Long Noncoding RNA and Circular RNA: Two Rising Stars in Regulating Epithelial-Mesenchymal Transition of Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with especially poor prognosis. However, the molecular mechanisms of pancreatic oncogenesis and malignant progression are not fully elucidated. Epithelial-mesenchymal transition (EMT) process is important to drive pancreatic carcinogenesis. Recently, long noncoding RNAs (lncRNAs) and circular RNAs(circRNAs) have been characterized to participate in EMT in PDAC, which can affect the migration and invasion of tumor cells by playing important roles in epigenetic processes, transcription, and post-transcriptional regulation. LncRNAs can act as competing endogenous RNAs (ceRNA) to sequester target microRNAs(miRNAs), bind to the genes which localize physically nearby, and directly interact with EMT-related proteins. Currently known circRNAs mostly regulate the EMT process in PDAC also by acting as a miRNA sponge, directly affecting the protein degradation process. Therefore, exploring the functions of lncRNAs and circRNAs in EMT during pancreatic cancer might help pancreatic cancer treatments.

Emerging roles of long noncoding and circular RNAs in pancreatic ductal adenocarcinoma

“…Although several lncRNAs may be involved in generating small functional proteins or peptides, sequence complementarity to other nucleotides probably helps regulate target stability or function (Yang et al, 2022). lncRNAs act as competing endogenous RNAs (ceRNAs) to sequester target miRNAs, bind nearby target genes, and directly control epithelial-mesenchymal transition (EMT)-related proteins (Yang et al, 2022); EMT characterizes the metastasis and invasion of cancer cells (Pastushenko and Blanpain, 2019). It is not an on-or-off binary process but occurs in distinct cellular states, involving multiple continuous dynamic transcriptional FIGURE 1 lncRNAs and subclass circRNAs in PDAC PDAC developed from normal ducts in the pancreas and its altered precancer lesion, pancreatic intraepithelial neoplasia (PanIN) (Suryavanshi et al, 2017;Ma et al, 2021).…”

“…Although several lncRNAs may be involved in generating small functional proteins or peptides, sequence complementarity to other nucleotides probably helps regulate target stability or function ( Yang et al, 2022 ). lncRNAs act as competing endogenous RNAs (ceRNAs) to sequester target miRNAs, bind nearby target genes, and directly control epithelial–mesenchymal transition (EMT)-related proteins ( Yang et al, 2022 ); EMT characterizes the metastasis and invasion of cancer cells ( Pastushenko and Blanpain, 2019 ). It is not an on-or-off binary process but occurs in distinct cellular states, involving multiple continuous dynamic transcriptional and translational mechanisms ( Pastushenko and Blanpain, 2019 ).…”

“…A recent study indicated that 50% lncRNAs in PDAC supposedly function as ceRNAs, which are any RNAs that bind other RNAs, such as miRNA sponges, thereby regulating other transcripts by competing for shared target sequences in miRNAs ( Salmena et al, 2011 ; Yang et al, 2022 ). The ceRNA hypothesis proposes that RNAs form a large-scale regulatory network across the transcriptome, extensively communicating functional genetic information in the whole genome, and play important roles in various disease pathologies, including cancer ( Salmena et al, 2011 ).…”

“…Considering that a finite number of lncRNAs exist, the ceRNA hypothesis supports the exchange of information between molecules for communication within a closed space ( Salmena et al, 2011 ). Of the remaining lncRNAs in PDAC, 9% are affected by the local regulators of their nearby genes ( Yang et al, 2022 ), suggesting that transcriptomal changes in lncRNAs are also involved in the transcriptional regulation of other genes. Hence, lncRNAs can be used to assess the epigenetic regulation of local gene expressions.…”

“…A recent study indicated that 34% lncRNAs in PDAC are involved in regulating EMT or transforming growth factor beta 1 (TGFB)-related mechanisms ( Yang et al, 2022 ), although lncRNAs are not mutually exclusive to the ceRNA functional group and overlap with each other.…”