Emerging roles of long noncoding RNAs in cholangiocarcinoma: Advances and challenges

Abstract

Cholangiocarcinoma (CCA), a cancer with a relatively low incidence rate, is usually associated with poor prognosis. Current modalities for the diagnosis and treatment of CCA patients are still far from satisfactory. In recent years, numerous long noncoding RNAs (lncRNAs) have been identified as crucial players in the development of various cancers, including CCA. Abnormally expressed lncRNAs in CCA, regulated by some upstream molecules, significantly influence the biological behavior of tumor cells and are involved in tumor development through various mechanisms, including interactions with functional proteins, participation in competing for endogenous RNA (ceRNA) regulatory networks, activation of cancer-related signaling pathways and epigenetic modification of gene expression. Furthermore, several lncRNAs are closely associated with the clinicopathological features of CCA patients, and are promising biomarkers for diagnosing and prognostication of CCA. Some of these lncRNAs play an important role in chemotherapy drug resistance. In addition, lncRNAs have also been shown to be involved in the inflammation microenvironment of CCA and malignant outcome of CCA risk factors, such as cholestatic liver diseases. In view of the difficulty of diagnosing CCA, more attention should be paid to detectable lncRNAs in the serum or bile. This review summarizes the recent knowledge on lncRNAs in CCA and provides a new outlook on the molecular mechanisms of CCA development from the perspective of lncRNAs. Moreover, we also discussed the limitations of the current studies and differential expression of lncRNAs in different types of CCA.

Keywords: bile; biomarkers; cancer development; cholangiocarcinoma; long noncoding RNA; molecular mechanisms; signaling pathways; tumor microenvironment.

FIGURE 1

CCA‐specific inflammatory microenvironment. LINC00340 (TLINC) is a novel transcriptional target of TGF‐β in CCA. After TLINC overexpression, some inflammation‐associated genes (e.g. IL6, IL8, and CXCL1) are induced. In addition, lncRNAs HULC and H19 can be induced by oxidative stress and then significantly promote migration and invasion of CCA cells by enhancing IL‐6 and CXCR4 levels. After the stimulation of TGF‐β1, lncRNA ASLNCS5088, which is enriched in M2 macrophage‐derived exosomes, can be efficiently transferred into fibroblasts, resulting in increased α‐SMA expression and activation of myofibroblasts in vitro. Abbreviations: IL‐6, interleukin 6; IL‐8, interleukin 8; CXCL1, C‐X‐C motif chemokine ligand 1; CXCR4, C‐X‐C motif chemokine receptor 4; TGF‐β, transforming growth factor‐beta; α‐SMA, α‐smooth muscle actin

FIGURE 2

Competitive endogenous RNA (ceRNA) mechanism. LncRNAs can function as ceRNAs to compete with mRNAs for binding to miRNAs like sponges, and further regulate gene expression, promoting the development of cholangiocarcinoma. Abbreviations: Pol II, polymerase II

FIGURE 3

The epigenetic modification mediated by lncRNAs. A. PRC2 is an extremely conserved protein complex capable of silencing gene expression by methylating lysine 27 on histone H3, and EZH2 is a catalytic subunit of PRC2. In CCA cells, lncRNAs can recruit EZH2 to the promoter region of the tumor suppressor, followed by epigenetically suppressing gene expression. B. SETDB1 protein belongs to the SET‐domain protein methyltransferase family, which is involved in the tri‐methylation of H3K9 and then silencing gene expression. In CCA cells, lncRNAs can recruit SETDB1 to the promoter region of the oncogene. The inhibition of oncogene expression is relieved with the downregulation of this kind of lncRNAs. Abbreviations: EZH2, enhancer of zeste 2; EED, embryonic ectoderm development; me, methyl group; H3K27, histone H3 lysine 27; KAP1, kinesin‐ii‐associated protein 1; SETDB1, SET domain bifurcated histone lysine methyltransferase 1; KRAB‐ZFP, KRAB domain‐containing zinc finger protein; HP1, heterochromatin protein 1. H3K9, histone H3 lysine 9

FIGURE 4

Activation of cancer‐related signaling pathways. Dysregulation of lncRNAs in CCA cells contributes to the activation of several signaling pathways. This figure depicts part of these lncRNAs. PCAT1 could relieve the negative regulatory effect of miR‐122 on Wnt1 and facilitated eCCA cell growth and restrained apoptosis via targeting the Wnt/β‐catenin signaling pathway. The nuclear translocation of β‐catenin is inhibited after overexpression of MIR22HG. Up‐regulated NNT‐AS1 can significantly increase the phosphorylation level of ERK1/2 and PI3K/AKT. SOX2‐OT positively regulates the phosphorylation of PI3K and AKT in CCA cells partially by interacting with FOXA1 in the nucleus to inhibit PTEN transcription. Overexpression of lncRNA SNHG1 in CCA can accelerate the expression of TLR4 and activate the NF‐κB pathway, thus regulating the growth and tumorigenesis of CCA. lnc‐LFAR1 is involved in activating the TGF‐β/Smad pathway and ASAP1‐IT1 can activate the Hedgehog signaling pathway, but only the improvement of signaling pathway protein levels was observed, and these functions are indicated by blue arrows in Figure 1. The signaling pathways are indicated by black arrows, and action of lncRNAs is indicated by red arrows. Final effects on CCA cells are indicated by green arrows. Activation is indicated by an arrow and inhibition by a T‐shaped arrow. Abbreviations: DVL, segment polarity protein disheveled homolog; GSK3β, glycogen synthase kinase 3 beta; MAPKKK, mitogen‐activated protein kinase kinase kinase; MEK1/2, MAP kinase/ ERK kinase 1/2; ERK1/2, extracellular regulated MAP kinase 1/2; PI3K, phosphatidylinositol 3‐kinase; PTEN, phosphatase and tensin homolog; mTOR, mechanistic target of rapamycin kinase; TGF‐β, transforming growth factor‐beta; TβR1/2, TGF‐beta receptor type‐1/2; SMO, smoothened, frizzled class receptor; Sufu, Sufu negative regulator of hedgehog signaling; gli1, gli family zinc finger 1; TLR4, toll‐like receptor 4; NF‐kB, nuclear factor kappa B; IKK, inhibitor of kappa B kinase beta; FOXA1, forkhead box A1

FIGURE 5

Adjuvant effect of lncRNAs on chemotherapy. A. LINC01714 can enhance the cytotoxic effect of gemcitabine on CCA cells by modulating phosphorylated FOXO3‐Ser318. B. In low BAP1‐expressing CCA cells, lncRNA NEAT1 was upregulated. NEAT1 can serve as a functional downstream target of BAP1 involved in drug responses. C. With the increase in lnc‐PKD2‐2‐3 levels in CCA cells, the expression of the apoptotic marker caspase‐3 as well as the apoptosis rate of cells were decreased after 5‐FU treatment. Abbreviations: FOXO3, forkhead box O3; Ser, serine; BAP1, BRCA1 associated protein 1; 5‐FU, 5‐Fluorouracil