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 TGFβ-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. Examination of the whole genome expression profiles of HCC95-GFP, HCC95GFP+TGFβ,HCC95-LZTFL1-GFP,HCC95-LZTFL1-GFP+TGFβ, H460-GFP, and H460-LZTFL1-GFP cells

既往研究表明，LZTFL1在包括肺癌在内的上皮性肿瘤中表达下调，并在胃癌中发挥抑癌因子的功能。然而，LZTFL1在肺肿瘤发生中的功能作用尚未明确。本研究发现，非小细胞肺癌中LZTFL1的表达下调与肿瘤复发及不良生存预后相关；而在肺肿瘤细胞中重新表达LZTFL1，可抑制循环肿瘤细胞向肺组织的外渗/定植，并在体内抑制肿瘤生长。机制层面，我们发现LZTFL1在纤毛人支气管上皮细胞（HBECs）中表达，且其表达水平与HBEC分化状态相关。LZTFL1可抑制转化生长因子β（TGFβ）激活的丝裂原活化蛋白激酶（MAPK）及刺猬信号通路；改变细胞内LZTFL1的表达水平，会导致上皮间质转化（EMT）相关基因的表达发生变化。综上，我们认为LZTFL1可通过维持上皮细胞分化状态、抑制介导EMT的信号通路，从而抑制肺肿瘤发生；这提示在肿瘤细胞中重新激活LZTFL1的表达，有望成为一种新型肺癌治疗策略。本研究对以下细胞的全基因组表达谱进行了检测：HCC95-GFP、HCC95GFP+TGFβ、HCC95-LZTFL1-GFP、HCC95-LZTFL1-GFP+TGFβ、H460-GFP及H460-LZTFL1-GFP。