Genetic variation in the non-coding genome: Involvement of micro-RNAs and long non-coding RNAs in disease

Hrdličková, Barbara; Almeida, Rodrigo Coutinho de; Borek, Z; Withoff, Sebo

doi:10.1016/j.bbadis.2014.03.011

Cited by 214 publications

(202 citation statements)

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“…Notably, lncRNAs play an important role in dosage compensation, epigenetics, the cell cycle and differentiation (12). The primary functions of lncRNA include genomic imprinting, chromatin remodeling, mRNA transcriptional regulation and cell cycle regulation (13). The present study determined the expression levels of lncRNA-AK058003 in breast cancer tissue and the potential correlation with the expression of SNCG, which regulates MCF-7 breast cancer cells.…”

Section: Discussionmentioning

confidence: 90%

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Unregulated long non-coding RNA-AK058003 promotes the proliferation, invasion and metastasis of breast cancer by regulating the expression levels of the γ-synuclein gene

Wang

2015

Experimental and Therapeutic Medicine

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Abstract. The aim of the present study was to investigate the function of long chain non-coding RNA (lncRNA) in breast cancer cells. Quantitative polymerase chain reaction was used to measure mRNA expression levels in breast cancer tissues, adjacent tissues and in MCF-7 breast cancer cells. Western blot analysis was used to determine the protein expression levels. In addition, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was employed to measure the rates of cell proliferation. The invasion and migration of the MCF-7 cells were examined using a Transwell ® assay. The expression levels of lncRNA-AK058003 were increased significantly in the breast cancer tissues and were found to strongly correlate with the severity of the breast cancer clinical stage. Bioinformatics analysis revealed that the γ-synuclein gene (SNCG) may be a target gene regulated by lncRNA-AK058003. Thus, lncRNA-AK058803 was downregulated using small interfering RNA, and the mRNA and protein expression levels of SNCG were shown to be significantly reduced. Furthermore, the proliferation, invasion and migration rates of the MCF-7 breast cancer cells were significantly reduced. Therefore, the results demonstrated that unregulated lncRNA-AK058003 in breast cancer cells promotes cancer cell proliferation, invasion and metastasis via the regulation of SNCG expression. IntroductionBreast cancer is a common clinical condition with increasing morbidity and high mortality rates (1). Previous studies have suggested that the development of breast cancer is associated with inactivated tumor suppressor genes, dysfunctional signaling transduction pathways and other malfunctioning molecular signaling processes (2-4). With the development of chemotherapy, hormonal therapy, immunotherapy, gene therapy and other treatment technologies, the long-term survival of breast cancer patients has become possible. Breast cancer patients continue to succumb to the disease due to tumor metastasis, drug resistance and other reasons including hemorrhage, infection and recurrence (5). Therefore, finding novel biomarkers for use in the early diagnosis and treatment of breast cancer has become increasingly studied.A high-throughput sequencing study revealed the existence of types of non-coding RNA in gene transcripts, including small non-coding RNA and long non-coding (lnc)RNA (6). LncRNA has a length of >200 nucleotides and a similar structure to mRNA, including a 5' cap and poly-A tail. However, lncRNA is unable to encode proteins due to the absence of an open reading frame (7). Increasing numbers of studies have indicated that lncRNA may play an important role in various cellular processes, including cell differentiation, proliferation and apoptosis (8,9). Notably, a previous study revealed a novel function of lncRNA in the development of prostate cancer (10). In addition, long non-coding homeobox antisense intergenic RNA is reported to be a highly valuable clinical biomarker for the prognosis and early diagnosis of ovarian cancer (11).The primary functio...

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Section: Discussionmentioning

confidence: 90%

“…The primary functions of lncRNA include genomic imprinting, chromatin remodeling, cell cycle regulation and transcriptional regulation of adjacent mRNA (13). The γ-synuclein gene (SNCG), also known as breast cancer-specific protein 1, encodes a synaptic protein that was first identified in breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Unregulated long non-coding RNA-AK058003 promotes the proliferation, invasion and metastasis of breast cancer by regulating the expression levels of the γ-synuclein gene

Wang

2015

Experimental and Therapeutic Medicine

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“…Increasing evidence suggests that increased miRNA expression, miRNA-target interaction and networks might contribute to disease processes, including genetic and infectious diseases as well as cancer (Hrdlickova et al, 2014). With increasing knowledge of miRNAs in a variety of diseases, the approach targeting host miRNAs has emerged as an interesting therapeutic strategy.…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of microRNA-122 binding sequences of hepatitis C virus and identification of variants with high resistance against a specific antagomir

Pham

Uzcátegui

et al. 2016

Journal of General Virology

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MicroRNA 122 (miR-122) stimulates the replication and translation of hepatitis C virus (HCV) RNA by binding to two adjacent sites, S1 and S2, within the HCV 5¢UTR. We demonstrated previously that the miR-122 antagomir miravirsen (SPC3649) suppresses the infection of HCV strain JFH1-based recombinants with HCV genotypes 1-6 5¢UTR-NS2 in human hepatoma Huh7.5 cells. However, specific S1 mutations were permitted and conferred virus resistance to miravirsen treatment. Here, using the J6 (genotype 2a) 5¢UTR-NS2 JFH1-based recombinant, we performed reverse-genetics analysis of S1 (ACACUCCG, corresponding to miR-122 seed nucleotide positions 8-1), S2 (CACUCC, positions 7-2), and ACCC (positions 1-4) at the 5¢ end of the HCV genome (5¢E); the CC at positions 2-3 of 5¢E is involved in miR-122 binding. We demonstrated that the 5¢E required four nucleotides for optimal function, and that G or A at position 3 or combined GA at positions 2-3 of 5¢E was permitted. In S1 and S2, several single mutations were allowed at specific positions. A UCC fi CGA change at positions 4-3-2 of S1, S2, or both S1 and S2 (S1/S2), as well as a C fi G change at position 2 of S1/S2 were permitted. We found that 5¢E mutations did not confer virus resistance to miravirsen treatment. However, mutations in S1 and S2 induced virus resistance, and combined S1 and/or S2 mutations conferred higher resistance than single mutations. Identification of miR-122 antagomir resistance-associated mutations will facilitate the study of additional functions of miR-122 in the HCV life cycle and the mechanism of virus escape to host-targeting antiviral approaches.

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“…Recent studies including the GWAS have identiied an important role for genetics as well as gene regulation and epigenetics in IBD [45,46]. To date the GWAS have identiied 163 loci that are associated with IBD; however, only approximately 10% of these loci are located in DNA coding regions suggesting an important role for gene regulation [47,48]. Given that genetics account for only 10% of cases of IBD, the increased incidence in developing countries and the identiied environmental inluences, IBD is likely due to a gene by environment interaction, which also implicates epigenetics as a key driver in disease pathogenesis.…”

Section: Hydroxymethylation In Ibdmentioning

confidence: 99%

Hydroxymethylation Influences on Intestinal Epithelial Cells in Health and Disease

Huff-Hardy¹,

Kwon²

2018

Gene Expression and Regulation in Mammalian Cells - Transcription Toward the Establishment of Novel Therapeutics

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Epigenetics describes modiications that afect gene expression that are not encoded within the DNA sequence. DNA methylation is the longest appreciated epigenetic modiication and has been accepted to play a critical role in maintaining euchromatin and silencing genes. Recently, a separate and distinct covalent modiication has been recognized; hydroxymethylation, which has been associated with increased gene expression as opposed to gene silencing. However, traditional methods to study DNA methylation also recognized hydroxymethylation and did not distinguish between these two distinct DNA covalent modiications. Furthermore, TET enzymes have been identiied to play a critical role in active hydroxymethylation of previously methylated cytosine residues and may further result in conversion to cytosine. TET1 plays a critical role in intestinal epithelial diferentiation and development, and this is also correlated with increased hydroxymethylation in terminally diferentiated epithelial cells. Colon cancer, which arises from the colonic epithelium, exhibits decreased hydroxymethylation and altered gene expression.

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Genetic variation in the non-coding genome: Involvement of micro-RNAs and long non-coding RNAs in disease

Cited by 214 publications

References 186 publications

Unregulated long non-coding RNA-AK058003 promotes the proliferation, invasion and metastasis of breast cancer by regulating the expression levels of the γ-synuclein gene

Unregulated long non-coding RNA-AK058003 promotes the proliferation, invasion and metastasis of breast cancer by regulating the expression levels of the γ-synuclein gene

Functional analysis of microRNA-122 binding sequences of hepatitis C virus and identification of variants with high resistance against a specific antagomir

Hydroxymethylation Influences on Intestinal Epithelial Cells in Health and Disease

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