CN107326067B - miRNA marker of non-alcoholic fatty liver - Google Patents
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Abstract
The invention discloses a miRNA marker, which is miRNA-653. miRNA-653 can be used for judging the progress and severity of the non-alcoholic fatty liver disease. The test proves that the miRNA-653 can effectively distinguish the non-alcoholic fatty liver sample from the normal sample. On the basis, the miRNA-653 can also be used for preparing a medicament for inhibiting the non-alcoholic fatty liver. The invention provides a new diagnosis method for clinically diagnosing the non-alcoholic fatty liver at a molecular level, and simultaneously provides a new drug target for treating the non-alcoholic fatty liver.
Description
Technical Field
The invention belongs to the field of biomedicine, relates to a non-alcoholic fatty liver miRNA marker and application thereof, and particularly relates to a non-alcoholic fatty liver related miRNA-653 marker and application thereof.
Background
miRNA are 21-22nt non-coding RNA molecules naturally existing in vivo, and are RNA for regulating target gene expression through post-transcriptional gene silencing. It is estimated that about 1/3 genes in organisms are regulated by mirnas. The miRNA and RISC complex can be combined with a complementary sequence in a target gene mRNA5 '-UTR or 3' -UTR through base pairing to inhibit protein translation or trigger mRNA degradation, thereby negatively regulating the expression of the target gene.
The nonalcoholic fatty liver refers to a clinical pathological syndrome which is mainly characterized by fat excessive deposition in liver cells caused by excrements and other definite liver damage factors, and acquired metabolic stress liver injury closely related to insulin resistance and genetic susceptibility. Including Simple Fatty Liver (SFL), non-alcoholic steatohepatitis (NASH) and its associated cirrhosis. With the global epidemic trend of obesity and related metabolic syndrome, the nonalcoholic fatty liver disease becomes an important cause of chronic liver disease in developed countries such as Europe and America and affluent areas of China, the prevalence rate of NAFLD of common adults is 10% -30%, wherein 10% -20% of NASH is NASH, and the incidence rate of cirrhosis of liver in 10 years of NASH is up to 25%.
Non-alcoholic fatty liver disease can directly cause decompensated liver cirrhosis, hepatocellular carcinoma and relapse of transplanted liver, can affect the progress of other chronic liver diseases, and is involved in the onset of type 2 diabetes and atherosclerosis. Malignant tumors related to metabolic syndrome, arteriosclerotic cardiovascular and cerebrovascular diseases and liver cirrhosis are important factors influencing the quality of life and the life expectancy of non-alcoholic fatty liver patients. For this reason, non-alcoholic fatty liver disease is a new challenge in the contemporary medical field, and the harm of non-alcoholic fatty liver disease to human health will continue to increase in the near future.
miRNA is endogenous non-coding small molecular RNA for regulating gene expression, regulates gene expression at the level after transcription, and participates in physiological processes such as cell cycle, apoptosis, development, differentiation, metabolism and the like. The misexpression of miRNA in cells can cause the occurrence of various diseases including nonalcoholic fatty liver, and recent research shows that some miRNA are abnormally expressed in the blood of nonalcoholic fatty liver patients, but no consensus is achieved on which miRNA is related to the occurrence and development of nonalcoholic fatty liver. Therefore, it is necessary to find miRNA associated with the occurrence and development of non-alcoholic fatty liver disease, so as to provide an effective means for clinical diagnosis and treatment of non-alcoholic fatty liver disease.
Disclosure of Invention
The invention aims to provide a miRNA marker for judging non-alcoholic fatty liver disease.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a miRNA marker for predicting the risk of nonalcoholic fatty liver and diagnosing the nonalcoholic fatty liver, wherein the miRNA marker is miRNA-653. The miRNA-653 is selected from at least one of the following groups: : miRNA-653 primary miRNA, miRNA-653 precursor miRNA, mature miRNA-653; the miRNA-653 primary miRNA can be cleaved and expressed into mature miRNA-653 in human cells; the miRNA-653 precursor miRNA can be cleaved and expressed in human cells to form a mature miRNA-653.
It will be appreciated that the miRNA-653 of the present invention includes functional equivalents of constitutive nucleic acid molecules, i.e., variants, which exhibit the same function as the entire miRNA-653 nucleic acid molecule, although they are mutated by deletion, substitution or insertion of nucleotide residues.
It is well known in the art that in order to ensure the stability of miRNA, protective bases such as TT may be added to one or both ends of miRNA, and miRNA bases may also be modified, but the function of miRNA is not affected. Therefore, it is well known to those skilled in the art that the sequence obtained by base-modifying the miRNA-653 or adding bases at both ends without affecting the function of the miRNA-653 is also included in the scope of the present invention.
In some specific embodiments of the invention, the miRNA-653 is a mature miRNA-653. The mature miRNA-653 comprises miRNA-653-5p and miRNA-653-3p, which share a common seed sequence.
Although mature miRNA-653 is used in some embodiments, one skilled in the art would expect that the primary miRNA (pi-miRNA-653) and the precursor miRNA (pre-miRNA-653) would achieve the same technical effect as the mature miRNA-653, because the cells have the ability to further process the primary miRNA (pi-miRNA-653) and the precursor miRNA (pre-miRNA-653) into the mature miRNA-653.
The miRNA-653 nucleic acid molecules of the invention can be present in single-stranded or double-stranded form. The mature miRNA-653 is predominantly in single-stranded form, while the miRNA-653 precursor is partially self-complementary to form a double-stranded structure. The nucleic acid molecules of the invention may be in the form of RNA, DNA, PNA, LNA.
The invention provides an application of miRNA-653 in preparation of a tool for predicting risk of non-alcoholic fatty liver.
The invention also provides application of the miRNA-653 in preparation of a tool for diagnosing the non-alcoholic fatty liver disease.
The experiment of the invention proves that the level of the miRNA-653 in the urine with the non-alcoholic fatty liver is obviously lower than the level of the miRNA-653 in the blood, the serum or the plasma without the non-alcoholic fatty liver. Therefore, if the miRNA-653 level in urine of a subject is significantly reduced compared with the miRNA-653 level in blood, serum or plasma without the non-alcoholic fatty liver, the subject can be judged to have the non-alcoholic fatty liver, so that a scheme for preventing the non-alcoholic fatty liver is adopted or a diagnosis basis is provided for the establishment of a clinical treatment scheme.
The invention also provides application of the miRNA-653 in a tool for judging the non-alcoholic fatty liver. If the level of miRNA-653 in the subject's blood, serum, or plasma is significant, as compared to the level of miRNA-653 in blood, serum, or plasma in which non-alcoholic fatty liver disease does not occur, then the subject is indicated to have non-alcoholic fatty liver disease.
Further, the tool for predicting the risk of the non-alcoholic fatty liver and determining whether the non-alcoholic fatty liver occurs includes, but is not limited to, a chip and a kit. The means include reagents for the expression level of miRNA-653 in a test sample. The reagent may be a primer or probe for miRNA-653.
The invention also provides application of the miRNA-653 in a high-throughput sequencing platform. The expression level of miRNA-653 in a blood, serum or plasma sample to be detected can be obtained through high-throughput sequencing, and compared with the result of the sample to be detected, the sample to be detected is easy to judge whether the risk of the sample to be detected to have non-alcoholic fatty liver disease or whether the sample to be detected to have the non-alcoholic fatty liver disease or not is easy to judge whether the sample to be detected to have the non-alcoholic fatty liver disease or not. Therefore, the application of miRNA-653 obtained by high-throughput sequencing and correlation with nonalcoholic fatty liver is also included in the protection scope of the invention.
The invention also provides a chip for pre-judging the risk of the non-alcoholic fatty liver and diagnosing whether the non-alcoholic fatty liver occurs, wherein the chip comprises a solid phase carrier; and an oligonucleotide probe immobilized on the solid support, the oligonucleotide probe comprising a portion or all of a sequence that specifically corresponds to miRNA-653. The oligonucleotide probe can also comprise an oligonucleotide probe aiming at miRNA which is reported in the prior art and can be used for judging whether the nonalcoholic fatty liver is generated or not. The condition that the non-alcoholic fatty liver is judged by jointly detecting multiple miRNA indexes by placing the detection probes of multiple miRNAs on the same chip is also included in the protection scope of the invention.
Further, the solid phase carrier, including the solid phase carrier, can adopt various materials commonly used in the field of gene chips, such as but not limited to nylon membrane, glass or silicon slice modified by active groups (such as aldehyde group, amino group, etc.), unmodified glass slice, plastic slice, etc.
The miRNA chip may be prepared by a conventional method for manufacturing a biochip known in the art, for example, if the solid support is a modified glass slide or a silicon wafer, and the 5' end of the probe contains a poly-dT string modified with an amino group, the oligonucleotide probe may be prepared as a solution, and then spotted on the modified glass slide or the silicon wafer using a spotting apparatus, arranged into a predetermined sequence or array, and then fixed by standing overnight, so as to obtain the miRNA chip of the present invention.
The invention also provides a kit for predicting the risk of the non-alcoholic fatty liver and diagnosing whether the non-alcoholic fatty liver occurs, wherein the kit comprises a reagent for detecting the expression level of the miRNA-653 in the blood, the serum or the plasma of a subject. And if the miRNA-653 expression level in the blood, the serum or the plasma is significantly reduced by the detection of the kit compared with the miRNA-653 expression level in the blood, the serum or the plasma without the non-alcoholic fatty liver, judging that the non-alcoholic fatty liver of the subject is high in risk or has already occurred.
Further, the reagents include primers and/or probes for miRNA-653. The reagent also comprises a primer and/or a probe aiming at miRNA which is reported in the prior art and can be used for judging the risk of the non-alcoholic fatty liver or judging whether the non-alcoholic fatty liver occurs. The condition that the non-alcoholic fatty liver disease is judged by jointly detecting multiple miRNA indexes by placing the detection primers and/or probes of multiple miRNAs in the same kit is also included in the protection scope of the invention.
The miRNA-653 of the invention can be natural or artificial, or obtained by transfecting cells with a vector capable of expressing a DNA fragment of the miRNA-653. The vector comprises a viral vector and a eukaryotic vector.
The viral vector may be any suitable vector, including but not limited to retroviral vectors, adenoviral vectors, adeno-associated viral vectors, herpes viral (e.g., herpes simplex, vaccinia and EB virus) vectors, alphaviral vectors.
The eukaryotic expression vector may be any suitable expression vector, including but not limited to a pCMV-Myc expression vector, pcdna3.0 expression vector, pcdna3.1 expression vector, pEGFP expression vector, pEFBos expression vector, pTet expression vector, pTRE expression vector, or a vector modified based on known expression vectors, such as pBin438, pCAMBIA1301, and the like.
The DNA fragment capable of expressing miRNA-653 can be obtained by the following steps: searching the position of miRNA-653 on a genome and specific sequence information from an miRNA database (http:// microrna. sanger. ac. uk/sequences /), determining the position of miRNA-653 initial miRNA according to a genome sequence, designing specific primers in the upstream and downstream 800bp intervals of the position of miRNA-653 initial miRNA, and amplifying the sequence in the middle of the primers to obtain a DNA fragment for expressing miRNA-653.
The invention also provides the application of the miRNA-653 in preparing a medicament for inhibiting or treating the non-alcoholic fatty liver.
The experiment proves that the miRNA-653 is related to the nonalcoholic fatty liver, and on the basis, the miRNA-653 can be used for inhibiting the risk of occurrence or development of the nonalcoholic fatty liver by promoting the expression of the miRNA-653.
Further, the medicament comprises a miRNA-653 agonist. The miRNA-653 agonist can promote the expression of miRNA-653 or can activate the function of miRNA-653. The target for inhibition by the miRNA-653 agonist is not limited to miRNA-653 itself, but includes both upstream and downstream of miRNA-653, for example: a genomic sequence encoding miRNA-653, a miRNA-653 target gene, a protein or gene that regulates miRNA-653.
Further, the miRNA-653 inhibitor comprises a protein, an oligonucleotide and a small molecule compound.
Preferably, the miRNA-653 inhibitor is an antisense oligonucleotide to miRNA-653 or a miRNA-653 mimetic.
The antisense oligonucleotide of the miRNA-653 can be easily designed according to the sequence of the miRNA-653, and can obviously down-regulate the expression of the miRNA-653 after the antisense oligonucleotide is transferred into a human body. "antisense oligonucleotides (AS-Ons or ASO)" also referred to AS "antisense nucleotides" refers to DNA or RNA molecules or analogs thereof having a length of about 18 to 26nt (more particularly about 19 to 22 nt).
In the present invention, the "antisense oligonucleotide" also includes modified antisense nucleotides obtained by means such as nucleic acid lock or nucleic acid chain skeleton modification technology, the modification does not substantially change the activity of the antisense oligonucleotide, and preferably, the modification can improve the stability, activity or therapeutic effect of the antisense oligonucleotide. Nucleic acid Locks (LNAs) generally refer to modification techniques that link the 2 'oxygen and 4' carbon atoms of ribose via a methylene bridge. The antisense medicine developed based on the modification technology of the nucleic acid chain skeleton has greatly improved solubility, nuclease degradation resistance and other aspects, and is easy to synthesize in large amount. There are various methods for modifying the backbone of an oligonucleotide, including a thio method, for example, thio-modifying a deoxynucleotide chain to a thiodeoxynucleotide chain. The method is characterized in that oxygen atoms of phosphate bonds on a DNA skeleton are replaced by sulfur atoms, and the DNA skeleton can resist degradation of nuclease. It is understood that any modification capable of maintaining most or all of the activity of the antisense oligonucleotide is encompassed by the invention.
The drug for inhibiting non-alcoholic fatty liver disease of the present invention further comprises pharmaceutically acceptable carriers, including but not limited to: diluents, buffers, suspensions, emulsions, granules, encapsulating agents, excipients, fillers, adhesives, sprays, transdermal absorbents, wetting agents, disintegrants, absorption enhancers, surfactants, colorants, flavors, or adsorptive carriers.
The medicament can be prepared into a micro-injection, a dosage form suitable for transfection, an injection, a tablet, a powder, a granule and a capsule. The medicaments in various dosage forms can be prepared according to the conventional method in the pharmaceutical field.
The drugs may be administered alone; or in combination with other drugs capable of inhibiting non-alcoholic fatty liver disease.
The medicament may be administered ex vivo: the expression vector of miRNA-653 or miRNA-653 is introduced or transfected into human body self or variant cells in vitro, and the human body self or variant cells are returned to the human body after the in vitro cell amplification.
The medicament may be administered in vivo: directly introducing the miRNA-653 or the miRNA-653 expression vector into the body. Such vectors may be viral or non-viral, even naked DNA or RNA.
The subject may be a human or other mammal. More specifically, the subject is an organ, tissue, cell.
Drawings
FIG. 1 shows the expression of miRNA-653 in the serum of non-alcoholic fatty liver disease (HALC) population and normal population;
FIG. 2 shows the expression of miRNA-653 in the serum of a rat model of nonalcoholic fatty liver;
FIG. 3 is a staining pattern of the hepatoma HepG2 cells after addition of oleic acid;
FIG. 4 shows the expression of miRNA-653 in a hepatic cell line HepG2 cultured with added oleic acid.
Sequence listing
Beijing
MicroRNA marker of non-alcoholic fatty liver
miR-653
guguugaaacaaucucuacug
Claims (1)
1. The application of the reagent containing miRNA-653 non-alcoholic fatty liver risk expression level in the preparation of a tool for predicting non-alcoholic fatty liver and/or a tool for diagnosing non-alcoholic fatty liver is characterized in that the miRNA-653 is mature miRNA-653; wherein the expression level of the miRNA-653 is significantly reduced in the blood, serum or plasma of a patient at risk of, or a patient with, non-alcoholic fatty liver disease.
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| CN110042157A (en) * | 2019-04-24 | 2019-07-23 | 河北仁博科技有限公司 | Application of the miR-380-3p in the product of preparation diagnosis, prevention and/or treatment nonalcoholic fatty liver |
| CN110734971A (en) * | 2019-11-27 | 2020-01-31 | 广州中医药大学(广州中医药研究院) | group biomarker for diagnosing metabolic fatty liver mediated vascular diseases and application thereof |
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