Non-coding RNAs and epithelial mesenchymal transition in cancer: molecular mechanisms and clinical implications

Abstract

Epithelial-mesenchymal transition (EMT) is a fundamental process for embryonic development during which epithelial cells acquire mesenchymal characteristics, and the underlying mechanisms confer malignant features to carcinoma cells such as dissemination throughout the organism and resistance to anticancer treatments. During the past decades, an entire class of molecules, called non-coding RNA (ncRNA), has been characterized as a key regulator of almost every cellular process, including EMT. Like protein-coding genes, ncRNAs can be deregulated in cancer, acting as oncogenes or tumor suppressors. The various forms of ncRNAs, including microRNAs, PIWI-interacting RNAs, small nucleolar RNAs, transfer RNA-derived RNA fragments, long non-coding RNAs, and circular RNAs can orchestrate the complex regulatory networks of EMT at multiple levels. Understanding the molecular mechanism underlying ncRNAs in EMT can provide fundamental insights into cancer metastasis and may lead to novel therapeutic approaches. In this review, we describe recent advances in the understanding of ncRNAs in EMT and provide an overview of recent ncRNA applications in the clinic.

Keywords: Cancer; EMT; Metastasis; Molecular mechanisms; Non-coding RNA.

Fig. 1

miRNAs regulate the EMT process in cancer. miRNAs post-transcriptionally suppress the expression of key players of the EMT program at multiple levels. Initially, EMT is triggered upon activation of several pathways such as TGF-β and WNT/β-catenin signaling pathways. The multiple components of these signaling pathways are targeted by various miRNAs. Activation of these signaling pathways promotes the expression of EMT-inducing transcription factors (ZEB, SNAIL and TWIST) that function pleiotropically to induce the acquisition of the mesenchymal properties. These transcription factors bind to the promoter regions of specific miRNAs and regulate their expression. On the other hand, miRNAs can target the 3′UTRs of the mRNAs that encode these transcription factors. Some of these miRNAs and transcription factors form a double negative feedback loop. The TGF-β signaling pathway regulates cytoskeletal dynamics through regulating RhoA and CDC42, which are targeted by miRNAs. mRNAs encoding adhesion molecules such as E-cadherin and N-cadherin are also targeted by miRNAs. Green boxes represent an EMT inhibitory role by the indicated miRNAs, whereas red boxes represent the induction of the EMT process by the indicated miRNAs.

Fig. 2

lncRNAs and circRNAs have versatile modes of action: A Guide lncRNAs can interact with regulatory proteins (such as epigenetic activators, epigenetic repressors or transcription factors) and direct them to their target regions. B Decoy lncRNAs and circRNAs can bind and sequester miRNAs or proteins. C Scaffold lncRNAs can function as a central platform to allow the assembly of various molecular components to facilitate their intermolecular interactions. D Enhancer RNAs are a class of ncRNAs that are transcribed from enhancer regions and act in regulating mRNA transcription. E mRNA-binding lncRNAs can bind to mRNAs and enhance or reduce its stability

Fig. 3

RNA modification alters ncRNA targeting. A Adenosine-to-inosine (A-to-I) editing of the seed sequence of a miRNA can alter the base pairing properties of the miRNA. The double-stranded RNA-specific adenosine deaminases (ADARs) can interact with target site (here the target site is the seed sequence of miR-200b) and change adenosine bases to inosine, thereby changing the sequence of the target site. In this example, ADARs change the seed sequence of the miR-200b. The edited miR-200b loses its ability to interact with 3′UTR of ZEB1 and ZEB2; while it concomitantly acquires the capability to interact with novel targets such as LIFR, a well-known anti-metastatic gene. Therefore, this process can change the tumor-suppressive miR-200b to an oncogenic miRNA. B Alternative polyadenylation (APA) in the 3′UTR can generate multiple mRNA transcripts with different 3′ UTRs. As shown here, the 3′ UTR of the candidate gene includes two APA sites which can give rise to two isoforms with short and long 3′ UTRs. The short isoform might produce more proteins due to escaping from repression by various components such as miRNAs, lncRNAs, and RNA-binding proteins