CN111893181B - Application of PRDM16 in enhancing sensitivity of colorectal cancer to oxaliplatin - Google Patents

Application of PRDM16 in enhancing sensitivity of colorectal cancer to oxaliplatin Download PDF

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CN111893181B
CN111893181B CN202010685883.XA CN202010685883A CN111893181B CN 111893181 B CN111893181 B CN 111893181B CN 202010685883 A CN202010685883 A CN 202010685883A CN 111893181 B CN111893181 B CN 111893181B
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prdm16
colorectal cancer
oxaliplatin
hct116oxr
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CN111893181A (en
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王允山
焦沁连
任一丹
杜鲁涛
王传新
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Second Hospital of Shandong University
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Abstract

The invention provides a drug resistance gene, wherein the sequence of PRDM16 is AGTGTGTGGCTGCTTCTGGACTCAAGGAGGAGGAGAGAGATTCCGCGAGCCGACACCATGCGATCCAAGG. The invention firstly detects the B region and the A region of the PRDM16 gene in HCT116 and HCT116OxR respectively through DLO Hi-C technology, and detects the higher expression of the PRDM16 gene in HCT116 OxR. Reduction of expression of PRDM16 in HCT116OxR PRDM16 is assessed for IC on resistant cells50Influence of value, the use of PRDM16 as a target gene for reducing colorectal cancer resistance is proposed.

Description

Application of PRDM16 in enhancing sensitivity of colorectal cancer to oxaliplatin
Technical Field
The invention belongs to the technical field of biology, and particularly relates to a method for enhancing sensitivity of colorectal cancer to oxaliplatin by taking PRDM16 as a target spot and application of the method.
Background
Colorectal cancer is a leading cause of cancer death worldwide. Chromosomal instability is a major driving force for colorectal cancer. Chromosomal instability is characterized by a large number of somatic chromosomal copy number aberrations that often affect oncogenes and cancer suppressor genes.
Currently, oxaliplatin resistance is a major challenge facing colorectal cancer patients clinically. It is not clear whether chromosomal instability is associated with the acquisition of oxaliplatin resistance.
In higher organisms, the genome is divided into two regions, the A region and the B region, which are generally spaced apart in the genome, with the A region usually associated with actively expressed open chromatin and the B region associated with transcriptionally repressed closed chromatin.
Disclosure of Invention
The invention provides application of improving the sensitivity of colorectal cancer to oxaliplatin by taking PRDM16 as a target point aiming at the phenomenon that the colorectal cancer is insensitive to the oxaliplatin clinically.
In order to achieve the purpose, the invention is realized by adopting the following technical scheme:
we detected the A/B region of colorectal cancer cell HCT116 and drug-resistant cell HCT116OxR by DLO Hi-C technology, and the result shows that PRDM16 gene is converted from the B region to the A region in the drug-resistant process, which indicates that PRDM16 can promote the acquisition of drug resistance by causing chromosome instability through converting structural domains.
A tumor therapeutic agent for increasing oxaliplatin sensitivity, which tumor therapeutic agent targets PRDM16, PRDM16 sequence AGTGTGTGGCTGCTTCTGGACTCAAGGAGGAGGAGAGAGATTCCGCGAGCCGACACCATGCGATCCAAGG.
Preferably, the tumor is colorectal cancer.
Preferably, the tumor treatment reagent is used for detecting the expression of PRDM16 in the sample by a high-throughput sequencing method and/or a quantitative PCR method.
Preferably, the high throughput sequencing method is DLO Hi-C sequencing.
Preferably, the method for quantitative PCR comprises primers that specifically amplify PRDM 16. The primer sequence is as follows: forward 5, -CGAGGCCCCTGTCTACATTC-3, reverse 5, -GCTCCCATCCGAAGTCTGTC-3.
Preferably, the method for reducing expression of PRDM16 comprises RNA interference (RNAi) technology. The RNA sequence is: 5, -AGGCUUCCUGGAGGAAGAGG-3.
Preferably, the sample is colorectal cancer cell HCT116 and colorectal cancer anti-oxaliplatin cell line HCT116OxR cell line (purchased from the cell resource center of the institute of basic medicine of Chinese medical sciences).
The application of the gene in preparing colorectal cancer preparations.
(1) DLO Hi-C technology
In higher organisms, the genome is divided into two regions, the A region and the B region, which are generally spaced apart in the genome, with the A region usually associated with actively expressed open chromatin and the B region associated with transcriptionally repressed closed chromatin. The development of Hi-C technology has enabled the identification of A/B regions throughout the genome.
(2) Real-time fluorescent quantitative PCR technology (Real-time PCR, RT-PCR)
The fluorescence detection PCR instrument can draw a dynamic change curve for the accumulation rate of the amplified sequence in the whole PCR process. The greater the initial concentration of target sequence in the reaction mixture, the fewer PCR cycles (typically expressed in terms of a particular threshold cycle number Ct) are required to obtain a particular yield of amplified product. RT-PCR has many advantages such as the specificity is high, the sensitivity is good, fast simple.
Compared with the prior art, the invention has the advantages and positive effects that:
the invention firstly detects that the PRDM16 gene is respectively positioned in the B region and the A region of a cancer cell HCT116 and a drug-resistant cell HCT116OxR by DLO Hi-C technology, and verifies that PRDM16 is more expressed in the HCT116OxR cell by RT-PCR (figure 1). The expression of PRDM16 was reduced in HCT116OxR cells by RNAi technology (figure 2), and the effect of PRDM16 on drug resistance of HCT116OxR was evaluated (figure 3), suggesting the use of PRDM16 in drug resistance therapy of colorectal cancer.
Drawings
FIG. 1 shows the expression of PRDM16 gene in HCT116 and HCT116 OxR.
FIG. 2 shows the expression of PRDM16 in HCT116OxR and si-HCT116OxR cells.
FIG. 3 is IC of HCT116OxR and si-HCT116OxR cells on oxaliplatin50The value is obtained.
Detailed Description
In order that the above objects, features and advantages of the present invention may be more clearly understood, the present invention will be further described with reference to specific embodiments. It should be noted that the embodiments and features of the embodiments of the present application may be combined with each other without conflict.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, however, the present invention may be practiced in other ways than those specifically described herein, and thus the present invention is not limited to the specific embodiments of the present disclosure.
The concrete operation steps
(one) A/B zone analysis
Collecting 1X 109Cross-linking and fixing HCT116 and HCT116OxR cells, cracking the cells, taking a proper amount of nuclear suspension, and limiting the nuclear suspensionCarrying out restriction enzyme digestion, extracting DNA by a phenol chloroform method, and identifying the DNA concentration by agarose gel running. And carrying out restriction enzyme digestion on the cyclized DNA by using restriction enzyme, and then carrying out gel cutting recovery, amplification and purification. After the library is constructed, detecting the insert size of the library by using Agilent 2100, and after the insert size meets the preset condition, accurately quantifying the effective concentration of the library by using a PCR method (the effective concentration of the library)>2 nM) to ensure library quality. Processing an observer matrix by adopting an Observed/Expected (O/E) standardized method, processing the observer matrix by adopting an Iced to obtain an Iced matrix, and performing Normalization on the Iced matrix by adopting an O/E method to obtain a basic matrix for A/B composition analysis. The interaction in the chromosome is found to present a lattice pattern through an O/E heat map, and the lattice pattern of the heat map is more obvious by carrying out Pearson Correlation analysis on sites (Bin pair) of the O/E matrix and carrying out heat map through a site Correlation matrix. Analyzing the obtained Pearson Correlation matrix by PCA (principal Component analysis) to obtain a First eigenvector (eigentor) of each position (Bin) of the chromosome, wherein positive and negative labels of the First eigentor of the general Bin respectively represent the division of the A/B region.
(II) Total RNA sample preparation in HCT116 and HCT116OxR cells
Extracting total RNA in cells according to the instructions of the Feijie total RNA rapid extraction kit.
Taking HCT116 and HCT116OxR cells in good growth states, digesting and dropping, centrifuging and collecting, leaving cell masses and 100 mu l of supernatant, and fully shaking until no cell masses exist; adding 500 mul of RA2 solution into the treated sample tube, fully reversing and uniformly mixing for 5-10 times, and standing for 1min at room temperature; sucking the lysate into the inner casing, and centrifuging at 12000rpm for 1 min; taking out the inner sleeve, sucking and removing the liquid in the outer sleeve, then putting the inner sleeve back, adding 500 mu l of Wash buffer, and centrifuging at 12000rpm for 1 min; washing again; taking out the inner sleeve, and centrifuging again without adding washing liquid after absorbing and discarding the liquid in the outer sleeve; the inner cannula was transferred to a new 1.5ml EP tube and 50 μ l of eluent was added to the center of the membrane; after standing at room temperature for 1min, the mixture was centrifuged at 12000rpm for 1min to obtain total RNA.
(III) RT-PCR detection of PRDM16 expression in HCT116 and HCT116OxR cells
Reverse transcription was performed according to the PrimeScript TM RT reagent Kit instructions, reverse transcription reaction 15min at 37 ℃ and inactivation reaction 5sec at 85 ℃. The reaction system was set as follows:
5×PrimeScriptTM Buffer (for real time) 2µl
PrimeScriptTM RT Enzyme Mix Ⅰ 0.5µl
Oligo dT Primer(50µM) 0.5µl
Random 6 mers(100µM) 0.5µl
Total RNA 500ng
RNase Free ddH2O added to 10 μ l
RT-PCR was then performed using the synthesized cDNA as template according to the TB Green TM Premix Ex Taq TM II kit instructions. The reaction conditions were 40 cycles of 42 ℃ for 5min,95 ℃ for 30s of pre-denaturation, 95 ℃ for 5s, 58 ℃ for 30 s. The reaction system is as follows:
TB Green 5µl
ROX Reference Dye Ⅱ 0.2µl
PCR Forward Primer (10µM) 0.2µl
PCR Reverse Primer (10µM) 0.2µl
ddH2O 3.4µl
template cDNA 1 mu l
The total volume is 10 mu l
In the PCR experiments, the replicates and negative control experiments (no cDNA template added in the negative control experiments) were performed, and each sample was repeated 3 times in the quantification experiments. Relative expression level of PRDM16 with GAPDH as internal reference 2-ΔΔCtAnd (4) calculating.
(IV) RNAi technique
Will be 5X 105The individual cells were seeded in 6-well plates and the cells were allowed to growConfluency reached 70% the next day; adding 5 μ l Lipofectamine 2000 into 250 μ l Opti-MEM, and standing at room temperature for 5 min; add 5. mu.l siRNA to 250. mu.l Opti-MEM; mixing the diluted Lipofectamine 2000 and siRNA gently, and standing for 20min at room temperature; adding the mixed solution into the well plate paved the previous day, incubating for 4-6h, removing the mixed solution, and replacing with a normal culture medium containing serum. Total RNA was extracted after 48h and expression of PRDM16 was detected using RT-PCR.
(V) IC50Measurement of (2)
Taking HCT116 and HCT116OxR cells with good growth state, digesting, counting, and dividing by 5X 10 per well3The individual cells were seeded in 96-well plates, and the medium was added to 100. mu.l per well, and cultured in an incubator for 48 hours. Oxaliplatin (purchased from zilu pharmaceuticals) was added to each well in order at final concentrations of 0, 5, 10, 15, 20, 25, 30 μ M and the culture was continued for 48 h. Add 10. mu.l of CCK-8 to each well in the dark and incubate for 2h in the incubator. The light absorption of each well was measured using a microplate reader at a wavelength of 450 nm. Growth curves for each group were plotted using GraphPad Prism software.
Secondly, analyzing the results
The A region of PRDM16 gene in drug-resistant cell HCT116OxR was detected by DLO Hi-C technique, and the expression of PRDM16 in HCT116OxR was confirmed to be increased by RT-PCR, as shown in FIG. 1.
The expression of PRDM16 was reduced by RNAi technology in HCT116OxR cells and verified by RT-PCR, see figure 2.
IC of HCT116OxR cells on oxaliplatin following decreased expression of PRDM1650The value was 15. mu.M, see FIG. 3.
As can be seen from fig. 1, PRDM16 was expressed in higher amounts in HCT116OxR cells.
As can be seen in FIG. 2, the expression of PRDM16 decreased after transfection of the small interfering RNA of PRDM 16.
As can be seen in FIG. 3, after transfection of the small interfering RNA of PRDM16, the IC of the drug-resistant cells50The temperature dropped to 15. mu.M.
The above description is only a preferred embodiment of the present invention, and not intended to limit the present invention in other forms, and any person skilled in the art may apply the above modifications or changes to the equivalent embodiments with equivalent changes, without departing from the technical spirit of the present invention, and any simple modification, equivalent change and change made to the above embodiments according to the technical spirit of the present invention still belong to the protection scope of the technical spirit of the present invention.
SEQUENCE LISTING
<110> secondary Hospital of Shandong university
<120> use of PRDM16 for enhancing sensitivity of colorectal cancer to oxaliplatin
<130> 1
<160> 3
<170> PatentIn version 3.5
<210> 1
<211> 70
<212> DNA
<213> Artificial sequence
<400> 1
agtgtgtggc tgcttctgga ctcaaggagg aggagagaga ttccgcgagc cgacaccatg 60
cgatccaagg 70
<210> 2
<211> 40
<212> DNA
<213> Artificial sequence
<400> 2
cgaggcccct gtctacattc gctcccatcc gaagtctgtc 40
<210> 3
<211> 20
<212> RNA
<213> Artificial sequence
<400> 3
aggcuuccug gaggaagagg 20

Claims (4)

  1. Use of PRDM16 as a target gene for the manufacture of a medicament for increasing the sensitivity of colorectal cancer to oxaliplatin.
  2. 2. Application of a primer for specifically amplifying PRDM16 in preparation of a kit for detecting sensitivity of colorectal cancer to oxaliplatin, wherein the primer sequence is 5'-CGAGGCCCCTGTCTACATTC-3' in the forward direction and 5'-GCTCCCATCCGAAGTCTGTC-3' in the reverse direction.
  3. 3. Application of RNAi for reducing PRDM16 expression in preparation of drugs for improving sensitivity of colorectal cancer to oxaliplatin.
  4. 4. The use of claim 3, wherein the RNAi sequence is 5'-AGGCUUCCUGGAGGAAGAGG-3'.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102329871B (en) * 2011-09-29 2013-03-20 中南大学 Application method of low-methylation gene PRDM 16 (PR domain containing 16)
CN106480178B (en) * 2016-09-27 2019-11-19 华中农业大学 DLO Hi-C chromosomal conformation catching method
US20200048716A1 (en) * 2017-11-03 2020-02-13 Twister Biotech, Inc Using minivectors to treat ovarian cancer

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