Abstract
The transforming growth factor β (TGF-β) signaling pathway plays anti- and pro-tumoral roles in the vast majority of cancers, and long noncoding RNAs have been reported to play key roles in the highly contextual response process. However, the roles of long noncoding RNAs (lncRNAs) in TGF-β signaling in esophageal squamous cell carcinoma (ESCC) remain unknown. In this study, we performed RNA-seq to compare lncRNAs expression levels between TGF-β1-treated and untreated ESCC cells and observed that NF-kappaB-interacting lncRNA (NKILA) was remarkably upregulated by the classical TGF-β signaling pathway. RNA profiling of 39 pairs ESCC tumor and adjacent nontumor samples using RT-qPCR demonstrated that NKILA is significantly downregulated in ESCC tumor tissues, and NKILA expression levels were significantly decreased in advanced tumor tissues (III and IV) compared to early stages (I and II) (p < 0.01). Gain- and loss-of-function assays showed that NKILA inhibited ESCC cell metastasis in vitro and in vivo, and mechanism studies showed that NKILA repressed MMP14 expression by inhibiting IκBα phosphorylation and NF-κB activation. Collectively, these findings suggest that the TGF-β-induced lncRNA NKILA has potential as an antimetastasis therapy.Key messagesLong noncoding RNA NKILA could be remarkably upregulated by classical TGF-β signal pathway in ESCC.NKILA was significantly downregulated in esophageal squamous cell carcinoma and negatively correlated with TNM stage.NKILA inhibits ESCC cell metastasis via repressing MMP14 expression by suppressing the phosphorylation of IκBα and NF-κB activation.
Highlights
Esophageal cancer is one of the leading causes of cancerrelated death worldwide, and half of the cases of the disease occur in China [1]
We found that 249 mRNAs were upregulated, and 468 mRNAs were downregulated in TGF-β1-treated KYSE30 and KYSE180 cells compared with the corresponding untreated cells (Fig. 1a)
We found that the long noncoding RNAs (lncRNAs) NF-kappaB-interacting lncRNA (NKILA) was dramatically induced by TGF-β1 in KYSE30 and KYSE180 esophageal squamous cell carcinoma (ESCC) cells via RNA-seq, findings that were validated by RT-qPCR
Summary
Esophageal cancer is one of the leading causes of cancerrelated death worldwide, and half of the cases of the disease occur in China [1]. 90% of the cases of esophageal cancer occurring in China and worldwide are squamous cell carcinomas [2,3,4]. Improving the understanding of the molecular mechanisms underlying cancer progression and metastasis may accelerate the. J Mol Med (2018) 96:301–313 development of effective metastasis-targeting therapies for patients with esophageal squamous cell carcinoma (ESCC). The TGF-β pathway promotes cell cycle arrest and apoptosis in early stage tumors but promotes tumor progression and metastasis in advanced disease, either by inactivating core components of the pathway, such as TGF-β receptors, or by inducing downstream alterations that disable only the tumor-suppressive arm of the pathway [6,7,8]. A better understanding of the specific and time-dependent downstream effectors of TGF-β signaling is urgently needed to accelerate the development of targeted TGF-β signaling pathway therapies
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