Abstract
Transmembrane protein (TMEM) is a family of protein that spans cytoplasmic membranes and allows cell–cell and cell–environment communication. Dysregulation of TMEMs has been observed in multiple cancers. However, little is known about TMEM116 in cancer development. In this study, we demonstrate that TMEM116 is highly expressed in non-small-cell lung cancer (NSCLC) tissues and cell lines. Inactivation of TMEM116 reduced cell proliferation, migration and invasiveness of human cancer cells and suppressed A549 induced tumor metastasis in mouse lungs. In addition, TMEM116 deficiency inhibited PDK1-AKT-FOXO3A signaling pathway, resulting in accumulation of TAp63, while activation of PDK1 largely reversed the TMEM116 deficiency induced defects in cancer cell motility, migration and invasive. Together, these results demonstrate that TMEM116 is a critical integrator of oncogenic signaling in cancer metastasis.
Highlights
Membrane proteins represent a large population of cellular proteins and a lot of them play a fundamental role during cancer development by transmitting information between the extracellular environment and the cytoplasmic proteins
To investigate whether TMEM116 expression was altered in lung cancer, we examined its expression in the clinical samples of two main subtypes of non-small-cell lung cancer (NSCLC), lung adenocarcinoma (LUAD) and lung squamous cell carcinomas (LUSC)
Most of them appear crucial for the metastatic cascade in several cancer types and their expression is often correlated with a poor prognosis for patient survival
Summary
Membrane proteins represent a large population of cellular proteins and a lot of them play a fundamental role during cancer development by transmitting information between the extracellular environment and the cytoplasmic proteins. PI3Ks are a family of lipid kinases that regulate multiple cellular functions including cell proliferation, survival, differentiation, adhesion, motility and invasion [10]. AKT is common downstream effector of PI3K signaling pathway and considered as a master regulator of tumor cell proliferation, survival, and motility [20, 21]. Several signaling pathways, such as Ras and Her, promote cancer cell motility and tumor metastasis by targeting and repressing ΔNp63α expression [14]. Targeting TMEM116 by CRISPR-Cas in A549 cells significantly reduced cell migration in vitro and tumor metastasis in vivo. Further analysis revealed the latter functions of TMEM116 is mediated through PDK1/AKT/FOXO3A/TAp63 signaling. The sequences of TMEM116 sgRNAs were as follows: sgRNA1: 5′-ACGGGTGCGCTTCTACCCAG-3′; sgRNA2: 5′-CATA AAGCTGACTAAGCCAC-3′
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