Long Non-coding RNAs (LncRNA) Regulated by Transforming Growth Factor (TGF) β

Richards, Edward J.; Z, Gu; Li, Zhu Peng; Permuth-Wey, Jennifer; Challa, Sridevi; Li, Yajuan; Kong, William; Su, Dan; Bui, Marilyn M.; Coppola, Domenico; Mao, Wei; Sellers, Thomas A.; Cheng, Jin Q.

doi:10.1074/jbc.m114.610915

Cited by 132 publications

(62 citation statements)

References 28 publications

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“…LncRNA, as an emerged crucial regulators of various biological processes, present strong ability to link different signal pathway together, and supplement the signal network of cancer [32]. For example, the TGF-β1-upregulated lncRNA malat1 can active PI3K/AKT pathway and promote the proliferation and invasion of human osteosarcoma [33–35]. For the genome location of NKILA just besides PMEPA1, which has been proven being upregulated by TGF-β [15, 36],and play an important role in NSCLC [37, 38].…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA NKILA inhibits migration and invasion of non-small cell lung cancer via NF-κB/Snail pathway

Wang

et al. 2017

J Exp Clin Cancer Res

115

112

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BackgroundNumerous studies have shown that long non-coding RNAs (lncRNAs) play key roles during multiple cancer processes, such as cell proliferation, apoptosis, migration and invasion. The previous studies found that NKILA interacted with and suppressed the nuclear translocation of NF-KappaB, which influenced metastasis and prognosis in breast cancer. However the clinical significance and biological role of NKILA in non-small cell lung cancer (NSCLC) remains unknown.MethodsWe examined expression levels of NKILA in 106 pairs of NSCLC tissues and cell lines. The expression level of NKILA after TGF-β1 stimulation also was examined by qRT-PCR and validated by Chromatin immunoprecipitation (ChIP). Gain-of-function and loss-of-function assays were performed to examine the effect of NKILA on proliferation, migration and invasion of NSCLC cells. RNA immunoprecipitation (RIP), western blot and rescue experiments were carried out to reveal the interrelation between NKILA, NF-κB and EMT signal pathway.ResultsThe expression of NKILA was down-regulated in NSCLC cancer tissues compared with matched adjacent noncancerous tissues, and lower NKILA expression in tumor tissues were significantly correlated with lymph node metastasis and advanced TNM stage. We found that the expression of NKILA was mainly regulated by classical TGF-β signal pathway in NSCLC cells rather than NF-κB pathway reported in breast cancer. Gain and loss of function assays found that NKILA inhibited migration, invasion and viability of NSCLC cells. Mechanistic study showed that NKILA attenuated Snail expression via inhibiting the phosphorylation of IκBα and NF-κB activation, subsequently suppressed the expression of markers of epithelial-mesenchymal transition process.ConclusionsThe present study found that the expression of NKILA was downregulated in tumor tissues of NSCLC, which improved the metastasis of NSCLC patients. In vitro studies further clarified that the expression of NKILA was regulated through classical TGF-β signal pathway, which subsequently inhibited migration and invasion of NSCLC cells through interfering NF-κB/Snail signal pathway in NSCLC cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0518-0) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Long non-coding RNA NKILA inhibits migration and invasion of non-small cell lung cancer via NF-κB/Snail pathway

Wang

et al. 2017

J Exp Clin Cancer Res

115

112

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“…The expression of hundreds of lncRNAs is regulated during activation of EMT by TGF-β [230,395]. Many of the lncRNAs upregulated by TGF-β seem to be important in the downstream activation genes involved in EMT, including expression of EMT associated TFs (Table 1).…”

Section: Lncrnas In Signalling Pathways Governing Emtmentioning

confidence: 99%

Long Non-Coding RNAs: Key Regulators of Epithelial-Mesenchymal Transition, Tumour Drug Resistance and Cancer Stem Cells

Heery

Finn

Cuffe

et al. 2017

Cancers

160

140

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Epithelial mesenchymal transition (EMT), the adoption by epithelial cells of a mesenchymal-like phenotype, is a process co-opted by carcinoma cells in order to initiate invasion and metastasis. In addition, it is becoming clear that is instrumental to both the development of drug resistance by tumour cells and in the generation and maintenance of cancer stem cells. EMT is thus a pivotal process during tumour progression and poses a major barrier to the successful treatment of cancer. Non-coding RNAs (ncRNA) often utilize epigenetic programs to regulate both gene expression and chromatin structure. One type of ncRNA, called long non-coding RNAs (lncRNAs), has become increasingly recognized as being both highly dysregulated in cancer and to play a variety of different roles in tumourigenesis. Indeed, over the last few years, lncRNAs have rapidly emerged as key regulators of EMT in cancer. In this review, we discuss the lncRNAs that have been associated with the EMT process in cancer and the variety of molecular mechanisms and signalling pathways through which they regulate EMT, and finally discuss how these EMT-regulating lncRNAs impact on both anti-cancer drug resistance and the cancer stem cell phenotype.

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“…Cell migration and invasion assays were performed as described previously (38). Cell cycle analysis was performed using PI staining and followed by flow cytometry.…”

Section: Methodsmentioning

confidence: 99%

IKBKE Is a Substrate of EGFR and a Therapeutic Target in Non–Small Cell Lung Cancer with Activating Mutations of EGFR

et al. 2016

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Non-small cell lung cancers (NSCLC) marked by EGFR mutations tend to develop resistance to therapeutic EGFR inhibitors, often due to secondary mutation EGFRT790M but also other mechanisms. Here we report support for a rationale to target IKBKE, an IκB kinase family member which activates the AKT and NF-κB pathways, as one strategy to address NSCLC resistant to EGFR inhibitors. While wild-type and mutant EGFR directly interacted with IKBKE, only mutant EGFR phosphorylated IKBKE on residues Y153 and Y179. The unphosphorylatable mutant IKBKE-Y153F/Y179-F which lost kinase activity failed to activate AKT and inhibited EGFR signaling. In clinical specimens of NSCLC with activating mutations of EGFR, we observed elevated levels of phospho-Y153 IKBKE. IKBKE ablation with shRNA or small molecule inhibitor amlexanox selectively inhibited the viability of NSCLC cells with EGFR mutations in vitro. In parallel, we found that these treatments activated the MAPK pathway due to attenuation of an IKBKE feedback mechanism. In vivo studies revealed that combining amlexanox with MEK inhibitor AZD6244 significantly inhibited the xenograft tumor growth of NSCLC cells harboring activating EGFR mutations, including EGFRT790M. Overall, our findings define IKBKE as a direct effector target of EGFR and provide a therapeutic rationale to target IKBKE as a strategy to eradicate EGFR-TKI resistant NSCLC cells.

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Long Non-coding RNAs (LncRNA) Regulated by Transforming Growth Factor (TGF) β

Cited by 132 publications

References 28 publications

Long non-coding RNA NKILA inhibits migration and invasion of non-small cell lung cancer via NF-κB/Snail pathway

Long non-coding RNA NKILA inhibits migration and invasion of non-small cell lung cancer via NF-κB/Snail pathway

Long Non-Coding RNAs: Key Regulators of Epithelial-Mesenchymal Transition, Tumour Drug Resistance and Cancer Stem Cells

IKBKE Is a Substrate of EGFR and a Therapeutic Target in Non–Small Cell Lung Cancer with Activating Mutations of EGFR

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