长期以来,对于肿瘤的发病机制,就存在两种意见,一种意见认为,肿瘤的发生是由于基因突变导致的遗传特性改变引起的,另一种意见认为,肿瘤的发生是由于基因表达的失调,即通过表遗传学机制引起的.只是近几十年来,由于癌基因与抑癌基因的发现及对之研究的巨大进步,使得肿瘤表遗传学的研究一直处于遗传学研究的阴影之下而已[1]。

Cancer epigenetics

MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

This monthly, peer-reviewed journal includes studies devoted to molecular medicine, underscoring aspects including pharmacology, pathology, genetics, neurosciences, infectious diseases, molecular cardiology and molecular surgery. In vitro and in vivo studies of experimental model systems pertaining to the mechanisms of a variety of diseases offer researchers the necessary tools and knowledge with which to aid the diagnosis and treatment of human diseases.

Molecular Medicine Reports

Long noncoding RNAs (lncRNAs) are non-protein coding transcripts longer than 200 nucleotides. Aberrant expression of lncRNAs has been found associated with gastric cancer, one of the most malignant tumors. By complementary base pairing with mRNAs or forming complexes with RNA binding proteins (RBPs), some lncRNAs including GHET1, MALAT1, and TINCR may mediate mRNA stability and splicing. Other lncRNAs, such as BC032469, GAPLINC, and HOTAIR, participate in the competing endogenous RNA (ceRNA) network. Under certain circumstances, ANRIL, GACAT3, H19, MEG3, and TUSC7 exhibit their biological roles by associating with microRNAs (miRNAs). By recruiting histone-modifying complexes, ANRIL, FENDRR, H19, HOTAIR, MALAT1, and PVT1 may inhibit the transcription of target genes in cis or trans. Through these mechanisms, lncRNAs form RNA-dsDNA triplex. CCAT1, GAPLINC, GAS5, H19, MEG3, and TUSC7 play oncogenic or tumor suppressor roles by correlated with tumor suppressor P53 or onco-protein c-Myc, respectively. In conclusion, interaction with DNA, RNA and proteins is involved in lncRNAs' participation in gastric tumorigenesis and development.

/pdf/molecular-mechanisms-of-long-noncoding-rnas-on-gastric-1ny5b8nk9h.pdf

Molecular mechanisms of long noncoding RNAs on gastric cancer

MicroRNAs (miRNAs) are short non-coding RNAs that act as important regulators of gene expression as part of the epigenetic machinery. In addition to posttranscriptional gene silencing by miRNAs, the epigenetic mechanisms also include DNA methylation, histone modifications and their crosstalk. Epigenetic modifications were reported to play an important role in many disease onsets and progressions and can be used to explain several features of complex diseases, such as late onset and fluctuation of symptoms. However, miRNAs not only function as a part of epigenetic machinery, but are also epigenetically modified by DNA methylation and histone modification like any other protein-coding gene. There is a strong connection between epigenome and miRNome, and any dysregulation of this complex system can result in various physiological and pathological conditions. In addition, miRNAs play an important role in toxicogenomics and may explain the relationship between toxicant exposure and tumorigenesis. The present review provides information on 63 miRNA genes shown to be epigenetically regulated in association with 21 diseases, including 11 cancer types: cardiac fibrosis, cardiovascular disease, preeclampsia, Hirschsprung’s disease, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, temporal lobe epilepsy, autism, pulmonary fibrosis, melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal, gastric, cervical, ovarian, prostate, lung, breast, and bladder cancer. The review revealed that hsa-miR-34a, hsa-miR-34b, and hsa-miR-34c are the most frequently reported epigenetically dysregulated miRNAs. There is a need to further study molecular mechanisms of various diseases to better understand the crosstalk between epigenetics and gene expression and to develop new therapeutic options and biomarkers.

MicroRNA epigenetic signatures in human disease.

The long non-coding RNA MEG3 has been reported to be a tumor suppressor in a number of malignant tumors including gastric cancer. Several studies have shown that the regulation of MEG3 may attribute to the promoter hypermethylation. However, the mechanism of MEG3 regulation in gastric cancer is still not well understood. MiR-148a can suppress gastric tumorigenesis through regulating the expression of target genes such as DNA methyltransferase 1(DNMT-1). We examined the expression of MEG3 in 52 gastric cancer samples using quantitative real-time PCR and found the down-regulation of MEG3 in both gastric cancer tissues and cell lines. The positive correlation of MEG3 and miR-148a was further confirmed in SGC-7901 and BGC-823 gastric cancer cell lines. Hypermethylation of MEG3 differentially methylated regions was identified by methylation-specific PCR, and MEG3 expression was increased with the inhibition of methylation with siRNA to DNMT-1 in gastric cancer cells. In addition, transfection of MEG3 siRNA into gastric cancer cells diminished the suppression of proliferation induced by overexpression of miR-148a. Our results suggest that the suppression of miR-148a may contribute to the down-regulation of MEG3 in gastric cancer by modulation of DNMT-1.

MiR-148a regulates MEG3 in gastric cancer by targeting DNA methyltransferase 1.

Gastric cancer is one of the most common malignant diseases worldwide, although much progress has been achieved in recent years, the early diagnosis and treatment for gastric cancer are not yet satisfactory and, thus the prognosis is still poor. MicroRNAs (miRNAs) can regulate a variety of physiological and developmental processes, it has been revealed that many miRNAs contribute the initiation and progression of various cancers. MiR-148a is one of the most important miRNAs in gastric cancer, and the aim of this paper is to provide an overview of various roles of miR-148a in gastric cancer. We searched studies in electronic databases. MiR-148a was down-regulated in gastric cancer tissues and cell lines, which was resulted from the hypermethylation in its promoter region. Furthermore, miR-148a could regulate several different target genes and pathways involving tumor proliferation, invasion and metastasis. MiR-148a may serve as a novel biomarker for the diagnosis and as a new therapeutic target in gastric cancer.

The role of miR-148a in gastric cancer

Underexpression of the gene runt-related transcription factor 3 (RUNX3), an important tumor suppressor, is known to contribute to gastric cancer progression. However, the mechanism underlying aberrant RUNX3 expression has not been fully elucidated. We investigated the role of microRNA-148a (miR-148a) and DNA methyltransferases (DNMTs) in RUNX3 promoter methylation and gene expression. RUNX3 mRNA, RUNX3 protein, and methylation levels were assayed in human gastric cancer tissues and matched normal tissues, and AGS and BGC-823 cells by real-time reverse transcription PCR, Western blot, and methylation-specific PCR, respectively. A correlation between RUNX3 mRNA levels and that of miR-148a was also investigated in gastric cancer tissues. We found that RUNX3 mRNA levels were significantly downregulated in gastric cancer tissues compared with their matched normal tissues, and were closely associated with miR-148a expression. After treatment of human gastric cancer AGS and BGC-823 cells with the DNA methylation inhibitor 5-aza-2’-deoxycytidine, a significant increase in RUNX3 mRNA, RUNX3 protein, and the non-methylated form of the RUNX3 promoter were observed relative to untreated cells. Enforced expression of miR-148a, which can modulate DNMT1 and DNMT3B, also increased the expression of RUNX3 in gastric cancer cells. Knockdown of DNMT1 was associated with increased levels of RUNX3 mRNA and RUNX3 protein, while knockdown of DNMT3B did not have any effect on these in BGC-823 cells. Our results show that miR-148a may regulate RUNX3 expression through modulation of DNMT1-dependent DNA methylation in gastric cancer and highlight a miRNA-epigenetics regulation mechanism of gene expression.

/pdf/microrna-148a-can-regulate-runt-related-transcription-factor-p4dizjit0y.pdf

MicroRNA-148a can regulate runt-related transcription factor 3 gene expression via modulation of DNA methyltransferase 1 in gastric cancer

Gastric cancer (GC) is the fourth most commonly diagnosed type of cancer worldwide and has the second highest mortality rate of all cancer types. Classical genetics alone does not fully explain how GC occurs; however, epigenetics provides a partial explanation with regard to the cause of cancer. DNA methylation, the best-known type of epigenetic marker, represses the expression of tumor-suppressor genes and is involved in the pathogenesis of various types of human cancer, including GC. Micro (mi)RNAs are critical in the initiation, progression, metastasis and invasion of GC through gene regulation. The dysregulation of miRNAs is widely recognized as a hallmark of cancer. Recently, studies concerning DNA methylation of miRNAs in GC have been frequently reported, and these studies deepen the knowledge of how epigenetic regulation of miRNAs results in GC pathogenesis and indicate novel therapeutic strategies for GC. The present review provides an overview of the reported DNA methylation of miRNAs in GC.

/pdf/promoter-methylated-micrornas-potential-therapeutic-targets-313ahdb6kz.pdf

Jiang Yan

Papers

MiR-148a regulates MEG3 in gastric cancer by targeting DNA methyltransferase 1.

The role of miR-148a in gastric cancer

MicroRNA-148a can regulate runt-related transcription factor 3 gene expression via modulation of DNA methyltransferase 1 in gastric cancer

Promoter methylated microRNAs: potential therapeutic targets in gastric cancer.