Yali Han
Guo Zhao
Xinhang Shi
Yushan Wang
Xin Wen
Lu Zhang
Xiangqian Guo- 1Departments of Physiology, Institute of Biomedical Informatics, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Academy for Advanced Interdisciplinary Studies, Henan University, Kaifeng, China
- 2Department of Preventive Medicine, Institute of Biomedical Informatics, Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Academy for Advanced Interdisciplinary Studies, Henan University, Kaifeng, China
Esophageal cancer (EC) is one of the most common malignancies of digestive tracts with poor five-year survival rate. Hence, it is very significant to further investigate the occurrence and development mechanism of esophageal cancer, find more effective biomarkers and promote early diagnosis and effective treatment. Long non-coding RNAs (lncRNAs) are generally defined as non-protein-coding RNAs with more than 200 nucleotides in length. Existing researches have shown that lncRNAs could act as sponges, guides, scaffolds, and signal molecules to influence the oncogene or tumor suppressor expressions at transcriptional, post-transcriptional, and protein levels in crucial cellular processes. Currently, the dysregulated lncRNAs are reported to involve in the pathogenesis and progression of EC. Importantly, targeting EC-related lncRNAs through genome editing, RNA interference and molecule drugs may be one of the most potential therapeutic methods for the future EC treatment. In this review, we summarized the biological functions and molecular mechanisms of lncRNAs, including oncogenic lncRNAs and tumor suppressor lncRNAs in EC. In addition, we generalized the excellent potential lncRNA candidates for diagnosis, prognosis and therapy in EC. Finally, we discussed the current challenges and opportunities of lncRNAs for EC.
1 Introduction
Esophageal cancer (EC), as a malignancy of the digestive tracts, is one of the most common cancers and ranks 10th in terms of morbidity and sixth in mortality across the world in 2020 cancer statistics (Sung et al., 2021). EC is typically characterized by progressive dysphagia, which tends to occur in middle-aged and elderly people especially male (Falk, 2009; Massey, 2011). There are two main histologic subtypes of EC: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). EAC is more common in western countries, while the proportion of ESCC patients is increasing in Asian countries, which also gradually occupies the main position worldwide. Meanwhile, ESCC is the second most common primary cancer in head and neck areas (Chuang et al., 2008). Compared with other HNSCC (head and neck squamous cell carcinoma) subtypes, such as oral, dental, and maxillofacial squamous cell carcinoma, ESCC has a higher incidence rate and lower survival rate (Nikbakht et al., 2020). Due to the late appearance of obvious clinical symptoms, EC is commonly diagnosed in advanced clinical stages with low five-year survival rate (less than 20%) (Dubecz et al., 2012). At present, the main therapeutic regimen for esophageal cancer is individualized and comprehensive, which is based on surgery, but the patient outcome is not satisfactory (Deng and Lin, 2018; Watanabe et al., 2020). Therefore, to further explore the occurrence and development mechanism of esophageal cancer, find more effective biomarkers, and promote early diagnosis and effective treatment, are greatly needed.
The ENCODE project showed that about 70% of the human genome is transcribed (Tay et al., 2009). However, only 1–2% RNAs encode proteins, and a majority of the human genome is transcribed into non-coding RNAs (Al-Tobasei et al., 2016). There are many types of non-coding RNAs, including microRNA (miRNA), long non-coding RNAs (lncRNAs), small nuclear RNA (snRNA), circular RNAs (circRNAs) and so on (Abraham and Meltzer, 2017; Wu and Kuo, 2020). Although most non-coding RNAs remain unstudied, there are still many ncRNAs that have been revealed to play important roles in normal cellular function and disease development (Slack and Chinnaiyan, 2019; Toden and Goel, 2022). For example, some small non-coding RNAs which are stable in blood could be used for non-invasive cancer screening (Toiyama et al., 2013; Imaoka et al., 2016). Besides, some diseases, like myotonic dystrophy, can be treated by targeting some non-coding RNAs (Wheeler et al., 2012; Levin, 2019).
LncRNAs are defined as non-coding RNAs with greater than 200 nucleotides (Cui et al., 2019). Studies showed that lncRNAs play vital roles in regulating gene expression at transcriptional, post-transcriptional and epigenetic levels in multiple cellular processes in tumors (Slack and Chinnaiyan, 2019). Interestingly, some lncRNAs have been reported to possess the small open reading frame (sORF), which could encode the small peptides to regulate multiple signaling pathways (Chen et al., 2021). Meanwhile, lncRNAs have the potential to be the biomarkers and therapeutic targets for various cancers (Dong et al., 2018). Abnormal expressions of lncRNAs were also found in the occurrence and progression of EC, and some of them were even detected in body fluid for potential biomarker (Pardini et al., 2019). Here, we summarized the biological functions of lncRNAs in the pathogenesis and progression of EC, and discussed the values of lncRNAs as biomarkers for early diagnosis, prognosis and treatment targets in EC.
2 Functions of lncRNAs
Growing studies showed that lncRNAs can be involved in different biological processes, for instance, epigenetic regulation, stem cell differentiation, inflammation-related diseases and tumorigenesis by mediating the transcription and translation process of protein-related coding genes (Shi et al., 2013; Hon et al., 2017; Bao et al., 2019; Zhu et al., 2019). We summarized the specific regulation mechanisms of lncRNAs in Figure 1 (Camier et al., 1990; Houseley et al., 2008; Tripathi et al., 2010; Cesana et al., 2011; Wang and Chang, 2011; Steck et al., 2012; Hu et al., 2014; Yuan et al., 2014; Yin et al., 2015; Nachtergaele and He, 2017; Wang et al., 2019c; Liu et al., 2021a; Liu et al., 2021b; Pietropaolo et al., 2021; Song et al., 2021; Zhang et al., 2021).
FIGURE1. Functional molecular mechanisms of lncRNAs. ①LncRNAs change the location and modification of TFs (Hu et al., 2014). ②LncRNAs regulate the combination of the TFs, RNA polymerase Ⅱ and the promoter, enhancer (Wang and Chang, 2011). ③LncRNAs interact with DNA as a platform for TFs (Yin et al., 2015). ④LncRNAs act as competitive endogenous RNAs (Cesana et al., 2011). ⑤LncRNAs promoter may act as cis-acting enhancer elements (Liu et al., 2021b). 1) LncRNAs act as the precursor for siRNAs or miRNAs (Steck et al., 2012). 2) LncRNAs regulate the distribution of miRNA (Nachtergaele and He, 2017). 3) LncRNAs act as antisense transcripts (Liu et al., 2021a). 4) LncRNAs form the double-stranded RNA complex by binding to mRNAs (Yuan et al., 2014). 5) LncRNAs regulate the selective splicing process of pre-mRNAs (Tripathi et al., 2010). I. LncRNAs regulate histone modification through affecting the modification factors (Houseley et al., 2008). II. LncRNAs bind to DNA modification to modify the DNA methylation (Song et al., 2021). III. LncRNAs bind to chromatin modification complexes to affect chromatin structure and remodeling (Pietropaolo et al., 2021). IV. LncRNAs locate molecules by binding to DNA, RNA and proteins as a “guide” (Camier et al., 1990). V. LncRNAs participate in the formation of exosomes (Zhang et al., 2021). VI. LncRNAs that contain sORFs can encode small peptide (Wang et al., 2019c). Abbreviations: P, promoter; E, enhancer; M, modification; Pro, protein; D, DNA; R, RNA; miRNA, microRNA; TFs, transcription factors; siRNA, small-interfering RNA; RNAPII, RNA polymerase II; DNAM, DNA modification; sORFs, small open reading frames.
At transcription level, lncRNA targets the transcription factors to regulate gene transcription through trans-activation behaviors, thus affecting the gene activation, repression, cell proliferation and apoptosis (Melendez-Zajgla and Maldonado, 2021). Besides, lncRNAs could bind to DNA strand or some proteins, affecting the localization of transcription factors, decreasing the transcript elongation through inhibiting the activation of elongation factors, and inhibiting polymerase II activity via targeting the trans region (Kapranov et al., 2007).
At post-transcriptional level, lncRNAs function as the regulators of some miRNAs to regulate the gene expression, or as the competitive endogenous RNAs (ceRNAs) to regulate the expression of corresponding gene by binding miRNAs (Maass et al., 2014). For example, lncRNAs regulate the dosage compensation effect, genomic imprinting, DNA methylation, and small polypeptides coding (Sleutels et al., 2002; Ponting et al., 2009; Cai et al., 2021). Interestingly, small polypeptides encoded by small open reading frames enriched in lncRNA transcripts have been reported to play important roles in circulating extracellular vesicles (Cai et al., 2021), cancer development (Cao et al., 2021), and neuronal differentiation (Douka et al., 2021). However, the functions of most lncRNAs are still unclear and require further comprehensive study.
3 LncRNAs Related to Esophageal Cancer
Many kinds of cancers, including EC, are associated with the imbalance of lncRNAs (Leucci et al., 2016; Hua et al., 2018; Lv et al., 2022). A study, which analyzed the lncRNAs expression profile in more than 200 EC samples from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA), demonstrated that thousands of lncRNAs were differentially expressed between EC and normal tissues, and many of them are related with patient survival time (Liu et al., 2018). LncRNAs could be divided into oncogenic lncRNAs and tumor suppressive lncRNAs based on their functions in EC, as shown in Figure 2 (St Laurent et al., 2015).
FIGURE 2. The molecular functions of lncRNAs in EC. LncRNAs function as oncogenes or tumor suppressors. On the left, lncRNAs act as oncogenes and are overexpressed in EC. On the contrary in right, lncRNAs act as tumor suppressors and are down-regulated in EC. As reported for the functional mechanisms, lncRNAs can be divided into the cis-acting lncRNAs and trans-acting lncRNAs. Cis-acting lncRNAs can regulate the chromatin state and/or expression of nearby genes: 1) the lncRNA transcript regulates the expression of nearby genes through recruiting regulatory factors (Kopp and Mendell, 2018); 2) the transcription or splicing-dependent regulation of the lncRNA execute the gene-regulation that is independent of the sequence of the RNA transcript but with structural functions (Engreitz et al., 2016); 3) Cis regulation depends on DNA elements within the lncRNA promoter (Dimitrova et al., 2014). And trans-acting lncRNAs leave the site of transcription and execute the functions: 1) lncRNAs regulate gene expression and chromatin states at genomic loci far distant from their transcription region (Rinn et al., 2007); 2) lncRNAs influence the nuclear organization and structure (Clemson et al., 2009); 3) lncRNAs interact with other proteins and/or RNA molecules (Hafner et al., 2010). In addition, lncRNA can be classified into following three categories by genic position: 1) intronic lncRNA, lncRNA within introns: mainly produced in the intron region of the coding gene (Rinn and Chang, 2012); 2) intergenic lncRNA, also known as lincRNA, mainly derived from the intergenic region of two coding genes (Ransohoff et al., 2018); 3) antisense lncRNA, mainly produced in the antisense chain of the coding gene (Rinn and Chang, 2012).
3.1 Oncogenic lncRNAs
As illustrated in Table 1, these lncRNAs are upregulated in EC and facilitate the malignant biological properties of EC cells. Here, we discussed some lncRNAs in more detail according to the oncogenic mechanisms of action in EC.
TABLE 1. EC-associated oncogenic lncRNAs.
3.1.1 Oncogenic lncRNAs Involving Wnt Signaling Pathway
Wnt signaling is one of the crucial pathways regulating cell biology (Clevers and Nusse, 2012). The dysregulation of Wnt signaling has been described in various cancers, including lung cancer (Stewart, 2014), colorectal cancer (Zhan et al., 2017), etc. Currently, several studies revealed that lncRNAs can affect the malignant behaviors of EC through Wnt signaling pathway.
Small nucleolar RNA host gene 16 (SNHG16), Colon cancer-associated transcript 2 (CCAT2) and FEZ family zinc finger 1 antisense RNA 1 (FEZF1-AS1) were upregulated in EC cells and the knockdown of them inhibited the malignant behaviors of EC via the reduction of β-catenin expression in Wnt signaling pathway (Cai et al., 2015; Xu et al., 2018b; Han et al., 2018; Yang et al., 2019a; Wang and Wang, 2019). Ma et al. (2021) reported that lncRNA VPS9D1 antisense RNA1 (VPS9D1-AS1) was overexpressed in ESCC cell lines and tissues compared with normal controls. Silencing of VPS9D1-AS1 could inhibit the proliferation, invasion, and migration ability in vitro. Mechanically, VPS9D1-AS1 knockdown can inhibit the Wnt/β-catenin pathways through regulating the expression of β-catenin and c-Myc (Ma et al., 2021). Guo et al. (2021) revealed that DDX11 antisense RNA 1 (DDX11-AS1) overexpression enhanced cell proliferation, invasion, migration, and epithelial - mesenchymal transition (EMT) process of EC through activating the Wnt/β-catenin pathway via targeting miR-30d-5p. Meanwhile, DDX11-AS1 could act as a ceRNA through sponging miR-30d-5p, thus upregulating the expression of SNAI1 and Zinc Finger E-Box Binding Homeobox 2 (ZEB2) (Guo et al., 2021). You et al. (2019) found that LncRNA HERES, as an oncogene, can activate Wnt signaling by interacting with enhancer of zeste homolog 2 (EZH2) via its G-quadruple structure-like motif. Additionally, TUG1 exerts oncogenic ability though activating the Wnt/β-catenin pathway via miR-148a-3p/myeloid cell leukemia-1 (MCL-1) axis (Tang et al., 2020). Similarly, lncRNA growth arrest-specific transcript 5 (GAS5), as a molecular sponge, can regulate miR-301a, thus enhancing C-X-C chemokine receptor 4 (CXCR4) expression and activating NF-κB pathways and the Wnt/β-catenin pathway in EC (Li et al., 2018). Yang et al. (2021) found that knockdown of CCAT2 inhibited the mRNA and protein levels of wnt-induced-secreted-protein-1 (WISP1), β-catenin, and the mRNA levels of their downstream target genes in ESCC. Similarly, HOX transcript antisense intergenic RNA (HOTAIR) directly inhibited the Wnt inhibitory factor 1 (WIF-1) expression by promoting the histone methylation on H3K27 in the promoter region, thus activating the Wnt/β-catenin signaling pathway in ESCC (Ge et al., 2013).
Given the above, many lncRNAs play an important role in the occurrence and development of EC by regulating the Wnt signaling pathway.
3.1.2 Oncogenic lncRNAs Involving PI3K/AKT Signaling Pathway
PI3K/AKT signaling pathway has been reported to be frequently activated in a variety of tumors and has been considered as a potential therapeutic target (Aoki and Fujishita, 2017). Here, we showed that some lncRNAs can regulate the EC progression through PI3K/AKT signaling pathway.
LINC00152 was up-regulated in EC tissues, and knockdown of LINC00152 significantly inhibited the cell proliferation of EC by decreasing the expression levels of PI3K and AKT (Ding et al., 2020). Another study showed that LncRNA HLA complex P5 (HCP5) promoted malignant behaviors of ESCC through regulating the miR-139-5p/phosphodiesterase 4A (PDE4A) axis and activating the PI3K-AKT-mammalian target of rapamycin (mTOR) signaling pathway (Xu et al., 2021b). Similarly, overexpression of LINC01518, PTCSC1, LINC01617, and methyltransferase like 3 (METTL3) can also enhance the malignant behaviors of EC cells through activating the AKT pathway (Zhang et al., 2018a; Zhang et al., 2019b; Liu et al., 2020c; Hou et al., 2020). Liang et al. (2018) found that focally amplified lncRNA (FAL1) promoted the proliferation of EC cells by stimulating the AKT pathway via regulating the 3-phosphoinositide-dependent kinase 1 (PDK1). Importantly, EIF3J-AS1, as an oncogene, can sponge the miR-373-3p to up-regulate mRNA level of AKT1 in EC (Wei et al., 2020). Another study showed that ESCC-related lncRNAs transcript 1 (ESSCAL-1) downregulation can induce the cell apoptosis by the downregulation of the PI3K/AKT signaling via miR-590-3p/apolipoprotein mRNA-editing enzyme catalytic polypeptide 3 protein G (APOBEC3G) axis (Liu et al., 2020a). Xu et al. (2021a) reported that KCNQ1 overlapping transcript 1 (KCNQ1OT1) can activate the PI3K/AKT pathway via inhibiting the repression of miR-133b and indirectly upregulating epidermal growth factor receptor (EGFR). In addition, LINC00184 regulated the glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) of EC cells through inducing the phosphorylation of Akt (Li et al., 2019).
In conclusion, numerous lncRNA dysregulation participates in the occurrence and development of EC through affecting the PI3K/AKT pathway.
3.1.3 Oncogenic lncRNAs Involving TGF-β Signaling Pathway
TGF-β signaling pathway has been showed to regulate numerous cellular functions, including cell proliferation, apoptosis, invasion, and migration (Colak and Ten Dijke, 2017). Current studies revealed that some lncRNAs can regulate the EC progression by affecting the TGF-β signaling pathway.
Zhu et al. (2021) found that lncRNA FAM225A facilitated the ESCC development through sponging miR-197-5p, thus upregulating the non-POU domain-containing octamer-binding protein (NONO) expression and activating the transforming growth factor-β (TGF-β) pathway in ESCC cells. Another study revealed that NCK1-AS1 may promote ESCC progression by upregulating the expression of TGF-β1 (Fu et al., 2022). Similarly, ANRIL knockdown inhibit EC cell proliferation by increasing the expression of p15 via TGFβ1 (Chen et al., 2014).
In brief, some lncRNAs can regulate the TGF-βpathway to affect the EC development.
3.1.4 Oncogenic lncRNAs Involving Other Regulatory Mechanisms
We also discussed lncRNAs promote the tumorigenesis and development of EC through other regulatory mechanisms. Here, we mainly discussed the HOX transcript antisense intergenic RNA (HOTAIR), MALAT1 LINC01535 and BRAF-activated non-coding RNA (BANCR), which have got wide attention in multiple studies.
Several studies have revealed that HOTAIR, as a competing endogenous RNA, plays the oncogenic role through the lncRNA-miRNA-mRNA function network in EC. Ren et al. (2016) reported that HOTAIR was abnormally increased in ESCC cells and could facilitate ESCC occurrence through sponging miR-1 and upregulating CCND1. Xu et al. found that HOTAIR may promote epithelial–mesenchymal transition (EMT) through acting as the miR-148a sponge to facilitate the expression of snail2 (Xu and Zhang, 2017). It was reported that the up-regulation of homeobox C8 (HOXC8) was observed in a variety of cancer types and involved in tumor formation (Li et al., 2020a; Jiang et al., 2021). Importantly, Wang et al. (2019a) showed that HOTAIR could regulate HOXC8 by specifically binding to miR-204 as a competing endogenous RNA. CC motif chemokine ligand 18 (CCL18) has crucial roles in tumor progression and metastasis (Cardoso et al., 2021). Wang et al. (2019e) revealed that HOTAIR upregulated by CCL18 advanced malignant progression of ESCC through miR-130a-5p-zinc finger E-box binding homeobox 1 (ZEB1) axis. Hexokinase 2 (HK2) expression is increased in tumors and contributes to aerobic glycolysis. Ma et al. (2017) found that HOTAIR promoted HK2 expression by sponging miR-125/miR-143, thus facilitating the tumorigenesis of ESCC.
Researchers have also revealed that MALAT1 played a crucial role in the tumorigenesis and development of EC. MALAT1 was significantly up-regulated in EC tissues and cells than the normal controls (Huang et al., 2016). A study showed that the up-regulation of MALAT1 in advanced stage ESCC tissues may facilitate ESCC growth by the ataxia-telangiectasia mutated (ATM)/checkpoint kinase 2 (CHK2) pathway dephosphorylation (Hu et al., 2015). MALAT1 knockdown suppressed the invasion, migration and EMT of EC. Mechanically, MALAT1 could target and sponge the miR-1-3p, thus affecting the coronin-1C (CORO1C)/tropomyosin3 (TPM3) pathway in EC (Li et al., 2020c). Besides, knockdown of MALAT1 inhibited the proliferation, migration and tumor sphere formation of tumors cells by decreasing the expression of β-catenin, Lin28 and EZH2 in ESCC (Wang et al., 2016a). Another study found that MALAT1 could promote the EMT and metastasis of EC cells through Ezh2-Notch1 signaling pathway (Chen et al., 2018). Importantly, down-regulation of MALAT1 by miR-101 and miR-217 through a post-transcriptional regulation mechanism inhibited proliferation, invasion, and migration of ESCC cells (Wang et al., 2015). Subsequently, Wang et al. (2021b) found that N 6-methyladenosine (m6A) modification of MALAT1 promotes the metastasis ability of ESCC through reshaping nuclear speckles (NSs). The transcription events in downstream activated by NSs is partially intermediated through the binding of YTH-domain-containing protein 1 (YTHDC1) onto MALAT1-Δm6A. Interestingly, artificially tethering YTHDC1 onto MALAT1-Δm6A ESCC cells leads to the restoring of migration ability (Wang et al., 2021b), indicating that post-transcriptional modification may affect the oncogenic activity of MALAT1 in EC.
LINC01535 promoted the proliferation and decreased the apoptosis in ESCC cells via activating the JAK/STAT3 pathway (Fang et al., 2020). Another study showed that small nucleolar RNA host gene 20 (SNHG20) played the oncogenic role through enhancing the growth and metastasis of ESCC through the ataxia telangiectasia-mutated kinase (ATM)-JAK-programmed cell death 1 ligand 1 (PD-L1) axis (Zhang et al., 2019a).
BRAF-activated non-coding RNA (BANCR) was revealed to enhance the cell proliferation, invasion and migration of ESCC by Raf/MEK/ERK signaling (Yu et al., 2021). Song et al. (2020) also found that BANCR can promote the malignant behaviors of ESCC and BANCR downregulation inhibited the ESCC development by inactivating the insulin like growth factor 1 receptor (IGF1R)/Raf/MEK/ERK axis by sponging the miR-338-3p.
To sum up, the oncogenic effects of lncRNAs in EC are multi-channel through various cell pathways.
3.2 Tumor-Suppressive lncRNAs
Deregulation of tumor suppressors plays important roles during carcinogenesis and tumor progression. In-depth understanding of tumor suppressors can serve new ideas for tumor-targeted therapy. It can promote EC occurrence and development once the tumor suppressive lncRNAs are downregulated. We summarize the information about tumor suppressive lncRNAs in Table 2. In this section, we discussed the tumor-suppressive role of some lncRNAs according to the mechanisms of action in EC.
TABLE 2. EC-associated tumor suppressive lncRNAs.
3.2.1 Tumor-Suppressive lncRNAs Involving Wnt Signaling Pathway
Overexpression of lncRNA-neighboring enhancer of FOXA2 (NEF), growth-arrest associated lncRNA 1 (GASL1), LINC00675 inhibited cell proliferation, invasion and migration through decreasing the expression of β-catenin in ESCC (Zhang et al., 2018b; Zhong et al., 2018; Ren et al., 2021). Urothelial carcinoma-associated (UCA1) expression was significantly lower in ESCC tissues than adjacent normal tissues. And mRNA microarray analysis indicated the overexpression of UCA1 can inhibit the Wnt signaling pathway through reducing the β-catenin (active form) levels (Wang et al., 2016b). Another study displayed that miR-4261, which could promote ESCC cell function in vitro, is one of maternally expressed gene 3 (MEG3) targets. The anti-tumor effect of MEG3 in ESCC was related to MEG3-miR-4261 axis regulating the dickkopf-2 (DKK2) and Wnt/β-catenin signaling (Ma et al., 2019).
3.2.2 Tumor-Suppressive lncRNAs Involving Other Regulatory Mechanisms
Here, we discussed other regulatory mechanisms lncRNAs, which can inhibit the tumorigenesis and development of EC. We mainly discussed the regulatory mechanisms regulated by MEG3 and GAS5 in EC.
The results of Li’s study proposed that MEG3 may inhibit EMT and EC cell function through downregulating phosphoserine aminotransferase 1 (PSAT1) and restraining the PSAT1 dependent GSK-3β/Snail signaling pathway (Li et al., 2020b). In addition, MEG3 was found to be significantly reduced in ESCC tissues, which was mediated by DNA methylation. And ectopic expression of MEG3 could promote ESCC cell apoptosis and inhibit cell proliferation and metastasis. Tumor protein 53 (TP53) is one of best-known tumor suppressors. One way of MEG3 inhibiting EC is by inducing p53 activation due to mouse double minute 2 (MDM2) downregulation (Lv et al., 2016). Moreover, lower expression of MEG3 predicted shorter survival by analyzing EC dataset from TCGA (Lv et al., 2016). Huang et al. (2017) also discovered MEG3 expression was diminished in ESCC tissue. MEG3 could suppress EC cell growth and induce apoptosis through activating endoplasmic reticulum stress pathway because the overexpression of MEG3 increased endoplasmic reticulum stress - related proteins (ATF6, GRP78, CHOP, PERK, IRE1, and cleaved caspase-3) expression (Huang et al., 2017). Dong et al. (2017) observed that there were hypermethylation of MEG3 both in ESCC tissue and EC cell lines, and it is crucial to MEG3 gene silencing. They also found that MEG3 may regulate forkhead box other 1 (FOXO1) and E-cadherin expression through competitively binding miR-9 (Dong et al., 2017).
In Wang’s study, GAS5 was lower in tumor tissues than that in healthy tissues, and the serum GAS5 level in EC patients was significantly lower than that in normal controls. Overexpression of GAS5 inhibited EC cell proliferation and migration by inactivating PI3K/AKT/mTOR signal pathway (Wang et al., 2018). Huang et al. (2018) found that tumor-suppressive lncRNA GAS5 was regulated by interferon (IFN) responses through the JAK/STAT signaling pathway. A study discovered the level of NBAT-1 was lower in EC tissue than adjacent normal tissues. And NBAT-1 overexpression could inhibit EC cell proliferation and tumor glycolysis partially by reducing pyruvate kinase M2 (PKM2) protein expression (Zhao et al., 2019). According to Ke et al. (2018)’s study, they also found that the expression of GAS5 was downregulated in ESCC tissue and ESCC cell. GAS5 overexpression may suppress ESCC cell function through inducing cell cycle arrest at G2/M stage by activating the ATM-CHK2 pathway and affecting EMT-associated proteins (Ke et al., 2018).
4 LncRNAs in Diagnosis, Prognosis and Therapy of Esophageal Cancer
LncRNAs play crucial roles in both cellular physiological and pathological processes, including in the pathogenesis of various tumors and often reveal a higher cell/tissue specificity than mRNA (Derrien et al., 2012; De Falco et al., 2021; Turai et al., 2021), so they were suggested as potential valuable diagnostic, prognostic factors even therapeutic targets. Below, we summarize the excellent potential lncRNA candidates for diagnosis, prognosis and therapy in EC.
4.1 LncRNAs in Esophageal Cancer Diagnosis
The treatment effect is not satisfactory for EC patients with advanced stages who have lost the opportunity of surgical treatment. To improve the therapy efficacy, it is urgent to find more excellent EC biomarkers for early diagnosis. We have summarized the present EC-related lncRNA diagnostic biomarkers in Table 3.
TABLE 3. EC-associated diagnostic lncRNAs.
Most of the lncRNAs with diagnostic potential are located in tumor tissues. Compared with the diagnostic markers derived from tumor tissues, the markers in peripheral blood are easy to be obtained and non-invasive, which are more suitable for early screening and early diagnosis of tumors. Tong et al. (2015) identified three stable plasma ESCC-related lncRNAs. By receiver operating characteristic curve (ROC) analysis, plasma lncRNA POU3F3 could be used as a promising biomarker for the diagnosis of ESCC. A study found serum level of lncRNA HOTAIR was increased in ESCC patients, and it was positively associated with the expression of HOTAIR in ESCC tissues. Through ROC analysis, it was detected that the serum level of HOTAIR can distinguish ESCC patients from healthy controls. The results indicated that serum HOTAIR could be a promising diagnostic indicator of ESCC (Wang et al., 2017). Small nucleolar RNA host gene 1 (SNHG1) has abnormal expression in many cancers and plays a key role in ESCC (Zhang et al., 2017; Luo et al., 2020). Luo et al. (2020) discovered that SNHG1 can promote ESCC cells proliferation, and its expression level in frozen cancer tissues is significantly related to its serum level. Combined with the results of ROC analysis, it was showed that SNHG1 can be applied as a potential diagnostic biomarker for ESCC patients. In ESCC, GAS5 is considered to be a tumor suppressor (Huang et al., 2018). GAS5 serum level in EC patients was lower compared within healthy controls, and it was decreased with the primary tumor stage (T stage) increasing. Combined with the results of AUC analysis, serum GAS5 may have diagnostic values for EC (Wang et al., 2018). LncRNA PGM5 antisense RNA 1 (PGM5-AS1) was markedly decreased in ESCC cell lines, plasma and tissues. And plasma PGM5-AS1 level was promising in diagnosis of ESCC (Zhihua et al., 2019).
In summary, because of the characteristics and important functions, lncRNAs have important significance and great potential for EC diagnosis.
4.2 LncRNAs in Esophageal Cancer Prognosis
Recent studies have found that several lncRNAs have characteristic prognostic functions in EC (Yang et al., 2019b). Owing to the important roles in tumorigenesis and progression, combined with the stability and specificity, lncRNAs have been considered as promising biomarkers for evaluating the prognosis of EC patients, such as HOTAIR, MALAT1, non-coding RNA activated by DNA damage (NORAD), LincRNA-uc002yug.2, and long non-coding RNA activated by transforming growth factor-β (lncRNA-ATB) (Wu et al., 2014; Khorkova et al., 2015). We summarized the lncRNA prognostic biomarkers for EC in Table 4.
TABLE 4. EC-associated prognosis lncRNAs.
As previously mentioned, HOTAIR is an important oncogenic lncRNA and has great potential for EC diagnosis. At the same time, it is also an important prognostic biomarker for EC. Kaplan–Meier survival curves showed, compared with patients with low HOTAIR expression, patients with high HOTAIR expression had noticeably shorter survival times (HR value >1). The results indicate that HOTAIR is an unfavorable factor for the prognosis of EC and can be used as a prognostic biomarker for EC (Ge et al., 2013; Li et al., 2013). LncRNA MALAT1 is located on chromosome 11q13.1 and its expression is conserved in multiple species (Ji et al., 2003; Huang et al., 2016). MALAT1 is involved in multiple biological functions and overexpressed in many cancers, such as liver cancer, lung cancer, renal cancer, gastric cancer (Ji et al., 2003; Su et al., 2021). MALAT1 acts on proliferation, metastasis, cell cycle and drug resistance in these cancer cells (Su et al., 2021). Compared with the expression in adjacent non-carcinoma tissues, MALAT1 expression is higher in EC tissues and correlates with unfavorable prognosis (Wang et al., 2019b; Syllaios et al., 2021). MALAT1 promotes EC cell proliferation, migration and invasion (Wang et al., 2019b; Syllaios et al., 2021). According to the multivariate analysis of prognostic factors (HR,6.638, 95% CI,2.948–14.947), MALAT1 was significantly related to the prognosis of EC patients and could be applied as an independent factor to EC prognosis (Huang et al., 2016). NORAD, a 5300 nt lncRNA and annotated in RefSeq as LINC00657, is a highly conserved lncRNA. It takes a primary part in regulating both ploidy and chromosomal stability in diploid cells. And the loss of NORAD function can result in chromosomal instability (Lee et al., 2016). Importantly, lncRNA NORAD is overexpressed in many cancers, including breast cancer, gastric cancer, bladder cancer, liver cancer, and so on (Soghli et al., 2021). Studies showed that NORAD could act as a ceRNA (Yang et al., 2019c). A meta-analysis reported that higher NORAD expression was significantly related with poorer overall survival in cancers (Wang et al., 2021a). And its expression level was appreciably higher in ESCC tissues than that in adjacent normal tissues. The multivariate analysis indicated that NORAD was an independent predictor of ESCC overall survival, which showed that NORAD is a potential ESCC prognostic marker (Wu et al., 2017).
In addition, many lncRNAs, such as LincRNA-uc002yug.2, ATB, are shown to be potential prognostic biomarkers for EC by the Multivariate Cox regression model (Table 4). Whether these lncRNAs can be further applied in clinic needs further verification, and the combined application of multiple lncRNAs is an important direction for future research.
4.3 LncRNAs in Esophageal Cancer Therapy
Therapy resistance leads to poor treatment efficacy and high recurrence rate of cancers to result in dismal prognosis. Resistance to cancer therapy ordinarily stems from deregulation of signaling pathways. LncRNAs are involved in many these pathways (Askarian-Amiri et al., 2016; Majidinia and Yousefi, 2016; Borkiewicz et al., 2021). For example, exogenous lncRNA UCA1 increased the invasiveness of cancer cells and worked in cisplatin resistance to bladder cancer therapy (Wang et al., 2008). LncRNA HOTAIR overexpression increased breast cancer cell proliferation and contributed to tamoxifen resistance in breast cancer (Xue et al., 2016). We summarized the lncRNAs involved in resistance of EC therapy (Table 5).
TABLE 5. LncRNAs and drugs resistance/radioresistance in EC.
MALAT1 is a potential prognostic biomarker for EC. Knockdown of MALAT1 could enhance the radiosensitivity and chemosensitivity of ESCC cells (Yao et al., 2019). And MALAT1 overexpression inhibited the viability decrease and apoptosis increase of EC cells which were induced by irradiation (Li et al., 2017).
H19 is an oncogenic lncRNA and takes part in the tumorigenesis and progression of EC (Huang et al., 2015). Radioresistance is a main factor limiting the efficacy of radiotherapy for EC. H19 was upregulated in an ESCC radioresistant cell line. And H19 knockdown downregulated Wnt1 through upregulating miR-22-3p expression, then resulted in the inhibition of radioresistance, proliferation and migration in radioresistant ESCC cell (Luo et al., 2019).
Prostate cancer associated transcripts 1 (PCAT-1) was first discovered in patients with prostate cancer by transcript sequencing and was identified as a transcriptional repressor (Prensner et al., 2011). LncRNA PCAT-1 is up-regulated and could play an oncogenic role in multiple cancers, such as prostate cancer, ESCC, gastric cancer, ovarian cancer (Prensner et al., 2011; Shi et al., 2015; Bi et al., 2017; Ding et al., 2019). PCAT-1 expression is remarkably increased in ESCC tissues, which is significantly related to tumor invasion (Shi et al., 2015; Razavi and Ghorbian, 2019). And it was found that PCAT-1 facilitated ESCC progression by PCAT-1/miR-508-3p/ANXA10 axis in cell experiments (Zang et al., 2019). When PCAT-1 was inhibited, the chemosensitivity of EC to cisplatin was increased (Zhen et al., 2018).
Taurine up-regulated gene 1 (TUG1) is a lncRNA which is abnormally expressed in various tumors (Da et al., 2021). It was found that TUG1 could function as ceRNA to specifically sponging microRNAs to regulate gene expression and was involved in oncogenesis and development of many malignant tumors, such as gastric cancer (Ren et al., 2017), osteosarcoma (Sheng and Li, 2019). And TUG1 could regulate resistance and sensitivity of some cancers to chemotherapeutic drugs, such as bladder cancer (Yu et al., 2019), cervical cancer (Wei et al., 2019) and EC. TUG1, as an oncogenic lncRNA in EC, is significantly upregulated in EC and promotes EC development (Jin et al., 2020; Tang et al., 2020; Zong et al., 2020). TUG1 is also related to radiotherapy resistance and chemotherapy resistance of ESCC. Patients with high TUG1 expression displayed more resistance to chemotherapy (platinum-based chemotherapy combined with paclitaxel or 5-fluo-rouracil) compared with low TUG1 expression group (Jiang et al., 2016). Mechanically, TUG1 can promote cisplatin resistance in ESCC through upregulating Nrf2 or epigenetically suppressing PDCD4 expression via EZH2 (Xu et al., 2018a; Zhang et al., 2019c). In addition, TUG1 can increase radiotherapy resistance of ESCC by reducing miR-144-3p and regulating MET/EGFR/AKT axis (Wang et al., 2020).
Notably, lncRNA POU3F3 was reported to promote ESCC cell proliferation and cisplatin resistance through exosomal POU3F3-induced transformation of normal fibroblasts to cancer-associated fibroblasts in ESCC (Tong et al., 2020). However, studies about exosomal lncRNAs and chemoresistance are relatively scarce, especially those about the association between lncRNAs and multidrug resistance in EC.
In summary, recent advances have found that many lncRNAs participate in the drug resistance of EC. However, the exact role of lncRNAs is unclear in the entire regulatory network of drug resistance, and exploring the underlying mechanism will help us to reverse drug resistance of EC via using lncRNA-targeting strategy.
5 Conclusion and Future Perspectives
With the high-speed development of high-throughput sequencing technology, Genome Map and bioinformatics, a great deal of lncRNAs have been discovered. LncRNA is involved in various processes such as epigenetic regulation, chromatin remodeling and gene expression regulation (Shi et al., 2013; Beermann et al., 2016; Quinn and Chang, 2016). Many human diseases, including cancers, are related to the dysregulation of lncRNA (Bhan et al., 2017; Chi et al., 2019). Increasing evidence indicates that lncRNAs are involved in regulating the carcinogenesis and progression of EC. Importantly, these dyregulated lncRNAs may be useful for the early diagnosis, prognosis, and treatment of EC.
Nowadays, the researches of lncRNA mainly focus on several aspects: identification and classification of lncRNA; the interaction between lncRNA and other factors; the roles of lncRNA in major diseases; the potential of lncRNA as biomarkers and drug targets of diseases. The role of lncRNA in cancers is a hotspot. In this paper, we mainly summarized the biological functions and molecular mechanisms of lncRNAs. At the same time, we reviewed the main oncogenic lncRNAs and suppressive lncRNAs in EC, and lncRNAs related to EC diagnosis, treatment, and prognosis. The previous studies have shown that lncRNAs play important roles in the occurrence and development of EC and hold much promise as novel biomarkers and therapeutic targets for EC.
However, the research on lncRNAs in EC is still in initial phase and faced with a number of challenges especially in clinical application. Moreover, several novel mechanisms of lncRNAs in EC should be focused on in the future. Currently, despite the dysregulated lncRNAs seem to be important in the tumorigenesis or progression, there are still some questions required to be answered by further studies before their clinical translation. First, although multiple screening wet methods (microarrays, next-generation sequencing and qRT-PCR) have been used to identify the cancer-associated lncRNAs, more effective bioinformatics tools need to be developed. OSescc for identifying the prognosis-related genes in ESCC patients (Wang et al., 2019d), have been developed in recent years, however available clinical lncRNA testing method has not been seen to now. Second, how do lncRNAs co-regulate with other functional molecules (such as miRNAs, circRNAs, proteins) in the pathogenesis of EC? For example, the disordered regulatory networks of lncRNAs-miRNAs-mRNAs can induce the occurrence and development of EC (Karreth and Pandolfi, 2013). Third, the small peptides encoded by ncRNAs have been recurrently reported (Wang et al., 2019c). It will be very interesting to explore whether these lncRNAs encode small peptides, which is the direct regulator for malignant behaviors of EC.
In addition, increasing evidences showed that EC-derived exosomes may be useful for the early detection of EC. RNA sequencing revealed that dysregulated exosomal lncRNAs are associated with early-stage ESCC (Tian et al., 2020). Some lncRNA-based signature shows the higher efficiency of the prognosis of EC. Liu et al. (2020b) reported a toll-like receptor (TLR)-related four-lncRNA signature as a prognostic biomarker in EC. Moreover, several effective machine learning methods have been developed to identify and predict lncRNAs in various organisms (Xu et al., 2021c). For instance, Liu et al. (2022) constructed an immune-associated lncRNA signature to predict the clinical outcome of colorectal cancer patients based on machine learning-based methods. Zhang et al. (2018c) constructed the CRlncRC, a machine learning-based method for identifying the cancer-related lncRNAs. Therefore, the application of machine learning-based lncRNAs in the diagnosis of EC will be interesting.
In brief, lncRNAs might be promising biomarkers or therapeutic targets for clinical application for EC after in-depth basic and clinical investigations.
Author Contributions
Conceptualization, YH and XG. Writing—original draft preparation, YH, GZ, XS, and XW. Writing—review and editing, YH, GZ, YW, LZ, and XG. Funding acquisition, YH and XG. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by the National Natural Science Foundation of China (No. U2004136), supporting program for Central Plain Young Top Talents (No. ZYQR201912176), supporting grant of Henan University (Nos. 2018YLJC01, 2019YLXKJC01 and 2020YLZDYJ14), program for Science and Technology Development in Henan Province (Nos. 212102310158 and 212102310709), Program from Academy for advanced interdisciplinary studies of Henan University (No. Y21008L).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Keywords: long non-coding RNAs, esophageal cancer, biological function, clinical application, cancer therapy
Citation: Han Y, Zhao G, Shi X, Wang Y, Wen X, Zhang L and Guo X (2022) The Emerging Role of Long Non-Coding RNAs in Esophageal Cancer: Functions in Tumorigenesis and Clinical Implications. Front. Pharmacol. 13:885075. doi: 10.3389/fphar.2022.885075
Received: 27 February 2022; Accepted: 12 April 2022;
Published: 13 May 2022.
Edited by:
Nicola Amodio, Magna Græcia University, ItalyReviewed by:
Marco Bocchetti, University of Campania Luigi Vanvitelli, ItalyPrashanth N. Suravajhala, Amrita Vishwa Vidyapeetham University, India
Copyright © 2022 Han, Zhao, Shi, Wang, Wen, Zhang and Guo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Xiangqian Guo, eHFndW9AaGVudS5lZHUuY24=
†These authors have contributed equally to this work