Non-coding RNAs as emerging regulators of epithelial to mesenchymal transition in non-small cell lung cancer

Abstract

Non-small cell lung cancer (NSCLC) remains a major health problem that patients suffer from around the world. The epithelial to mesenchymal transition (EMT) has attractive roles in increasing malignant potential and reducing sensitivity to conventional therapeutics in NSCLC cells. Meanwhile, it is now evident that non-coding RNAs (ncRNAs), primarily microRNAs and long non-coding RNAs contribute to tumorigenesis partially via regulating EMT. This article briefly summarizes current researches about EMT-related ncRNAs in NSCLC and discusses their crucial roles in the complex regulatory network. Also, the authors will show the evidence that ncRNAs not only contribute to cancer cells migration and invasion, but also take charge of the resistance of chemotherapy, radiotherapy and EGFR-TIKs. Then, we will further discuss the potential of inhibition of EMT via manipulating relevant ncRNAs to change our current treatment of NSCLC patients.

Keywords: epithelial-mesenchymal transition; long-coding RNA; microRNA; non-coding RNA; non-small cell lung cancer.

Figure 1. Highly simplified diagram illustrating some better elaborated transduction pathways related to EMT/MET

EMT is a highly complex process under the strict control of growth factors and downstream transcription factors. It seems to occur in a context where main roles are played by tyrpsine kinase receptors, Wnt and TGF-β pathways. These pathways are involved in the upregulation of Snail and Twist family via signaling through downstream transcriptional factors (such as Ras, PI3K, Rac, Src, Smad and β-catenin), which then represses E-cadherin. What's more, the inhibition of E-cadherin can induce EMT and, on the other hand, its re-activation can stimulate the reverse process, suggesting that E-cadherin takes center stage in mediating the switches between EMT and MET.

Figure 2. Suppressive roles of special miRNAs in the EMT-associated regulatory networks

The diagram shows the major signal transduction pathways leading to EMT in NSCLC. Currently, dozens of miRNAs are identified to function as vital inhibitors in the development of EMT. In NSCLC, loss of these specific miRNAs leads to expression of target oncogenes, which in turn contributes to cancer cell invasion and resistance to chemotherapy, radiotherapy and EGFR-TKIs.