LncRNA NKILA suppresses TGF‐β‐induced epithelial–mesenchymal transition by blocking NF‐κB signaling in breast cancer

Abstract

TGF-β plays a central role in mediating epithelial-mesenchymal transition (EMT) by activating the Smad pathway. In addition, accumulating evidence suggests that TGF-β-induced EMT is NF-κB-dependent in various cancer types. However, it is largely unclear if NF-κB mediates TGF-β-induced EMT in breast cancer, and if this mediation occurs, the regulatory mechanisms are unknown. In our study, we found that TGF-β activates the NF-κB pathway. Inhibition of NF-κB signaling markedly abrogates TGF-β-induced EMT. By studying the regulatory mechanism of TGF-β-induced NF-κB signaling, we found that lncRNA NKILA was upregulated by TGF-β and was essential for the negative feedback regulation of the NF-κB pathway. Accordingly, overexpression of NKILA significantly reduced TGF-β-induced tumor metastasis in vivo. Consistent with the results from mice, the expression of NKILA was negatively correlated with EMT phenotypes in clinical breast cancer samples. Collectively, our study indicated that the NKILA-mediated negative feedback affects TGF-β-induced NF-κB activation and that NKILA may be a therapeutic molecule in breast cancer metastasis via inhibition of EMT.

Highly‐expressed P2X7 receptor promotes growth and metastasis of human HOS/MNNG osteosarcoma cells via PI3K/Akt/GSK3β/β‐catenin and mTOR/HIF1α/VEGF signaling

“…Previous studies indicate that stimulating EMT and increasing CSCs can promote cancer metastasis and relapse . Cells undergoing EMT are known to acquire stem cell‐like properties.…”

“…Previous studies indicate that stimulating EMT and increasing CSCs can promote cancer metastasis and relapse. 34,[47][48][49][50] Cells undergoing EMT are known to acquire stem cell-like properties. Loss of epithelial marker E-cadherin, increased expression of mesenchymal markers Fibronectin and Vimentin and the EMT regulator Snail, which are important events in EMT.…”

Targeting cancer stem cell pathways for cancer therapy

“…346 Activation of TGF-β1 induces lncRNA NKILA expression to block NF-κB signaling, which inhibits metastasis of breast CSCs. 412 TGF-β also directly regulates the expression of Wnt5a in breast CSCs to limit the stem cell population. 413 Furthermore, Notch, IKK/NF-κB, and other pathways together regulate the proliferation and metastasis of CD133 + cutaneous SCC stem cells.…”

The expression of ubiquitin‐specific peptidase 8 and its prognostic role in patients with breast cancer

“…Notch signaling was also proved to promote HER2 + breast cancer cell proliferation and stem cell survival. [40][41][42] However, we future molecular and large scale, multicenter studies should be designed to analyze the exact mechanisms that USP8 regulate the proliferation of BC. Meanwhile, lots of studies have shown that epithelial-mesenchymal transition played an important role in the progression of BC.…”