CN109652550B - Application of circ-HUWE1 as diagnosis biomarker and treatment target of gastric cancer and colorectal cancer - Google Patents

Application of circ-HUWE1 as diagnosis biomarker and treatment target of gastric cancer and colorectal cancer Download PDF

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CN109652550B
CN109652550B CN201910052867.4A CN201910052867A CN109652550B CN 109652550 B CN109652550 B CN 109652550B CN 201910052867 A CN201910052867 A CN 201910052867A CN 109652550 B CN109652550 B CN 109652550B
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李向南
王振军
陈泓宇
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Abstract

The invention discloses application of circular RNA HUWE1(circ-HUWE1) as a novel potential diagnosis biomarker and therapeutic target of gastric cancer and colorectal cancer. The circ-HUWE1(hsa _ circ _0140388| chrX: 53641494-53644407- | HUWE1) is formed by reverse splicing of exon 20-23 of HUWE1 gene, and the cyclization sequence has 589 bases. The invention prepares the qRT-PCR primer of circ-HUWE1 and small interfering RNA (siRNA) for interfering circ-HUWE1 in vitro. As compared to normal controls, circ-HUWE1 was significantly up-regulated in tumor and plasma samples from both gastric and colorectal cancer patients. In vitro experiments show that circ-HUWE1 plays a role of a oncogene in gastric cancer and colorectal cancer cells. The research result of the invention shows that circ-HUWE1 is a new potential biomarker and therapeutic target for diagnosing gastric cancer and colorectal cancer.

Description

Application of circ-HUWE1 as diagnosis biomarker and treatment target of gastric cancer and colorectal cancer
Technical Field
The invention belongs to the technical field of medicine, and relates to application of a circular RNA HUWE1 as a diagnosis biomarker and a treatment target of gastric cancer and colorectal cancer.
Background
More than 60% of malignant tumors are digestive system tumors, wherein gastric cancer and colorectal cancer are the most common digestive system tumors. According to the latest global cancer statistical report of 2018, the stomach cancer mortality rate is third worldwide and the incidence rate is fifth worldwide in all malignant tumors; colorectal cancer mortality is second worldwide and morbidity is third worldwide. Current studies indicate that molecular pathogenesis of gastric cancer includes gene mutations (P53, AR1D1A, FAT4, CDH1), tumorigenesis-related signal pathway abnormalities (Wnt, RTK, PI3K signal pathway), chromosome instability (somatic copy number change, chromosome translocation), epigenetics (mismatch repair gene CpG island cytosine methylation, histone modification), microsatellite instability; molecular pathogenesis of colorectal cancer includes oncogene activation (K-ras, c-myc, EGFR), oncogene inactivation (APC, DCC, P53), mismatch repair gene mutation (hMLH1, hMSH2, hMSH6, hPMS2), and gene overexpression (COX-2, CD44v), among others. However, only a small fraction of the above molecular targets have been applied in clinical practice for gastric and colorectal cancer. Therefore, there is a need to explore other potential pathogenesis leading to the development of gastric and colorectal cancer.
Circular RNA (circular RNA/circular RNA) is a large class of noncoding RNA that covalently bind to form a circular structure. Circular RNA was first discovered in 1976 in plant viruses and was originally thought to be a class of mis-spliced and unexplored RNA. Subsequent research finds that the circRNA has an important regulation effect on gene expression in organisms, and the circRNA has a structural characteristic of a closed ring structure without a 5 'cap end and a 3' tail end. This loop is formed by the reverse splicing of the upstream 3 'splice acceptor to the downstream 5' splice donor. This covalently bound circular closed structure results in a circRNA that is not affected by exonuclease and is more stable than linear RNA. In recent years, research shows that the circRNA has the following basic functions: adsorbing microRNA as competitive endogenous RNA (cepRNA); regulation of transcription and alternative splicing; acting on RNA binding proteins; translated into protein. Based on the above functions of circRNA, related studies have demonstrated that circRNA is closely associated with human diseases, including tumors. Therefore, the deep research on the action mechanism of the circRNA in gastrointestinal tract tumors has potential great significance for the diagnosis and treatment of the gastrointestinal tract tumors.
Disclosure of Invention
The invention provides application of circRNA HUWE1(circ-HUWE1) in diagnosis and treatment of gastric cancer and colorectal cancer. The invention discloses a circ-HUWE1 as a new potential diagnosis biomarker and treatment target for gastric cancer and colorectal cancer: circ-HUWE1 showed significant up-regulation in tumor and plasma samples from patients with gastric and colorectal cancer; the Receiver Operating Characteristic (ROC) curve shows that the circ-HUWE1 has good potential for diagnosing gastric cancer and colorectal cancer; circ-HUWE1 promotes the proliferation of gastric and colorectal cancer cells.
The first purpose of the invention is to provide a potential diagnosis biomarker and a treatment target point of gastric cancer and colorectal cancer, which is circ-HUWE1(hsa _ circ _0140388| chrX: 53641494-. The circ-HUWE1 is formed by reverse splicing of exon 20-23 of HUWE1 gene, and the circulant sequence has 589 bases.
The second purpose of the invention is to provide a primer pair which specifically recognizes the circ-HUWE1, and comprises an upstream primer and a downstream primer. The nucleotide sequence of the upstream primer is shown as SEQ ID No. 2; the nucleotide sequence of the downstream primer is shown as SEQ ID No. 3.
The third purpose of the invention is to disclose the expression of circ-HUWE1 in tumor tissues of patients with gastric and colorectal cancers.
A fourth object of the present invention is to disclose the expression of circ-HUWE1 in plasma of patients with gastric and colorectal cancer, and the corresponding ROC curve for evaluating the diagnostic ability of circ-HUWE 1.
A fifth object of the invention is to disclose the function of circ-HUWE1 in gastric and colorectal cancer cells.
The invention has the following beneficial effects: 1) the circ-HUWE1 can be used as a biomarker for diagnosing the gastric cancer and the colorectal cancer and a drug treatment target point for the first time; 2) circ-HUWE1 was significantly upregulated in both tumor and plasma samples from both gastric and colorectal cancer patients compared to normal controls; 3) the ROC curve shows that circ-HUWE1 has good ability to diagnose gastric cancer and colorectal cancer. 4) The result of the invention shows that the interference of circ-HUWE1 can inhibit the proliferation of gastric cancer and colorectal cancer cells, and shows that circ-HUWE1 plays a role of cancer promotion genes in the occurrence and development of gastric cancer and colorectal cancer, thereby providing a new target for clinical treatment of gastric cancer and colorectal cancer.
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FIG. 1 is a schematic diagram of the biological synthesis and structure of circ-HUWE 1.
FIG. 2 is a graph showing the results of examination of tissue expression levels of gastric cancer patients using the circ-HUWE1 primer. Represents p value < 0.01.
FIG. 3A is a graph showing the results of plasma expression measurements in gastric cancer patients and physical examiners using the circ-HUWE1 primer; and B is an ROC curve chart for evaluating the potential of the circ-HUWE1 in diagnosing the gastric cancer. Represents p value < 0.0001.
FIG. 4 is a graph showing the results of the measurement of the tissue expression level of a patient with colorectal cancer using the circ-HUWE1 primer. Represents a p value < 0.001.
FIG. 5A is a graph showing the results of plasma expression level measurements of colorectal cancer patients and healthy subjects using the circ-HUWE1 primer; b is ROC plot for evaluating the potential of circ-HUWE1 in diagnosing colorectal cancer. Represents p value < 0.0001.
FIG. 6 is a qRT-PCR validation graph of the transfection and knockdown efficiency of circ-HUWE1 small interfering RNA (siRNA) in both HGC-27 and SW480 cell lines. si-NC stands for negative control group; si-circHUWE1#1 and si-circHUWE1#2 represent groups of siRNA transfecting two reverse splice sites targeting circ-HUWE1, respectively; represents a p value < 0.05, represents a p value < 0.01, represents a p value < 0.001, represents a p value < 0.0001.
FIG. 7 is a graph showing the results of cell proliferation changes of gastric cancer and colorectal cancer after knocking down circ-HUWE 1. Represents a p value < 0.05, represents a p value < 0.01, represents a p value < 0.001, represents a p value < 0.0001.
Detailed Description
The following detailed description of embodiments of the present invention is provided in connection with the accompanying drawings and examples. The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example (b):
1. experimental materials and methods:
clinical samples: tumor tissues and paracancerous normal mucosal tissues of 30 patients with gastric and 60 colorectal cancers were collected during 2016-. The tissue specimen is quickly frozen by liquid nitrogen and then is transferred to a refrigerator at the temperature of minus 80 ℃. Preoperative blood was collected from 30 gastric cancer and 60 colorectal cancer patients. Blood from 45 healthy examinees age-and-gender-matched was collected as a control. Plasma was obtained by centrifugation and stored in a freezer at-80 ℃.
Cell lines and cell culture: human gastric cancer cell line HGC-27 and colorectal cancer cell line SW480, purchased from American Type Culture Collection (ATCC). Cell culture 100U/ml penicillin and 100. mu.g/ml streptomycin (Gibco, NY, USA) were added to DMEM (Invitrogen, Carlsbad, CA, USA) medium containing 10% fetal bovine serum (Gibco, NY, USA). At 37 deg.C, contains 5% CO 2 Culturing the cells in the environment of (a).
RNA extraction and real-time fluorescent quantitative PCR (qRT-PCR): by usingTrizol (Invitrogen, Carlsbad, Calif., USA) extracts total RNA from cells and tissues; using TRIzol TM LS (Invitrogen, Carlsbad, Calif., USA) extracts total RNA from plasma. The reverse transcription kit adopts PrimeScript TM RT reagent Kit (TaKaRa, Dalian, China); the fluorescent quantitative PCR kit adopts TB Green TM Premix Ex Taq TM II (TaKaRa, Dalian, China); performing PCR reaction with AB17500 real-time fluorescent quantitative PCR instrument (Applied Biosystems, Foster City, CA, USA); adopting 18S rRNA as an internal reference; by using 2 -ΔΔCt Calculating the relative expression quantity of RNA; the primers were synthesized by Biotechnology engineering (Shanghai) GmbH; primer sequences are shown in Table 1.
TABLE 1 primer sequences used for qRT-PCR
Figure BSA0000178015500000021
Transfection: specific small interfering RNA (siRNA) targeting the reverse splice site of circ-HUWE1 and a negative control (si-NC) were synthesized from the Jima gene (Shanghai); 50nM siRNA was transfected into gastric and colorectal cancer cells using Lipofectamine 3000(Invitrogen, Carlsbad, Calif., USA); the siRNA sequences are shown in Table 2.
TABLE 2 siRNA sequences
Figure BSA0000178015500000031
CCK-8 experiment: cell proliferation experiments were performed using CCK-8 reagent (Dojindo Laboratories, Kumamoto, Japan). About 1000 cells were seeded in 96-well plates. At 0, 24, 48, 72, 96 hours, 10. mu.l CCK-8 reagent was added to the 96-well plate. After two hours of incubation, 450nm Optical Density (OD) values were read using a multifunctional microplate reader (Thermo Fisher Scientific, Waltham, MA, USA). Each group was tested for 5 replicates.
Statistical analysis: the results were statistically analyzed using SPSS 23.0 software. Plots were made using GraphPad Prism 7.0 software. Statistical analysis was performed using paired t-test or Wilcoxon signed rank test as appropriate. Data are presented as mean ± standard deviation of at least three independent experiments, all P values are bilateral and P < 0.05 is considered statistically significant.
2. The experimental results are as follows:
as shown in FIG. 1, circ-HUWE1 was formed by reverse splicing of exon 20-23 of HUWE1 gene.
As shown by qRT-PCR results in fig. 2, circ-HUWE1 was significantly up-regulated in gastric cancer tumor tissue compared to normal tissue. Represents p value < 0.01.
As shown in the qRT-PCR results of FIG. 3A, circ-HUWE1 was significantly up-regulated in the plasma of gastric cancer patients compared to healthy examiners. The area under the ROC curve (AUC) in FIG. 3B was 0.856, indicating that circ-HUWE1 has good potential for diagnosing gastric cancer patients. Represents p value < 0.0001.
As shown in figure 4 by the qRT-PCR results, circ-HUWE1 was significantly up-regulated in tumor tissue in colorectal cancer patients compared to normal tissue. Represents a p value < 0.001.
As shown by qRT-PCR results in fig. 5A, circ-HUWE1 was significantly up-regulated in plasma of colorectal cancer patients compared to healthy examiners. AUC in FIG. 5B was 0.822, indicating that circ-HUWE1 has good potential for diagnosing colorectal cancer patients. Represents p value < 0.0001.
As shown in FIG. 6, after si-circHUWE1#1 and si-circHUWE1#2 were transfected in HGC-27 gastric cancer and SW480 colorectal cancer cell lines, the expression level of circ-HUWE1 was significantly reduced, while the expression level of its corresponding HUWE1 mRNA was not significantly changed. Represents a p value < 0.05, represents a p value < 0.01, represents a p value < 0.001, represents a p value < 0.0001.
As shown in FIG. 7, after transfection of si-circHUWE1#1, the proliferation capacity of gastric and colorectal cancer cells was significantly decreased. Represents a p value < 0.05, represents a p value < 0.01, represents a p value < 0.001, represents a p value < 0.0001.
The results show that circ-HUWE1 is up-regulated in tumor tissues and blood plasma of patients with gastric cancer and colorectal cancer; the ROC curve shows that circ-HUWE1 has good ability to diagnose gastric cancer and colorectal cancer. In vitro experiments show that the circ-HUWE1 promotes the proliferation of cells of the gastric cancer and the colorectal cancer, and show that the circ-HUWE1 plays a role of cancer promotion genes in the gastric cancer and the colorectal cancer; the circ-HUWE1 is expected to become a new biomarker and a new therapeutic target for diagnosing the gastric cancer and the colorectal cancer.
The above-described embodiments are merely exemplary and are merely preferred embodiments of the present invention, and the scope of the present invention is not limited thereto, and those skilled in the art can make various modifications and variations without departing from the technical principle of the present invention, and these modifications and variations should be construed as the scope of the present invention.
Figure ISA0000178015520000011
Figure ISA0000178015520000021

Claims (4)

1. The application of circular RNA circ-HUWE1 in preparing gastric cancer and colorectal cancer diagnostic products is characterized in that: the circBase ID of the circular RNA circ-HUWE1 is hsa _ circ _0140388, is derived from a human X chromosome, is generated by reverse splicing and cyclization of No. 20 to No. 23 exons of a HUWE1 host gene, the length of a cyclized mature sequence of the cyclized mature sequence is 589bp, and the nucleotide sequence is shown as SEQ ID No. 1.
2. Use according to claim 1, characterized in that: the product is selected from a formulation, a chip or a kit.
3. Use according to claim 1, characterized in that: the product comprises a primer pair which specifically recognizes the circ-HUWE 1.
4. Use according to claim 3, characterized in that: the primer pair comprises an upstream primer and a downstream primer, and the nucleotide sequence of the upstream primer is shown as SEQ ID No. 2; the nucleotide sequence of the downstream primer is shown as SEQ ID No. 3.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103502473A (en) * 2011-03-01 2014-01-08 耶鲁大学 Predicting gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs)
US20150141273A1 (en) * 2012-04-26 2015-05-21 Stichting Vu-Vumc Biomarkers

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103502473A (en) * 2011-03-01 2014-01-08 耶鲁大学 Predicting gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs)
US20150141273A1 (en) * 2012-04-26 2015-05-21 Stichting Vu-Vumc Biomarkers

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RNA sequencing reveals the expression profiles of circRNA and indicates that circDDX17 acts as a tumor suppressor in colorectal cancer;Xiang-Nan Li等;《Journal of Experimental & Clinical Cancer Research》;20181227;第37卷(第1期);325 *

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