformation. Our results showed that Nrf2 expression was gradually decreased whereas no significant change was observed on NF-κB activation with increased time of arsenite exposure. To test the roles of Nrf2-meidtaed oxidative damage in the arsenite-induced malignant transformation, we compared the levels of cGMP, PKG and oxidative damage-related indicators between arsenic-transformed cells and control cells. Our data demonstrated there were no significantly differences on the contents of cGMP, PKG, MDA and the production of ROS, but the levels of GSH and NO, the activities of SOD, tNOS and iNOS were significantly enhanced in the arsenic-transformed cells. Importantly, Nrf2 inactivation could be modulated by miR-155, and inhibition of miR-155 remarkably attenuated the malignant phenotypes and promoted apoptotic cell death in the arsenic-transformed cells. Together, our findings provide the novel mechanism that miR-155 may regulate arsenite-induced cell malignant transformation by targeting Nrf2-mediated oxidative damage, indicating that inhibition of miR-155 may be a potential strategy against lung carcinogenesis of arsenite.
Insights
Arsenite exposure decreases Nrf2 expression, promoting lung cancer. Inhibiting miR-155 counteracts this, reducing malignant transformation and increasing cell death, offering a potential lung cancer treatment.
Area of Science:
- Cell Biology
- Toxicology
- Oncology
Background:
- Arsenite is a known human lung carcinogen, but its precise mechanisms of carcinogenesis are not fully understood.
- Understanding the molecular pathways involved in arsenite-induced lung cancer is crucial for developing effective prevention and treatment strategies.
Purpose of the Study:
- To investigate the role of Nrf2-mediated oxidative damage in arsenite-induced malignant transformation of human bronchial epithelial cells.
- To explore the potential involvement of microRNA-155 (miR-155) in regulating Nrf2 expression and arsenite-induced carcinogenesis.
Main Methods:
- Human bronchial epithelial (16-HBE) cells were exposed to arsenite for 13 weeks to induce malignant transformation.
- Nrf2 and NF-κB activation levels were assessed over time.
- Levels of oxidative stress markers (cGMP, PKG, MDA, ROS, GSH, NO) and enzyme activities (SOD, tNOS, iNOS) were compared between control and arsenic-transformed cells.
- The effect of miR-155 inhibition on malignant phenotypes and apoptosis was evaluated.
Main Results:
- Arsenite exposure led to a gradual decrease in Nrf2 expression but did not significantly alter NF-κB activation.
- Arsenic-transformed cells showed enhanced levels of GSH, NO, and activities of SOD, tNOS, and iNOS, without significant changes in cGMP, PKG, MDA, or ROS.
- Inhibition of miR-155 significantly attenuated malignant phenotypes and promoted apoptotic cell death in arsenic-transformed cells.
- Nrf2 inactivation was modulated by miR-155.
Conclusions:
- Arsenite-induced lung carcinogenesis involves Nrf2 inactivation and altered oxidative stress pathways.
- miR-155 plays a critical role in regulating arsenite-induced malignant transformation by targeting Nrf2-mediated oxidative damage.
- Inhibition of miR-155 presents a potential therapeutic strategy against arsenite-induced lung cancer.
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