Tumor Necrosis Factor-Induced miR-146a Upregulation Promotes Human Lung Adenocarcinoma Metastasis by Targeting Merlin

Inflammation plays a key role in carcinogenesis and metastasis. This process involves the inactivation of tumor suppressor molecules, yet the molecular mechanisms by which inflammation impairs tumor suppressors are not completely understood. In this study, we show that proinflammatory signals such as tumor necrosis factor (TNF) support lung cancer metastasis by reducing the levels of the tumor suppressor Merlin through regulation of miR-146a. Immunodeficient mice inoculated with A549 cells expressing high miR-146a levels and low Merlin protein levels exhibited reduced survival, which correlated with the number of metastatic nodes formed. Accordingly, restoring Merlin protein levels inhibited metastasis and increased survival of the mice. Consistent with these results, we found that elevated miR-146a expression levels correlated with low Merlin protein levels in human lung adenocarcinoma. Furthermore, human invasive and metastatic tumors showed higher TNF and miR-146a levels, but lower Merlin protein levels than noninvasive tumors. These findings indicate that upregulation of miR-146a by TNF in lung adenocarcinoma promotes Merlin protein inhibition and metastasis. Thus, we suggest that the ratio between miR-146a and Merlin protein levels could be a relevant molecular biomarker that can predict lung cancer progression and that the TNF/miR-146a/Merlin pathway is a promising new therapeutic target to inhibit lung adenocarcinoma progression.