The emerging role of long noncoding RNAs in esophageal carcinoma: from underlying mechanisms to clinical implications

Abstract

Long noncoding RNAs (lncRNAs), a type of transcriptional product more than 200 nucleotides in length, have emerged as crucial regulators in human cancers. Accumulating data have recently indicated relationships between lncRNAs and esophageal carcinoma (EC). Of note, lncRNAs act as decoys/sponges, scaffolds, guides, and signals to regulate the expression of oncogenes or tumor suppressors at epigenetic, post-transcriptional, and protein levels, through which they exert their unique EC-driving or EC-suppressive functions. Moreover, the features of EC-related lncRNAs have been gradually exploited for developing novel diagnostic and therapeutic strategies in clinical scenarios. LncRNAs have the potential to be used as diagnostic and prognostic indicators individually or in combination with other clinical variables. Beyond these, although the time is not yet ripe, therapeutically targeting EC-related lncRNAs via gene editing, antisense oligonucleotides, RNA interference, and small molecules is likely one of the most promising therapeutic strategies for the next generation of cancer treatment. Herein, we focus on summarizing EC-driving/suppressive lncRNAs, as well as discussing their different features regarding expression profiles, modes of action, and oncological effects. Moreover, we further discuss current challenges and future developing possibilities of capitalizing on lncRNAs for EC early diagnosis and treatment.

Keywords: Biomarker; Drug resistance; Early diagnosis; Esophageal cancer; Noncoding RNA; Targeted therapy.

Fig. 1

EC-driving lncRNAs and their modes of action. A. HOTAIR competitively bind to miR-148a as a decoy/sponge to inhibit the formation of the complex consisting of miR-148a, RISC, and Snail2 mRNA, thus upregulating Snail2 expression and facilitating EMT. B. CCAT1 functions as a scaffold and simultaneously binds to PRC2 and SUV39H1 to facilitate H3K27me3 and H3K9me3 near the promoter region of SPRY4, resulting in promoted cell proliferation and migration. C. EZR-AS1 guide SMYD3 to the GC-rich region downstream of the EZR promoter and upregulate EZR expression, leading to enhanced cell mobility and invasiveness. D. HERES activates Wnt signaling pathway through both canonical and noncanonical manners to promote cell proliferation, metastasis and EMT

Fig. 2

EC-related lncRNAs act regulatory functions at multiple levels. In the nucleus, EC-related lncRNAs can participate in a variety of epigenetic and post-transcriptional regulations including a DNA histone modifications, b DNA methylations, and c alternative splicing (AS). In the cytoplasm, EC-related lncRNAs can act as d endogenous competitive RNAs (ceRNAs) of miRNAs to alleviate their inhibition of target mRNAs of protein-coding genes. In addition, some EC-related lncRNAs can act on proteins e to affect their functions, stability, and localization

Fig. 3

Exosomal EC-driving lncRNAs and their modes of action. a EC-driving lncRNA FMR1-AS1 in cancer stem cells (CSCs) could be packaged into exosomes and thereafter released into tumor microenvironment, resulting in the activation of NF-κB pathway in recipient non-CSCs and the delivery of malignant phenotypes such as promoted cell proliferation, invasion, and reduced apoptosis. b The activation of PART1 enhanced gefitinib resistance via competitively sponging miR-129 and subsequently upregulating the expression of Bcl-2. PART1 could be packed into exosomes and transferred to recipient cells that were sensitive to gefitinib, resulting in the acquisition of gefitinib resistance property

Fig. 4

Exosomal lncRNAs and EC diagnosis. Some EC-related LncRNAs are enriched and detectable in circulating exosomes and are considered as promising biomarkers for EC non-invasive diagnosis

Fig. 5

Targeting EC-related lncRNAs in various potential therapeutic approaches. Given the irreplaceable role of lncRNAs in the carcinogenesis of EC, targeting EC-related lncRNAs may produce encouraging therapeutic results. a transcriptionally silencing EC-driving lncRNAs via deleting regions of interest in specific loci such as the promoter region; b ASOs bind to and repress EC-driving lncRNAs via multiple ways including steric hindrance, alternative splicing, and target degradation, which partially depend on different chemical modifications; c inhibiting EC-driving lncRNAs by inducing the RNA interference process via transfecting siRNAs; d targeting secondary or tertiary structures of EC-driving lncRNAs using small molecules; e targeting EC-driving lncRNAs via using corresponding miRNAs delivered by nanovectors; f therapeutically targeting specific NATs (lncRNAs) to upregulate downregulated tumor-suppressive genes which are transcriptionally inhibited by NATs