Affiliation:
1. Department of Nutrition and Food Hygiene School of Public Health Guangzhou Medical University Guangdong Guangzhou China
2. Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences Wenzhou Medical University Wenzhou Zhejiang China
3. Laboratory of Environmental Medicine, Tianjin Institute of Environmental and Operational Medicine Tianjin China
Abstract
AbstractNickel pollution is a recognized factor contributing to lung cancer. Understanding the molecular mechanisms of its carcinogenic effects is crucial for lung cancer prevention and treatment. Our previous research identified the downregulation of a long noncoding RNA, maternally expressed gene 3 (MEG3), as a key factor in transforming human bronchial epithelial cells (HBECs) into malignant cells following nickel exposure. In our study, we found that deletion of MEG3 also reduced the expression of RhoGDIβ. Notably, artificially increasing RhoGDIβ levels counteracted the malignant transformation caused by MEG3 deletion in HBECs. This indicates that the reduction in RhoGDIβ contributes to the transformation of HBECs due to MEG3 deletion. Further exploration revealed that MEG3 downregulation led to enhanced c‐Jun activity, which in turn promoted miR‐200c transcription. High levels of miR‐200c subsequently increased the translation of AUF1 protein, stabilizing SOX2 messenger RNA (mRNA). This stabilization affected the regulation of miR‐137, SP‐1 protein translation, and the suppression of RhoGDIβ mRNA transcription and protein expression, leading to cell transformation. Our study underscores the co‐regulation of RhoGDIβ expression by long noncoding RNA MEG3, multiple microRNAs (miR‐200c and miR‐137), and RNA‐regulated transcription factors (c‐Jun, SOX2, and SP1). This intricate network of molecular events sheds light on the nature of lung tumorigenesis. These novel findings pave the way for developing targeted strategies for the prevention and treatment of human lung cancer based on the MEG3/RhoGDIβ pathway.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Guangdong Province