An increasing number of lncRNAs have been identified as regulators that play a significant role in the regulation of DNA methylation in GC (Table
2). For example, promyelocytic leukemia zinc finger (PLZF), primarily confirmed as a gene fused to RARa in acute promyelocytic leukemia patients and functioned as a tumor suppressor, has been demonstrated that it wasn’t only involved in hematological malignancies but in various solid tumors, such as hepatocellular carcinoma, pancreatic and lung cancer, thyroid carcinoma, prostate, and gallbladder cancer, encompassing the multistep of cancer development including proliferation, invasiveness, motility, and resistance to apoptosis [
77‐
87]. ANRIL (CDKN2B antisense RNA 1), a long non-coding RNA associated with coronary disease, intracranial aneurysm, type 2 diabetes, and cancers, is transcribed in the opposite direction from the INK4b-ARF-INK4a gene cluster [
88,
89]. As previously mentioned and unexplored value in gastric cancer, it was identified in xenografts experiment and in vivo study that the expression of PLZF was remarkably low in GC tissues and cell lines responsible for GC cell proliferation and migration derived from EMT that is negatively correlated with E-cadherin but positively with Vimentin and N-cadherin, negatively related to ANRIL which indirectly caused DNA methylation of PLZF promoter through recruiting PRC2 (polycomb repressive complex 2), especially EZH2(histone-lysine N-methyltransferase enzyme) which is the functional enzymatic component of the PRC2 both in vitro and in vivo [
90]. And ANRIL knockdown can block the effects of TET2 on gastric cancer cell proliferation and colony formation [
91]. Otherwise, small Nucleolar RNA Host Gene 3 (SNHG3), a novel Long non-coding RNA, has been validated that it was concomitant with a variety of cancers, aimed at malignant progression as well as prognosis in vitro and
in xenograft
vivo, such as hepatocellular carcinoma [
92], colorectal cancer [
93], ovarian cancer [
94]. Accordingly, it was proposed that SNHG3 also had a significant impact on the positive progression of GC in the study that displayed that MED18, a tumor suppressor in respect to proliferation, migration, and invasion of GC, was downregulated by SNHG3 epigenetically via methylating MED18 promoter by binding to EZH2 [
95]. Except for the PRC2 family, DNA methyltransferase and mi-RNAs also make a pivotal difference. For instance, long non-coding RNA HOX transcript antisense intergenic RNA (HOTAIR) served as a regulatory factor, exerted epigenetic effects on progression in diverse cancers as well as GC [
96]. It was found that HOTAIR had an influence on PCDH10 renowned as a tumor suppressor gene, which suffered a methylated alteration resulted by HOTAIR through interacting with miR-148 and DNMT1, bringing about oncogenic changes in GC [
96]. Moreover, Acyl-CoA thioesterases (ACOTs) play an important role in the degradation of fatty acyl-CoA which participates in plentiful metabolic processes in humans [
97,
98]. ACOT7, one of the members of the ACOTs family, is necessary to cell cycle progression in pulmonary carcinoma [
99]. Hence, it was confirmed that lncRNA NMRAL2P showed overexpression in GC cells, inhibiting proliferation, migration, and invasion which was linked to DNA methylation of ACOT7 promoter, NMRAL2P regulating by binding to DNMT3b [
100]. Long non-coding RNA LUCAT1, known as lung cancer associated transcript 1, has been demonstrated to be engaged in the development of many cancers, such as clear cell renal cell carcinoma, non-small lung cancer, glioma, osteosarcoma, and colorectal cancer. Similarly, it was investigated the functions and molecular mechanisms of LUCAT1 in the carcinogenesis of GC. It was found that LUCAT1 induces methylation of CXXC4 (CXXC finger protein 4), a negative regulator of Wnt/β-catenin signaling and SFRP2, thereby regulating Wnt/β-catenin signaling whose alteration is closely related to the development and progression of GC [
21]. HOTTIP lncRNA, a component of the HomeoboxA cluster in its 5'-end, manipulated multiple processes of cancer like facilitating the proliferation of pancreatic cancer cells [
101], and metastasis of hepatoma [
102]. Interestingly, it was verified that HOTTIP enabled HoxA13 from Homeobox genes family concerned with migration and invasion of GC to express actively relying on DNA hypomethylation of HoxA13 promoter partly and it can be the target of HoxA13 reversely
in xenograft
vivo [
103]. Furthermore, in-depth research revealed that the insulin-like growth factor-binding protein-3(IGFBP-3), famous as a fundamental regulator in many signaling pathways, interacted with HoxA13 as its downstream target in GC and can be modulated by the p53 pathway. Therefore, the HoxA13–HOTTIP–IGFBP-3 axis may be considered as the underlying mechanism in GC [
103].
Table 2
Crosstalk between LncRNAs and DNA methylation of cancer-related genes in gastric cancer
HOTTIP | HOXA13 | Hypermethylation | High level | HOXA13-HOTTIP-IGFBP3 axis/p53 | Migration, invasion, prognosis |
AK058003 | SNCG | Hypermethylation | High level | Hypoxia-AK058003-SNCG axis | Migration, invasion |
AK123702 | EGFR | Hypermethylation | ↑ | Hypoxia-AK123702-EGFR axis | Migration, invasion |
ANRIL | PLZF | Hypermethylation | ↓ | EMT | Differentiation, invasion, metastasis, prognosis |
LUCAT1 | CXXC4 | Hypermethylation | ↓ | Wnt/β-catenin | Proliferation, migration, invasion |
SNHG3 | MED18 | Hypermethylation | ↓ | SNHG3/EZH2-MED18 signaling | Proliferation, migration, invasion, apoptosis |
NMRAL2P | ACOT7 | Hypermethylation | ↓ | - | Proliferation, migration, invasion, apoptosis |
HOTAIR | PCDH10 | Hypermethylation | ↓ | - | Progression, prognosis |
Oxygen is essential for the energy metabolism that drives cell biology, lower oxygen levels leading to more aggressive tumor cells. As a consequence, suffering hypoxia is not just considered to be a key microenvironmental factor that induces cancer metastasis but related to changes in gene expression [
104]. There is no doubt that the proceeding also presides over tumor metastasis in GC. For example, it was found that lncRNA AK058003 is upregulated by hypoxia, which is responsible for GC migration and invasion in vivo and in vitro. Otherwise, it was demonstrated that AK058003 is able to regulate the expression of metastasis-related gene γ-synuclein (SNCG), the further study showing that SNGG gene CpG island was hypomethylated while AK058003 was deleted. Furthermore, SNCG expression is also related to hypoxia inducing hypoxia-induced GC cell metastasis. Consequently, the hypoxia/lncRNA-AK058003/SNCG pathway may be a novel signaling pathway in GC [
105]. Surprisingly, another study found that the role of lncRNA AK123702 was similar to AK058003, suggesting that AK123702 was upregulated by hypoxia resulting in metastasis and invasion in vivo and
vitro, and metastasis of hypoxia-induced was mediated by AK123702 in GC cells alike. In addition, AK123702 regulated positively the expression of metastasis-related gene EGFR whose expression was also increased by hypoxia, and upregulation of EGFR by AK123072 could mediate hypoxia-induced metastasis in GC cells. Significantly, the EGFR gene CpG island was also hypomethylated in GC cells expurgated AK123702. As a consequence, the hypoxia/lncRNA-AK123072/EGFR pathway maybe another novel signaling pathway in GC [
106].