Promoter hypermethylation‐mediated downregulation of miR‐770 and its host gene MEG3, a long non‐coding RNA, in the development of gastric cardia adenocarcinoma

Guo, Wei; Zhao, Dong; Liu, Shengnan; Qiao, Yu; Kuang, Gang; Guo, Yanli; Shen, Supeng; Liang, Jia

doi:10.1002/mc.22650

Cited by 49 publications

(44 citation statements)

References 36 publications

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“…In regard to the functions of MEG3 in cancer, increasing evidence displayed that MEG3 decreases cell proliferation, invasion and metastasis [10-14, 24, 27], and reverses the chemoresistance [24,31]. Herein, our results illustrated that MEG3 repressed cell proliferation, colony formation and HAs xenograft tumorigenesis, but knockdown of MEG3 reversed these effects.…”

Section: Discussionmentioning

confidence: 46%

lncRNA MEG3 Suppresses the Tumorigenesis of Hemangioma by Sponging miR-494 and Regulating PTEN/ PI3K/AKT Pathway

Dai

Wan

Qiu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Dysregulation of long noncoding RNAs (lncRNAs) is associated with the proliferation and metastasis in a variety of cancers, of which lncRNA maternally expressed gene 3 (MEG3) has been indicated as a tumor suppressor in multiple malignancies. However, the underlying mechanisms by which MEG3 contributes to human hemangiomas (HAs) remain undetermined. Methods: qRT-PCR analysis was performed to examine the expression levels of MEG3 and VEGF in proliferating or involuting phase HAs. MTT, colony formation assay, flow cytometry analysis and a subcutaneous xenograft tumor model were conducted to assess the effects of MEG3 on the HAs tumorigenesis. The interaction between MEG3 and miRNAs or their downstream pathways was evidenced by bioinformatic analysis, luciferase report assays, RNA immunoprecipitation (RIP) assay. and Western blot analysis. Results: The expression of MEG3 was substantially decreased and had a negative correlation with VEGF expression in proliferating phase HAs, as compared with the involuting phase HAs and normal skin tissues. Ectopic expression of MEG3 suppressed cell proliferation, colony formation and induced cycle arrest in vitro and in vivo, followed by the downregulation of VEGF and cyclinD1, but knockdown of MEG3 reversed these effects. Furthermore, MEG3 was verified to act as a sponge of miR-494 in HAs cells, and miR-494 counteracted MEG3-caused anti-proliferative effects by regulating PTEN/PI3K/AKT pathway, and exhibited the negative correlation with MEG3 and PTEN expression in proliferating phase HAs. Conclusion: Our findings suggested that lncRNA MEG3 inhibited HAs tumorigenesis by sponging miR-494 and regulating PTEN/PI3K/AKT pathway.

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Section: Discussionmentioning

confidence: 46%

lncRNA MEG3 Suppresses the Tumorigenesis of Hemangioma by Sponging miR-494 and Regulating PTEN/ PI3K/AKT Pathway

Dai

Wan

Qiu

et al. 2018

Cell Physiol Biochem

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“…The proximal promoter aberrant hypermethylation and MEG3 enhancer region were seen in tissues of CGA. Also, the enhancer region and proximal promoter hypermethylation and dysregulation of MEG3 and miR‐770 were correlated with a survival of poorer CGA patients . Aberrant hypermethylation‐mediated downregulation of C5orf66‐AS1 may play critical roles in CGA tumorigenesis and C5orf66‐AS1 can be a prognostic marker in the prediction of CGA patients' survival .…”

Section: Epigenetic Risk Factorsmentioning

confidence: 94%

Risk factors predisposing to cardia gastric adenocarcinoma: Insights and new perspectives

et al. 2019

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Recent decades have seen an alarming increase in the incidence of cardia gastric adenocarcinoma (CGA) while noncardia gastric adenocarcinoma (NCGA) has decreased. In 2012, 260 000 CGA cases (age‐standardised rate (ASR); 3.3/100 000) and 691 000 NCGA cases (ASR; 8.8/100 000) were reported worldwide. Compared with women, men had greater rates for both the subsites, especially for CGA. Recently, four molecular subtypes of GC have been proposed by the Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG); however, these classifications do not take into account predisposing germline variants and their possible interaction with somatic alterations in carcinogenesis. The etiology of adenocarcinoma of the cardia and the gastroesophageal junction (GEJ) is not known. It is thought that CGA is distinct from adenocarcinomas located in the esophagus or distal stomach, both epidemiologically and biologically. Moreover, CGA is often identified in the advanced stage having a poor prognosis. Therefore, understanding the risk and the role of predisposing factors in etiology of CGA can inform clinical practice and counseling for risk reduction. In this paper, we showed that GC family history, lifestyle, demographics, gastroesophageal reflux disease, Helicobacter pylori infection, and multiple genetic and epigenetic risk factors as well as several predisposing conditions may underlie susceptibility to CGA. However, several genome‐wide association studies (GWASs) should be conducted to identify novel high‐penetrance genes and pathways as well as causal germline variants predisposing to CGA. They must include different ethnic groups, especially from high‐incidence countries for CGA, because some risk loci are ancestry‐specific. In parallel, statistical methods can be developed to identify cancer predisposition genes (CPGs) from tumor sequencing data. It is also necessary to find novel long noncoding RNAs related to the risk of CGA. Taken altogether, new cancer risk prediction models, including all genetic and nongenetic factors influencing risk, should be developed to facilitate risk assessment, disease prevention, and early diagnosis and intervention of CGA in the future.

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“…Furthermore, like protein coding genes, aberrant DNA methylation may be an epigenetic regulator of lncRNA expression. LncRNA MEG3 may play tumor suppressor role and hypermethylation of proximal promoter and enhancer region may be one of the critical mechanisms in inactivation of MEG3 in GCA development . However, the cancer‐related methylation patterns of human lncRNAs still remains to be fully investigated.…”

Section: Introductionmentioning

confidence: 99%

Aberrant methylation‐mediated downregulation of long noncoding RNA C5orf66‐AS1 promotes the development of gastric cardia adenocarcinoma

Guo

Liu

et al. 2018

Molecular Carcinogenesis

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As a long non-coding RNA, C5orf66-AS1 is located at 5q31.1. Downregulation and aberrant hypermethylation of C5orf66-AS1 have been detected in a limited several tumors. However, the biological role and distribution of methylated CpG sites of C5orf66-AS1 in gastric cardia adenocarcinoma (GCA) development and prognosis are poorly clarified. The present study was to investigate the expression status and function of C5orf66-AS1 in GCA, and to detect the distribution of methylated CpG sites within the three CpG islands of the promoter and gene body of C5orf66-AS1, further to clarify its prognostic value in GCA patients. C5orf66-AS1 was significantly downregulated in GCA tissues and cell lines, and the expression level was associated with TNM stage, pathological differentiation, lymph node metastasis, and distant metastasis or recurrence. The expression level of C5orf66-AS1 was significantly increased in cancer cells after treated with 5-Aza-dC. Further methylation analysis demonstrated that the aberrant hypermethylation of the regions around the transcription start site of C5orf66-AS1 was more tumor specific and was associated with its expression. Moreover, Sp1 may upregulate C5orf66-AS1 expression and CpG sites hypermethylation within the binding sites may abrogate Sp1 binding. In addition, C5orf66-AS1 inhibited gastric cancer cell proliferation and invasion, and the dysregulation and hypermethylation of the regions around the transcription start site of C5orf66-AS1 were associated with poorer GCA patients' survival. These findings suggest that aberrant hypermethylation-mediated downregulation of C5orf66-AS1 may play important roles in GCA tumorigenesis and C5orf66-AS1 may serve as a potential prognostic marker in predicting GCA patients' survival.

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Promoter hypermethylation‐mediated downregulation of miR‐770 and its host gene MEG3, a long non‐coding RNA, in the development of gastric cardia adenocarcinoma

Cited by 49 publications

References 36 publications

lncRNA MEG3 Suppresses the Tumorigenesis of Hemangioma by Sponging miR-494 and Regulating PTEN/ PI3K/AKT Pathway

lncRNA MEG3 Suppresses the Tumorigenesis of Hemangioma by Sponging miR-494 and Regulating PTEN/ PI3K/AKT Pathway

Risk factors predisposing to cardia gastric adenocarcinoma: Insights and new perspectives

Aberrant methylation‐mediated downregulation of long noncoding RNA C5orf66‐AS1 promotes the development of gastric cardia adenocarcinoma

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