A Circle RNA Regulatory Axis Promotes Lung Squamous Metastasis via CDR1-Mediated Regulation of Golgi Trafficking
Emily B. Harrison, Alessandro Porrello, Brittany M. Bowman, Adam R. Belanger, Gabriella Yacovone, Salma H. Azam, Ian A. Windham, Subrata Ghosh, Menglin Wang, Nicholas Mckenzie, Trent A. Waugh, Amanda E.D. Van Swearingen, Stephanie M. Cohen, Devon G. Allen, Tyler J. Goodwin, Teresa Mascenik, James E. Bear, Sarah Cohen, Scott H. Randell, Pierre P. Massion, Michael B. Major, Leaf Huang, Chad V. Pecot
Abstract
Abstract Lung squamous carcinoma (LUSC) is a highly metastatic disease with a poor prognosis. Using an integrated screening approach, we found that miR-671-5p reduces LUSC metastasis by inhibiting a circular RNA (circRNA), CDR1as. Although the putative function of circRNA is through miRNA sponging, we found that miR-671-5p more potently silenced an axis of CDR1as and its antisense transcript, cerebellar degeneration related protein 1 (CDR1). Silencing of CDR1as or CDR1 significantly inhibited LUSC metastases and CDR1 was sufficient to promote migration and metastases. CDR1, which directly interacted with adaptor protein 1 (AP1) complex subunits and coatomer protein I (COPI) proteins, no longer promoted migration upon blockade of Golgi trafficking. Therapeutic inhibition of the CDR1as/CDR1 axis with miR-671-5p mimics reduced metastasis in vivo. This report demonstrates a novel role for CDR1 in promoting metastasis and Golgi trafficking. These findings reveal an miRNA/circRNA axis that regulates LUSC metastases through a previously unstudied protein, CDR1. Significance: This study shows that circRNA, CDR1as, promotes lung squamous migration, metastasis, and Golgi trafficking through its complimentary transcript, CDR1.