Abstract
Gastric cancer (GC) is one of the most common cancers globally. Because of the high frequency of tumor recurrence, or metastasis, after surgical resection, the prognosis of patients with GC is poor. Therefore, exploring the mechanisms underlying GC is of great importance. Recently, accumulating evidence has begun to show that dysregulated long non-coding RNAs (lncRNAs) participate in the progression of GC via several typical signaling pathways, such as the AKT and MAPK signaling pathways. Moreover, the interactions between lncRNAs and microRNAs appear to represent a novel mechanism in the pathogenesis of GC. This review provides a synopsis of the latest research relating to lncRNAs and associated signaling pathways in GC.
Introduction
Gastric cancer (GC) is one of the world’s most common cancers [1]. Although the incidence of GC is generally decreasing, population growth and ageing still have led to a rising number of new cases in 2015 [2]. Moreover, most GC cases are diagnosed at advanced stages, with a consequential poor outcome, and therapeutic strategies are mostly restricted to either radiotherapy or chemotherapy. As a result, GC is still associated with a high mortality rate [3]. Consequently, identifying new and specific biomarkers of GC is becoming increasingly important.
Only 2% of the human genome is known to code for proteins. The remainder of the genome consists of non-coding RNAs (ncRNAs), which play a crucial role in various cellular and physiological functions [4]. An increasing volume of data now demonstrates that the dysregulation of ncRNAs is involved in a variety of human cancers, including GC. Furthermore, long non-coding RNAs (lncRNAs) are a newly emerging form of ncRNAs, which play an important role in a range of biological functions. Accumulating evidence now supports the fact that lncRNAs regulate the progression of GC and may be associated with specific signaling pathways; the expression of these lncRNAs indicates the presence of an active signaling event. This review aims to summarize our current understanding of the role of lncRNAs in the progression of GC and the signaling pathways involved [4].
The involvement of lncRNAs in gastric cancer
General characteristics of lncRNAs
lncRNAs represent a new class of ncRNAs, which are >200 nt in molecular size [5]. The lncRNA genomic locations and roles have been studied, and thus, lncRNAs can be classified into five categories: (a) sense lncRNAs that overlap with the sense strand of the protein-coding sequence; (b) antisense lncRNAs, which are transcribed in the opposite direction of protein-coding genes; (c) bidirectional lncRNAs that are reverse transcribed from the promoter region of the protein-coding gene; (d) intergenic lncRNAs also termed large intervening non-coding RNAs (linc-RNAs), which are not adjacent to any protein-coding gene and are derived from the intergenic region of two protein-coding genes; and (e) intronic lncRNAs that initiate inside of an intron of a protein-coding gene in either direction and terminate without overlapping exons [6, 7]. For instance, lncRNAs can combine with proteins, or DNA, and regulate their expression, or bind with promoter regions to regulate downstream genes at the epigenetic, transcriptional and posttranscriptional levels (Figure 1) [8], [9], [10]. Furthermore, over recent years, a growing number of research studies have indicated that lncRNAs are involved in a range of human diseases, including cardiovascular disease [11] and Alzheimer’s disease [12, 13]. In addition, lncRNAs are known to participate in cancerous processes, including GC. Accumulating evidence now suggests that lncRNAs exert effects on cell proliferation, invasion and metastasis and can also regulate drug resistance and stem cell formation [4], [5], [14] (Table 1).
The classification of lncRNAs.
(A) Sense lncRNAs: overlap with the sense strand of the protein-coding sequence; (B) antisense lncRNAs: transcribed in the opposite direction of protein-coding genes; (C) bidirectional lncRNAs: reverse transcribed from the promoter region of the protein-coding gene; (D) intergenic lncRNAs: derived from the intergenic region of two protein-coding genes; (E) intronic lncRNAs: transcribed from inside of an intron of a protein-coding gene.
Dysregulated lncRNAs in gastric cancer progression.
| lncRNA | Expression | Target | Process in GC | References |
|---|---|---|---|---|
| HNF1A-AS1 | Downregulated | – | Biomarker | [15] |
| H19 | Upregulated | – | Biomarker | [16], [17] |
| Upregulated | p53 | Cell proliferation | [18] | |
| Linc00152 | Upregulated | – | Biomarker | [17] |
| FEZF1-AS1 | Upregulated | p21 | Cell proliferation | [19] |
| XIAP-AS1 | Upregulated | XIAP | Cell proliferation | [20] |
| PVT1 | Upregulated | p15, p16 | Cell proliferation | [21] |
| CASC15 | Upregulated | – | Cell proliferation | [22] |
| GAS5 | Downregulated | E2F1, p21 | Cell proliferation, apoptosis | [23] |
| MALAT1 | Upregulated | EZH2, PCDH10, MMPs, EMT-associated genes | Metastasis, VM, angiogenesis, EMT | [24], [25], [26] |
| CASC2 | Downregulated | – | Metastasis, angiogenesis | [27] |
| NEAT1 | Upregulated | EMT-associated genes | Metastasis, EMT | [28] |
| UCA1 | Upregulated | EMT-associated genes | Metastasis, EMT | [29] |
| SNHG6 | Upregulated | p27 | Metastasis, EMT | [30] |
| HULC | Upregulated | EMT-associated genes | Metastasis, EMT | [31] |
| MRUL | Upregulated | ABCB1, P-gp | MDR | [32] |
| ANRIL | Upregulated | MDR1, MRP1 | MDR | [33] |
| ROR | Upregulated | OCT4, SOX2 | Stemness | [34] |
–, not mentioned.
The identification of lncRNAs in GC
RNA sequencing and microarrays were first used to screen for aberrantly expressed lncRNAs in GC, and then dysregulated lncRNAs were verified with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Bioinformaticsanalysis has also been used to predict enriched pathways and potential target genes of abnormally expressed lncRNAs [14]. For example, Song et al. reported 135 differentially expressed lncRNAs using an lncRNA microarray; H19, HMlincRNA717 and BM709340 were the most upregulated, whereas FER1L4, uc001lsz and uc009ycs were downregulated. The differential expression of H19 and uc001lsz was confirmed with qRT-PCR; H19 was suggested to be involved in GC processes, whereas uc0011sz was expressed at low levels and associated with TNM stage. The dysregulation of uc0011sz in the early stages of cancer, and in precancerous lesions, suggested that uc001lsz may represent a potential marker for the diagnosis of early GC [35]. In another study, Gu et al. used high-throughput sequencing to identify the expression profiles of lncRNAs and messenger RNAs (mRNAs) in three stomach adenocarcinoma tissues and three matched adjacent non-tumor tissues; 74 lncRNAs and 449 mRNAs were shown to be differentially expressed at statistically significant levels. Several lncRNAs, such as H19, HOX transcript antisense RNA (HOTAIR) and FEZF1 antisense RNA 1 (FEZF1-AS1) were identified to be differentially expressed using qRT-PCR; most of the differentially expressed lncRNAs (DElncRNAs) were linked to at least a twofold change in expression in stomach adenocarcinoma compared to adjacent non-tumor tissues. LOC105377924 was the most upregulated DElncRNA, whereas SEMA3B-AS1 was markedly decreased. Linc01105 was the DElncRNA, which was most commonly associated with mRNAs in the coexpression network. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were then adopted to analyze the enriched pathways and potential functions of DEmRNAs coexpressed with DElncRNAs, and these analyses may be the foundation for future investigation and provide novel potential diagnosis or therapeutic targets [36].
The involvement of lncRNAs in GC
Increasing evidence now suggests that lncRNAs play a key role in GC tumorigenesis and cancer progression. Various lncRNAs have been reported as potential biomarkers or have been identified as playing important roles in diagnosis and therapy. Next, we provide examples of some of the lncRNAs, which participate in GC.
lncRNAs function as biomarker in GC
In recent years, a series of convincing studies proved that lncRNAs could function as hallmarks in neoplastic diseases including GC [5]. Yuan et al. reported that lncRNA HNF1A-AS1 was lowly expressed in GC, and its expression level was associated with tumor size and invasion; further, several immunohistochemical features and tumor markers were analyzed to be related to HNF1A-AS1 expression like RRM1, CEA and CA19-9. HNF1A-AS1 may have the potential to serve as a novel treatment target and biomarker for GC [15]. Other studies demonstratedthat several lncRNAs such as H19, Linc00152, which can be detected in the serum samples and the expression levels, may be associated with clinicopathological features. These lncRNAs may be a potential biomarker for GC diagnosis and clinical prognosis evaluation [16, 17]. Accumulating evidence showed that lncRNAs not only act as potential biomarkers but also can participate in GC progression. Herein, we provide a synopsis of several lncRNAs, which have been confirmed to play crucial roles in the progression of GC.
lncRNAs in the regulation of biological functions in GC
lncRNAs involved in GC cell proliferation and apoptosis
H19 is a 2.3-kb ncRNA that is conserved on human chromosome 11p15 and acts as an oncogene in cancer. H19 is actively involved in all stages of tumorigenesis and is expressed in almost every human cancer [37, 38]. Yang et al. were the first to report that lncRNA H19 was significantly upregulated in GC, and that H19 increased cell proliferation and inhibited apoptosis via interacting with p53, a known suppressor, which resulted in the inactivation of p53. These data confirmed that upregulation of H19 expression contributed to tumorigenesis by regulating p53 activation [18].
Another study demonstrated that lncRNA FEZF1-AS1 induced by SP1 was overexpressed in GC. FEZF1-AS1 inhibited p21 transcription via recruiting LSD1, causing H3K4me2 demethylation at the p21 promoter and contributing to cell proliferation by arresting cell cycle progression [19]. A recent study showed that lncRNA XIAP-AS1 was highly expressed in GC tissues and cells, and that XIAP-AS1 bound with the XIAP gene to enhance XIAP transcription; knockdown of XIAP-AS1 promoted tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis in gastric tumor cells and reduced cell proliferation [20]. Studies have shown that other lncRNAs, such as PVT1 and CASC15, were all upregulated in GC and could promote cell proliferation in GC [21, 22].
There are also many cancer suppressors, such as growth arrest specific 5 (GAS5), which are reported to inhibit cell growth and promote apoptosis via regulating E2F1 and p21 expression. The authors found that patients with low GAS5 expression levels had poorer prognoses than those with high GAS5 expression [23]. All of these molecules could represent new targets for the diagnosis and therapy of GC.
lncRNAs related to GC invasion and metastasis
GC is known as a malignant tumor, and it could continuously grow in situ and disseminate to distant tissues through the blood vessels and lymphatic system [39]. Metastasis is an important element of GC and leads to a high mortality rate and a poor prognosis, and metastasis of GC has a complex progression pattern [5]. Accumulating evidence shows that lncRNAs participate in tumor metastasis by modulating interactive genes. Qi et al. identified enhancer of zeste homolog 2 (EZH2)-associated RNAs and found that metastasis associated lung adenocarcinoma transcript 1 (MALAT-1) only interacted with EZH2 in the metastatic cell line, MKN45. This interaction was absent in other GC cell lines, suggesting a probable role in GC metastasis. These authors also demonstrated that MALAT1 recruited EZH2 to the protocadherin 10 (PCDH10) promoter regions and inhibited its transcription, and that MALAT1 contributed to GC metastasis. Furthermore, the authors examined the prognostic value of MALAT1 in GC patients, and the results showed that highly expressed MALAT1 was associated with poor prognosis [24]. A recent report also showed that MALAT1 promoted vasculogenic mimicry (VM) and angiogenesis in GC. MALAT1 has also been shown to regulate the expression of matrix metalloproteinase 2 and 9 (MMP2 and 9), MT1-MMP, VE-cadherin, β-catenin, p-ERK, p-FAK and p-paxillin, which have all been established as classical markers of VM and angiogenesis. MALAT1 is known to promote VM via the ERK/MMP and FAK/paxillin signaling pathways [25]. Recent studies have also shown that lncRNA cancer susceptibility 2 (CASC2) was downregulated in GC, and low expression levels of CASC2 were associated with poorer survival. Overexpression of CASC2 inhibited cell invasion and angiogenesis [27].
Epithelial-to-mesenchymal transition (EMT), a process that endows epithelial tumor cells with mesenchymal properties, including reduced adhesion and increased motility, is considered to be a significant step driving the early phases of cancer metastasis [40]. Fu et al. reported that the lncRNA, nuclear paraspeckle assembly transcript 1 (NEAT1), is overexpressed in GC and associated with both lymph node metastasis and distant metastasis. These authors also found that NEAT1 promoted cell proliferation, invasion and migration, and also regulated EMT-associated genes, such as mesenchymal marker genes, vimentin and N-cadherin, the expressions of which were reduced. On the other hand, epithelial marker genes, including Zo-1 and E-cadherin, were expressed at higher levels and the knockdown of NEAT1 was shown to inhibit the EMT process. Patients with prognostic information showed that the expression levels of NEAT1 were correlated with overall survival of GC patients, and high expression levels of NEAT1 were related to malignant status and poor prognosis [28].
Other lncRNAs, such as MALAT1, urothelial cancer associated 1 (UCA1), SNHG6 and HULC, can also regulate the EMT-related factors in GC cells and modulate the progression of EMT. These lncRNAs related to invasion and metastasis are also associated with poor prognosis and malignant status [26], [29], [30], [31]. The utility of lncRNAs for GC prognosis monitoring and as therapeutic targets requires further exploration.
lncRNAs in the regulation of drug resistance and stemness in GC
Drug resistance and stem cell formation can cause drug treatments to fail and lead to the recurrence of cancer and death [8]. lncRNAs are also reported to regulate the mechanisms underlying GC drug resistance or stem cell formation. For example, Wang et al. found that lncRNA MRUL was upregulated in two multidrug-resistant GC cell sublines and that the reduction of MRUL could reduce the mRNA levels of ATP-binding cassette, subfamily B, member 1 (ABCB1). Moreover, P-glycoprotein (P-gp) is reported to be associated with multidrug resistance (MDR), and the reduction of MRUL leads to the inhibition of multidrug-resistant GC cell growth and a reduction of P-gp expression. In other words, the lncRNA MRUL may represent a target for chemotherapy in GC [32]. Another lncRNA, CDKN2B antisense RNA 1 (ANRIL), is reported to be related with MDR in GC. ANRIL was shown to be upregulated in both 5-fluorouracil (5-FU)-resistant cells and cisplatin-resistant cells, andsilencing ANRIL reduced the expression of MDR1 and multidrug resistance protein 1 (MRP1), both of which are MDR-related genes [33]. Wang et al. further found that gastric cancer stem cells (GCSCs) from MKN-45 cells, and lncRNA ROR, were highly expressed in CD133+ GCSCs, and that lncRNA ROR can upregulate stemness transcriptional factors, such as octamer-binding transcription factor 4 (OCT4), sex determining region Y-box 2 (SOX2) and nanog homeobox (NANOG). lncRNA ROR was also associated with core stemness transcriptional factors and the pluripotent state of GCSCs [34]. Consequently, these different lncRNAs play crucial roles, in different parts of the associated pathways, to participate in the progression of GC.
lncRNAs targeting signaling pathways in GC
Increasing evidence has identified that various lncRNAs play important roles in GC progression, including cell proliferation, invasion, migration, apoptosis, metastasis and other biological functions. Usually, these molecules modulate tumor progression by targeting certain genes in a variety of different signal pathways [8] (Table 2).
lncRNAs involved in signaling pathways in gastric cancer.
| lncRNA | Expression | Target | Signaling pathway | References |
|---|---|---|---|---|
| linc00152 | Upregulated | EGFR | PI3K/AKT pathway | [41] |
| AFAP1-AS1 | Upregulated | PTEN | PTEN/p-AKT pathway | [42] |
| HOTAIR | Upregulated | VEGFA, PIK3R2 | PI3K/AKT/MRP1 pathway | [43] |
| AK023391 | Upregulated | FOXO | PI3K/AKT pathway | [44] |
| UCA1 | Upregulated | EZH2 | AKT/GSK-3B/cyclin D1 axis | [45] |
| GAS5 | Downregulated | PTEN | PTEN/Akt/mTOR pathway | [46] |
| YBX1 | GAS5/YBX1/p21 pathway | [47] | ||
| H19 | Upregulated | RUNX1 | PTEN/Akt/mTOR pathway | [48] |
| HAGLROS | Upregulated | mTORC 1 | mTOR pathway | [49] |
| CCAT2 | Upregulated | – | PI3K/mTOR pathway | [50] |
| CASC2 | Upregulated | ERK1/2, JNK | MAPK signaling pathway | [51] |
| CARLo-5 | Upregulated | ERK, MAPK | ERK/MAPK pathway | [52] |
| MALAT1 | Upregulated | JMJD1A | JMJD1A-MALAT1-MAPK signaling pathway | [53] |
| GACAT3 | Upregulated | STAT3 | IL-6/STAT3 signaling pathway | [54] |
| HOXD-AS1 | Upregulated | JAK2, STAT3 | JAK2/STAT3 signaling pathway | [55] |
| AK058003 | Upregulated | SNCG | Hypoxia/lncRNA-AK058003/SNCG pathway | [56] |
| AK123072 | Upregulated | EGFR | hypoxia/lncRNA-AK123072/EGFR pathway | [57] |
| POU3F3 | Upregulated | TGF-β | TGF-β signal pathway | [58] |
| HOTAIR | Upregulated | C Met/Snail | HGF/C Met/Snail pathway | [59] |
| FEZF1-AS1 | Upregulated | – | Wnt/β-catenin signal pathway | [60] |
| ZFAS1 | Upregulated | – | Wnt/β-catenin signal pathway | [61] |
| EGOT | Upregulated | – | Hedgehog pathway | [62] |
| BANCR | Upregulated | NF-kB1 | NF-kB1 pathway | [63] |
–, not mentioned.
The AKT signaling pathway
Protein kinase B is also known as AKT. The AKT signaling pathway has been shown to modulate the molecular mechanisms underlying a variety of cancers and represents an essential pathway in tumor progression, including cell proliferation, metastasis, drug resistance, and other biological functions. Moreover, lncRNAs can affect tumor progression by altering the relative expression of key genes in the AKT pathway. The most well-known genes play pivotalrolesin the phosphoinositide 3-kinase (PI3K) and phosphatase and tensin homolog (PTEN) pathways [64, 65]. The following section summarizes a number of lncRNAs associated with GC, which may be associated with the AKT pathway.
Linc00152 has been reported to be related to tumorigenesis and GC progression. This molecule can modulate cell proliferation and cell cycle arrest; studies have also shown that linc00152 knockdown may suppress cell invasion and EMT [66]. Zhou et al. determined that linc00152 binds with the epidermal growth factor receptor (EGFR) to regulate EGFR activity. It is well known that EGFR can regulate cell proliferation through the PI3K/AKT pathway. Linc00152 shRNA could inhibit the protein levels of p-AKT, p-PI3K and p-EGFR both in vitro and in vivo. As a result, linc00152 is able to regulate GC progression through the PI3K/AKT pathway [41].
lncRNA is reported to act as an oncogene, is upregulated in GC cells and tissues and can contribute to cell cycle arrest. The knockdown of AFAP1-AS1 also increased levels of cycle related proteins such as caspase3, caspase9, as well as PTEN. Furthermore, levels of p-AKT and Bcl-2 are increased when transfected with si-AFAP1-AS1. Therefore, the lncRNA, AFAP1-AS1, was shown to regulate GC cell proliferation and apoptosis via the PTEN/p-AKT signaling pathway [42].
The lncRNA HOTAIR, UCA1, can regulate cisplatin resistance by activating the PI3K/AKT pathway. Recent studies have reported that lncRNA AK023391 also regulated the AKT pathway, and AK023391 acted as a key mediator of the PI3K/AKT pathway and its downstream FOXO, NF-κB and p53 pathways were involved in the regulation of AK023391 in GC tumorigenesis. In other words, the AKT pathway plays an important role in the tumorigenesis and metastasis of GC [43], [44], [45].
The mTOR signaling pathway
Mammalian target of rapamycin (mTOR) is the central regulator of cell nutrition induction and growth, including mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which regulate cell survival and proliferation in human cancers, including GC [67, 68].
lncRNA GAS5 is known as a suppressor of GC, and overexpressed GAS5 suppressed cell proliferation by targeting PTEN through the Akt/mTOR signaling pathway, whereas lncRNA H19 was upregulated in GC and modulated tumorigenesis via the PTEN/Akt/mTOR pathway [46], [48].
Autophagy is a process of engulfing and encapsulating damaged proteins or organelles into vesicles that fuse with lysosomes to form autophagy lysosomes, which degrade their contents [69], [70]. Studies have shown that lncRNAs regulated autophagy via different pathways, including the mTOR pathway. The mTOR pathway also plays an important role in regulating autophagy [71]. Chen et al. have reported that a novel lncRNA, HAGLROS, contributes to GC malignant progression via interacting with mTORC1 through mTOR pathway-mediated autophagy suppression [49]. Another study demonstrated that silencing lncRNA, CCAT2, induced apoptosis and autophagy in GC cells by inhibiting the PI3K/mTOR signaling pathway [50].
The MAPK signaling pathway
It is generally known that the mitogen-activated protein kinase (MAPK) signaling pathway plays a key role in many cell proliferation-related signaling pathways and is shared by four different cascades, which are associated with key components: extracellular signal-related kinases (ERK1/2), Jun amino terminal kinases (JNK1/2/3), p38-MAPK and ERK5 [72]. Of these, the MAPK/ERK pathway is reported to be associated with cell proliferation, differentiation, migration, senescence and apoptosis [73], [74].
The lncRNA, CASC2, is known to be downregulated in GC and can inhibit cell growth both in vitro and in vivo. Furthermore, CASC2 can regulate ERK1/2 and JNK, which are related to the MAPK signaling pathway. Research has shown that overexpressing of CASC2, combined with the suppression of ERK1/2 or JNK, can inhibit cell proliferation by inactivating the MAPK pathway [51].
Another report confirmed that the lncRNA, CARLo-5, was highly expressed in GC and regulated cell growth. The knockdown of CARLo-5 reduced the levels of MAPK and p-ERK. CARLo-5 also acted as an oncogene to promote cell proliferation and activated the ERK/MAPK signaling pathway [52]. There are also reports that Jumonji domain-containing protein 1A (JMJD1A) induces GC progression and that JMJD1A-MALAT1-MAPK signaling may participate in this process [53].
The STAT3 signaling pathway
The signal transducer and activator of transcription 3 (STAT3) signaling pathway is activated in a variety of tumor cells. Blocking or inhibiting the STAT3 signaling pathway in tumor cells can inhibit cell proliferation and survival and induce apoptosis. For example, Shen et al. reported that lncRNA GACAT3 (AC130710) was upregulated in GC and promoted cell proliferation by supporting the expression of cyclin D. Furthermore, GACAT3 and STAT3 have both been associated with inflammation. STAT3 was also shown to be activated by interleukin-6 (IL-6), whereas GACAT3 was shown to be directly activated by the STAT3 signaling pathway [54]. In addition, HOXD-AS1 is able to regulate the Janus kinase 2 (JAK2)/STAT3 pathway, which can inactivate the JAK2/STAT3 pathway both in vitro and in vivo to promote cell growth [55].
Hypoxia induced pathway
Increasing evidence shows that hypoxia plays a crucial role in the progression of cancer. It has been reported that lncRNA AK058003 is associated with hypoxia-induced GC cell metastasis. lncRNA AK058003 is upregulated in GC and regulates GC invasion and migration, as well as a metastasis-related gene γ-synuclein (SNGG). AK058003 can act as a regulator of hypoxia signaling, and the hypoxia/AK058003/SNGG pathway is known to contribute to hypoxia-induced GC therapy [56]. AK123072 is also a hypoxia-related lncRNA, which is upregulated by hypoxia and has been identified as a key factor in the hypoxia/lncRNA-AK123072/EGFR pathway in the pathogenesis of GC [57].
Other signaling pathways in GC
There are a many signaling pathways involved in cancer, and there are also many lncRNAs related to these signaling pathways. For example, Linc POU3F3 was reported to be upregulated in GC and promoted the distribution of Tregs via the TGF-β signaling pathway [58]. Other lncRNAs, such as lncRNA GAS5, are downregulated in GC, and it has been reported that GAS5 reduced the levels of Y-Box Binding Protein 1 (YBX1) protein and reduced p21 expression; consequently, the GAS5/YBX1/p21 pathway represents a target for GC [47]. Liu et al. also reported that HOTAIR regulated cell migration, invasion and metastasis and bound with polycomb repressive complex 2 (PRC2) and suppressed mir-34a by targeting C-met and snail through the HGF/C Met/Snail pathway [59]. Moreover, FEZF1-AS1 and ZFAS1 contribute to GC development via activation of the Wnt/β-catenin signaling pathway, and knockdown of EGOT might inhibit Hedgehog signaling pathway in GC cells [60], [61], [62]. Furthermore, lncRNA BANCR can regulate cell growth and apoptosis by regulating NF-κB1 [63].
Interactions between lncRNAs and microRNAs (miRNAs) in GC
miRNAs and lncRNAs are two important classes of ncRNAs. Recent studies have shown that lncRNAs exert their biological function through a variety of mechanisms, and accumulating evidence suggests that lncRNAs can interact with miRNAs to regulate gene expression. The following section describes some of the main lncRNAs, which are known to interact with miRNAs that can affect the occurrence and development of GC (Table 3).
lncRNA-miRNA interactions in gastric cancer.
| lncRNA | Expression | miRNA | Expression | Target | References |
|---|---|---|---|---|---|
| Linc01410 | Upregulated | miR-532-5p | Downregulated | NCF2 | [75] |
| TINCR | Upregulated | miR-375 | Downregulated | PDK1 | [76] |
| MALAT1 | Upregulated | miR-23b-3p | Downregulated | ATG12 | [69] |
| Linc01234 | Upregulated | miR-204-5p | Downregulated | CBFB | [77] |
| KRTAP5-AS1 | Upregulated | miR-596/miR-3620-3p | Downregulated | CLDN4 | [78] |
| TUBB2A | Upregulated | miR-3620-3p | Downregulated | ||
| SMARCC2 | Upregulated | miR-551b-3p | Downregulated | TMPRSS4 | [79] |
| H19 | Upregulated | miR-675 | Upregulated | FADD/RUN1 | [80], [81] |
| MEG3 | Downregulated | miR-141 | Downregulated | E2F3 | [82] |
Recent studies have shown that lncRNAs can act as competitive endogenous RNAs (ceRNAs), which can regulate the expression of miRNAs. For example, Linc01410 was reported to promote GC angiogenesis and metastasis by binding to and suppressing miR-532-5p and significantly enhancing neutrophil cytosolic factor 2 (NCF2) via activating the NF-κB pathway. NCF2 could, in turn, increase the promoter activity and expression of LINC01410 via NF-κB, thus forming a positive feedback loop that drives the malignant behavior of GC [75]. Recent reports also show that TINCR plays a critical role in GC cell proliferation and metastasis. TINCR has been shown to increase the expression of pyruvate dehydrogenase lipoamide kinase isozyme 1 (PDK1) via sponging miR-375 [76]. YiRen et al. have reported that MALAT1 competitively sequesters miR-23b-3p; therefore, the inhibitory effect on ATG12 of miR-23b-3p is relieved. MALAT1 promotes GC cell proliferation and contributes to autophagy-mediated chemoresistance [69]. Linc01234 was also found to promote GC cell proliferation and inhibited cell apoptosis via functioning as a ceRNA for miR-204-5p [77]. Another report showed that lncRNA KRTAP5-AS1 acted as a ceRNA through binding with miR-596 and miR-3620-3p, and lncRNA TUBB2A influenced tumor progression through directly binding to miR-3620-3p. Furthermore, miR-596 and miR-3620-3p interacted with Claudin-4 (CLDN4), which contributed to GC invasion and proliferation [78]. Recently, Yuan et al. found that lncRNA SMARCC2 inhibits miR-551b-3p via binding to its mRNA response elements in GC and SMARCC2-regulated miR-551b-3p expression, and lncRNA SMARCC2/miR-551b-3p/TMPRSS4 axis was an important regulation mechanism in GC [79].
In addition, interaction between lncRNAs and miRNAs is not only a ceRNA mechanism but is also indicated in other actions. MiR-675 is reported to be embedded in the H19 first exon [83]. H19 binds directly with miR-675 to act as an oncogene and promotes cell proliferation and suppresses apoptosis by targeting Fas-associated protein with death domain (FADD), which is involved in the caspase signaling pathway; knockdown of H19 and miR-675 inhibits these functions. As a result, the H19/miR-675 caspase signaling pathway may represent a potential target for GC. H19-miR-675-RUN1 also forms a feedback loop to enhance cell proliferation and invasion in GC [80], [81]. Another report showed that miR-141 and MEG3 were both downregulated in GC and that they were positively correlated. The overexpression of miR-141 or MEG3 inhibited cell proliferation. Moreover, miR-141 can interact with MEG3 and target E2F transcription factor 3 (E2F3) to suppress GC cell growth [82]. Therefore, the lncRNA-miRNA-mRNA axis represents a novel pathway for modulating the progression of GC.
Conclusions
Evidence has been increasing recently to suggest that lncRNAs are involved in GC by acting as regulators at the transcriptional or posttranscriptional level. lncRNAs are known to modulate cell proliferation, invasion, migration, metastasis and other biological functions by targeting downstream genes via different signaling pathways. This review summarized the dysregulation of lncRNAs in GC progression and the signaling pathways associated with the pathogenesis of GC.
Studies indicate that lncRNAs represent biological markers of GC and that their involvement in signaling pathways may provide novel targets for the diagnosis and treatment of GC. Moreover, the interactions between lncRNAs and miRNAs provide a new mechanism for GC progression. With continuing research on the interactions between lncRNAs and lncRNA-miRNA, more signaling pathways will be identified in GC. Collectively, such research will provide novel biomarkers for the diagnosis and prognosis of GC, and new targets will be identified for GC treatment.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This study was supported by the National Nature Science Foundation (grant nos. 81201349 and 81000775); the young medical key talents in Jiangsu province (grant nos. QNRC 2016686 and 2016687); the frontier and key technical innovation projects of Nantong (grant no. MS22015049); and the Nantong Science and Technology Plan Project (MS12017008-3).
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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