The Function And Mechanism Of TGF?-induced LncRNA TBILA In Non-small Cell Lung Cancer

Non-small cell lung cancer(NSCLC)is one of the leading causes of cancer-related death worldwide,and its morbidity and mortality are the first in malignant tumors.Local infiltration and distant metastasis are considered to be the main causes of death in patients with NSCLC.Therefore,in-depth study of the molecular mechanism of lung cancer metastasis,development of effective treatment and prevention methods for advanced NSCLC patients is the key to improve the efficacy and prognosis of lung cancer patients.A large number of studies have shown that transforming growth factor-beta(TGF?)pathway-mediated epithelialmesenchymal transition(EMT),immune tolerance and drug resistance play crucial roles in NSCLC progression.However,the study of TGF?-regulated genes can't fully explain the high spatial and temporal dependence of TGF? signaling pathway in NSCLC and its dual role in both tumor promotion and tumor suppression.Therefore,the presence of new TGF?-regulated non-coding genes may play an important role during NSCLC progression.Long non-coding RNA(LncRNA),a major member of non-coding RNA,plays a key role in various biological processes of NSCLC.However,the involvement of IncRNAs in the transforming growth factor-beta(TGF?)signaling pathway remains poorly understood.Here,we aimed to investigate the role of IncRNAs in TGF? signaling of NSCLC.In present study,we compared the expression level of IncRNA in NSCLC cell lines A549 and H226 treated with or without TGF? by next-generation high-throughput whole transcriptome sequencing,and further validated via RT-qPCR.One of the most prominent LncRNA TBILA(TGF? induced IncRNA,RP11757F18.5)was selected for further study.Firstly,we determined that TBILA is a long non-coding RNA located at chromosome 3 with a full-length of 1698 nt,which is directly regulated by the TGF?/Smad classical signaling pathway in non-small cell lung cancer cells.In vitro cell function experiments found that TBILA can promote cell proliferation,invasion and migration.In vivo mouse experiments confirmed that TBILA can promote subcutaneous tumor formation and distant metastasis of NSCLC cells.The mechanism study found that:on the one hand,TBILA can activate the downstream RhoA signaling pathway by facilating the expression of adjacent HGAL gene by inducing the Smad2/3 complex to the HGAL promoter region;on the other hand,it can bind to the S100A7 protein in the nucleus and regulate the activation of S100A7/Jab1 signaling pathway and its downstream molecules.Clinical pathological studies have found that TBILA is highly expressed in NSCLC tissues and has a significant positive correlation with HGAL gene.Moreover,its expression and biological function are regulated by TGF?secreted by cancer-associated fibroblasts(Cancer associated fibroblasts,CAF)in the tumor microenvironment.In summary,these findings have provided us with a new perspective regarding the regulation of the TGF? signaling pathway in NSCLC and demonstrate that TBILA acts as key regulator of the TGF? signaling pathway and revealed that TGF? plays a role in regulating IncRNAs in NSCLC.The findings of this study may have significant implications with respect to our understanding of the tumor-promoting arm of the TGFP signaling pathway and NSCLC progression.TBILA has pleiotropic pro-survival and invasion-metastasis cascade-inducing effects;thus,TBILA has potential to serve as a target for anticancer therapies.