LZTFL1 inhibits lung tumorigenesis by maintaining the differentiated state of lung epithelial cells and suppressing MAPK and SHH signaling pathways

Previously, we found that LZTFL1 is down-regulated in epithelial tumors including lung cancer and functions as a tumor suppressor in gastric cancers. However, the functional role of LZTFL1 in lung oncogenesis is undefined. We show here that downregulation of LZTFL1 expression in non-small cell lung cancer is associated with recurrence and poor survival, while re-expression of LZTFL1 in lung tumor cells inhibited extravasation/colonization of circulating tumor cells to the lung and inhibited tumor growth in vivo. Mechanistically, we found that LZTFL1 is expressed in ciliated human bronchial epithelial cells (HBECs) and its expression correlates with HBEC differentiation. LZTFL1 inhibits TGF-activated MAPK and hedgehog signaling. Alteration of intracellular levels of LZTFL1 resulted in changes of expression of genes associated with epithelial-to mesenchymal transition (EMT). We conclude that LZTFL1 inhibit lung tumorigenesis, possibly by maintaining epithelial cell differentiation and/or inhibition of signalings that lead to EMT, and suggest that reactivation of LZTFL1 expression in tumor cells may be a novel lung cancer therapeutic approach.

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