CN113943798B - Application of circRNA as hepatocellular carcinoma diagnosis marker and therapeutic target - Google Patents
Application of circRNA as hepatocellular carcinoma diagnosis marker and therapeutic target Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/178—Oligonucleotides characterized by their use miRNA, siRNA or ncRNA
Abstract
The invention relates to the field of molecular biology, in particular to application of circRNA in hepatocellular carcinoma diagnosis and targeted therapy. The circRNA marker is hsa_circRNA_0000384, and research finds that the expression of hsa_circRNA_0000384 in hepatocellular carcinoma tissues is obviously higher than that of other tissues and normal tissues, and the high expression of hsa_circRNA_0000384 implies the poor prognosis of hepatocellular carcinoma patients. Meanwhile, the invention also relates to an siRNA for specifically reducing the expression of the liver cancer cell line hsa_circRNA_0000384, and the siRNA can inhibit proliferation and migration of liver cancer cells, and can be used as an inhibitor for targeted therapy of liver cell cancer.
Description
Technical Field
The invention belongs to the field of biotechnology and biomedicine, and particularly relates to hsa_circRNA_0000384 serving as a marker and a therapeutic target for diagnosing hepatocellular carcinoma.
Background
Liver Cancer (Liver Cancer) is the sixth most common Cancer worldwide, and is also the fourth most fatal Cancer. 84.1 ten thousand liver cancer cases and 78.2 ten thousand liver cancer death cases are newly increased worldwide in 2018. Analysis of the epidemic situation of the malignant tumor in China shows that 37 ten thousand new liver cancer cases are increased in China in 2015, and the fourth new occurrence of main cancers is listed; 32.6 ten thousand cases of liver cancer death, the second most serious cancer death. Primary liver cancer is mainly divided into hepatocellular carcinoma (Hepatocellular carcinoma, HCC) with a ratio of 75% -85%; bile duct cancer (Intrahepatic cholangiocarcinoma) accounts for 10% -15%. Early hepatocellular carcinoma is not easily found, and most hepatocellular carcinoma patients are already in middle and late stages when they are diagnosed. Liver cancer is mainly treated by surgery, radiotherapy and chemotherapy, but the prognosis is worse, and the survival time of patients is generally shorter. At present, no specific early diagnosis target and prognosis biomarker for hepatocellular carcinoma exists, and the research and development of targeted therapeutic drugs for hepatocellular carcinoma still has no substantial breakthrough. Therefore, searching for the specific marker for early diagnosis of the hepatocellular carcinoma and simultaneously using the marker as a break-through to develop the hepatocellular carcinoma targeting drug has great significance.
Circular RNAs (circrnas) belong to the family of non-coding RNAs together with micro RNAs and long-chain non-coding RNAs, and in recent years, circular RNAs have become a hotspot in the research field of non-coding RNAs, and have received much attention. Circular RNAs are a class of closed circular RNA molecules that do not have a free 5 'terminal cap and a 3' terminal poly (a) tail and are formed in a covalent bond primarily depending on the reverse splicing mechanism. The current research result shows that the circular RNA is widely expressed in human body and has specificity in different tissues and organs, and the main function of the circular RNA is to serve as an endogenous competitive binding molecule of microRNA to regulate the expression of a downstream gene; decoys as RNA binding proteins regulate the function of RNA binding proteins; modification of scaffold molecules as proteins to regulate proteins; direct translation of polypeptides, and the like. There is increasing evidence that circular RNA plays an important role in the development and progression of hepatocellular carcinoma, and therefore circular RNA is expected to become an ideal diagnostic marker and therapeutic target for hepatocellular carcinoma.
Disclosure of Invention
In order to realize early diagnosis and targeted therapy of hepatocellular carcinoma, the invention provides hsa_circRNA_0000384 serving as an early diagnosis target and a clinical therapy target of hepatocellular carcinoma.
It is a first object of the present invention to provide a marker for diagnosing hepatocellular carcinoma using a circular RNA.
A second object of the present invention is to provide a hepatocellular carcinoma-specific diagnostic kit.
It is a third object of the present invention to provide a circular RNA as a therapeutic target for hepatocellular carcinoma.
To achieve the first object, the present invention provides that the circRNA is significantly highly expressed in hepatocellular carcinoma as a biomarker, which is hsa_circrna_0000384. The circularized sequence consists of 420 bases as shown in SEQ ID No. 1.
In order to achieve the second object, the invention adopts the following technical scheme: a fluorescent quantitative PCR-based detection kit is provided, which contains a specific detection primer of hsa_circRNA_0000384.
The sequence of the detection primer for fluorescent quantitative PCR is as follows
F:5'-CCCCAGAGCACGAGTAGTAG-3'
R:5'-TGCTGCAACTGGGTAAACAC-3'
The sequence of the beta-actin internal reference primer is as follows
F:5'-AGTGTGACGTGGACATCCGCA-3'
R:5'-ATCCACATCTGCTGGAAGGTGGAC-3'
In order to achieve the third object, the invention adopts the following technical scheme: provides an siRNA which can obviously reduce the expression of hsa_circRNA_0000384 in a liver cell cancer cell line and does not influence the expression of an hsa_circRNA_0000384 source gene MRPS35, and the siRNA is verified by utilizing a liver cancer cell line to inhibit the proliferation and migration of liver cancer cells by reducing the expression of hsa_circRNA_0000384.
The hsa_circRNA_0000384 specific siRNA sequence is as follows
F:5'-GUAGUCUUAAGACGGAAAGTT-3'
R:5'-CUUUCCGUCUUAAGACUACTT-3'
Drawings
FIG. 1 is an expression analysis of circular RNA markers.
FIG. 2 is a melting curve of detection primers used for fluorescence quantitative PCR detection of hsa_circRNA_0000384 expression.
FIG. 3 shows siRNA knockdown efficiency and specificity analysis.
FIG. 4 shows that decreasing hsa_circRNA_0000384 expression inhibits proliferation and migration of hepatoma cells.
Detailed Description
The present invention will be described in further detail with reference to the following examples and drawings.
The following experimental methods are conventional methods unless otherwise specified, and the experimental materials used are readily available from commercial companies unless otherwise specified.
Example 1
1.1 collection of samples
The cancer tissues and the paracancestral tissues of 20 hepatocellular carcinoma patients were collected.
1.2 extraction and reverse transcription of Paraffin tissue and cell line Total RNA
Paraffin tissue RNA was extracted using Paraffin tissue RNA extraction kit (Tiangen Co.) and RNA concentration was determined using Nano Drop. And extracting RNA of the liver cell line and the liver cancer cell line by using a Trizol method, and measuring the concentration of the RNA by using a Nano Drop.
Reverse transcription was performed using a reverse transcription kit (TAKARA Co.) as follows:
| composition of the components | Volume of |
| Total RNA | 500ng |
| RandomPrimer(50μM) | 0.5μL |
| dNTPs Mixture(10mM) | 0.5μL |
| 5x M-MLV Buffer | 2μL |
| RNase Inhibitor(40U/μl) | 0.25μL |
| RTase M-MLV(RNase H-)(200U/μl) | 0.5μL |
| RNase free H 2 O | up to 10μL |
Reaction conditions
30 ℃ for 10 minutes; 42 ℃ for 1 hour; 70 ℃ for 15 minutes; and cooling on ice to obtain cDNA solution.
1.4 dilution of cDNA
After reverse transcription, 40. Mu.L of RNase free H was added to each well 2 O dilution.
1.5 fluorescent quantitative PCR
Design of hsa_circRNA_0000384 Cross-cut Point primers three pairs of cross-cut Point primers (synthesized by Biotechnology) were designed and synthesized for PCR detection, from which a clear and single primer combination of primer amplification strips is preferred as follows:
F:5'-CCCCAGAGCACGAGTAGTAG-3'
R:5'-TGCTGCAACTGGGTAAACAC-3'
the size of the PCR product was 137bp. The PCR products were determined to be correct by sequencing.
The relative expression level was calculated by detecting hsa_circRNA_0000384 using SYBR Green Mixture (GenStar Co.) and beta-actin as an internal reference.
Fluorescent quantitative PCR system
PCR conditions
95 ℃ for 2min;40 PCR cycles (95 ℃,15 seconds; 60 ℃,15 seconds (fluorescence is collected)). After the amplification reaction was completed, the mixture was slowly heated from 60℃to 99 ℃ (automatic instrument-Ramp Rate of 0.05 ℃/sec) to obtain a melting curve of the PCR product.
Example 2
2 selection of 1hsa_circRNA_0000384 specific siRNA
Based on the sequence of hsa_circrna_0000384, 2 pairs of siRNA (synthesized by Ji Ma gene corporation) were designed that cross the hsa_circrna_0000384 loop cut point. The following siRNAs are preferred by detecting their specificity and knockdown efficiency, and their sequences are as follows:
F:5'-GUAGUCUUAAGACGGAAAGTT-3'
R:5'-CUUUCCGUCUUAAGACUACTT-3'
2.2siRNA transfected cells
Huh-7 cell line, HCCLM3 cell line was plated in 12-well plates, cells were transfected with lipo2000 transfection reagent (purchased from Ing Jieski Co.) at 60% -70%, 2. Mu.L siRNA (20. Mu.M) was added per well, cellular RNA was extracted after 48 hours, and expression of hsa_circRNA_0000384 and MRPS35 was detected by fluorescent quantitative PCR after reverse transcription.
Example 3
3.1CCK-8 detection of cell proliferation
Cells were plated in 24-well plates, transfected with siRNA or NC-siRNA, after 24 hours, cells were digested, counted, and plated in 96-well plates at about 1000 per well, 100 μl total volume per well, 5 time points were determined, 3 replicates per time point. After the cells were attached, 10. Mu.L of CCK-8 reagent (purchased from Biyundian Co.) was added to each well as a zero point, and the cells were incubated at 37℃for 1 hour in a dark place, and the absorbance at 450nm was measured by using an ELISA reader.
3.2 scratch assay to detect cell migration
Cells were plated in 12 well plates, transfected with siRNA or NC-siRNA, after 24 hours, cells were digested, passaged into 6 well plates, after cells were grown, replaced with serum-free medium, streaked straight in the well plates with a 10 μl gun head, photographed with a microscope bright field, recorded as zero point, photographed at the same position after 48 hours, and gap widths were compared.
3.3 in vivo tumor growth Rate was detected in nude mice tumorigenesis experiments
Cells were plated on 10cm dishes, transfected with siRNA or NC-siRNA, after 24 hours, the cells were digested, counted, BALB/c nude mice were injected subcutaneously with 200 ten thousand cells each, tumor size was measured every 5 days, tumors were removed 25 days, and weights were calculated.
Claims (3)
1. The application of a specific primer for detecting the expression quantity of a circRNA marker hsa_circRNA_0000384 for diagnosing the hepatocellular carcinoma in preparing a kit for diagnosing the hepatocellular carcinoma.
2. The use according to claim 1, wherein the specific primers for hsa_circ_0000384 expression are:
F:5'-CCCCAGAGCACGAGTAGTAG-3'
R:5'-TGCTGCAACTGGGTAAACAC-3'。
3. use of an siRNA for the preparation of a reagent for inhibiting the growth and metastasis of hepatocellular carcinoma, wherein the siRNA is:
F:5'-GUAGUCUUAAGACGGAAAGTT-3'
R:5'-CUUUCCGUCUUAAGACUACTT-3'。
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