Unboxing the network among long non-coding RNAs and TGF-β signaling in cancer

Abstract

Deeper analysis of molecular mechanisms arising in tumor cells is an unmet need to provide new diagnostic and therapeutic strategies to prevent and treat tumors. The transforming growth factor β (TGF-β) signaling has been steadily featured in tumor biology and linked to poor prognosis of cancer patients. One pro-tumorigenic mechanism induced by TGF-β is the epithelial-to-mesenchymal transition (EMT), which can initiate cancer dissemination, enrich the tumor stem cell population, and increase chemoresistance. TGF-β signals via SMAD proteins, ubiquitin ligases, and protein kinases and modulates the expression of protein-coding and non-coding RNA genes, including those encoding larger than 500 nt transcripts, defined as long non-coding RNAs (lncRNAs). Several reports have shown lncRNAs regulating malignant phenotypes by directly affecting epigenetic processes, transcription, and post-transcriptional regulation. Thus, this review aims to update and summarize the impact of TGF-β signaling on the expression of lncRNAs and the function of such lncRNAs as regulators of TGF-β signaling, and how these networks might impact specific hallmarks of cancer.

Keywords: Cancer; epigenetics; non-coding RNA; signal transduction; transforming growth factor-β.

Figure 1

Network of lncRNAs and TGF-β signaling in cancer. TGF-β binds to the type II and type I receptors (TβRs) on the cell surface, signaling via inter-receptor trans-phosphorylation. The type I receptor phosphorylates SMAD2/3, which promotes their oligomerization with SMAD4 (presented for simplicity as SMAD), and in parallel, TGF-β signaling induces RAS, MEK, ERK, and other protein kinase pathways (not shown), that, together with transcription factors (TFs), regulate the expression of lncRNAs (shown as multicolor single-stranded molecules in order to emphasize the diversity of the implicated lncRNA species). According to the respective cellular compartment, lncRNAs modulate TGF-β signaling at different steps. Nuclear lncRNAs act as (i) guide or decoy molecules for TF complexes to promote gene transcription (TSS, transcription start site) (ii) as DNA binding molecules inducing triple helix formations or (iii) facilitate protein translocation from one compartment to another. Cytoplasmic lncRNAs can regulate (iv) mRNA stability, (v) can act as scaffolds, stabilizing protein-RNA complexes, or (vi) can regulate mRNA translation and stability through competitive endogenous RNA (ceRNA) function against microRNAs (miRNAs). LncRNAs are also sorted as cargo in intraluminal vesicles of multivesicular bodies (MVBs), which release their lncRNA content into the extracellular milieu. Created with BioRender.com. TGF-β, transforming growth factor β; IncRNA, long non-coding RNAs.