CN113049824A - Application of apolipoprotein ApoA1 in detection of drug resistance of cervical cancer to platinum chemotherapy - Google Patents
Application of apolipoprotein ApoA1 in detection of drug resistance of cervical cancer to platinum chemotherapy Download PDFInfo
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Abstract
The invention relates to application of apolipoprotein ApoA1 in the detection of the platinum chemotherapy resistance of cervical cancer, and the research of the invention confirms that apolipoprotein ApoA1 can be used as a platinum chemotherapy resistance marker of cervical cancer, and promotes cell proliferation by STAT1 to promote the chemotherapy resistance of platinum drugs caused by cell proliferation.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to application of apolipoprotein ApoA1 in detection of drug resistance of cervical cancer to platinum chemotherapy.
Background
Cervical cancer is the fourth most common malignancy that endangers female health worldwide. According to the statistics in 2012, the number of new cases of cervical cancer is 52.8 ten thousand and the number of new death cases is 26.6 ten thousand every year in the world, and China is the country with the most new cases and death cases, so that the cervical cancer seriously threatens the lives of women. Although recently HPV vaccines have been marketed in our country, they are only suitable for a few specific populations and HPV vaccines do not prevent HPV infection of all types of high-risk types, meaning that it is not possible to completely block the development of cervical cancer; although a complete cervical cancer screening system is available for many years, the cervical cancer screening system can be found and treated early. However, based on the national conditions of China, the region is wide, the population is large, the culture level between urban and rural areas is still different, the medical care knowledge is not widely popularized, and the cervical cancer patients are in middle and late stages and have a youthful trend until the present time. Chemotherapy, as the third treatment means after radiotherapy and surgical treatment of cervical cancer, plays a major role in the treatment of advanced and recurrent cervical cancer, and is incorporated into the treatment guidelines of patients with cervical cancer by the National Comprehensive Cancer Network (NCCN). However, patients who develop chemoresistance have a significantly reduced five-year survival rate. Earlier researches show that paclitaxel and platinum combined preoperative neoadjuvant chemotherapy for patients with local advanced cervical cancer has a good tumor reduction effect, creates an opportunity for surgery, has an effective rate of 90%, and still nearly 10% of patients have chemotherapy resistance, so that neoadjuvant chemotherapy fails, and the patients lose the opportunity of surgery and even progress of disease. Chemotherapy resistance is one of the key factors affecting the treatment effect of advanced and recurrent cervical cancer. Therefore, intensive research on the chemotherapy resistance of cervical cancer is urgently needed.
Meanwhile, currently, the research on the ApoA1 and the tumor chemotherapy drug resistance is less, and in the field of gynecological tumors, proteomics research shows that the ApoA1 is highly expressed in platinum chemotherapy drug resistance samples of ovarian cancer compared with tissue samples beside cancer. In the study of Wuwenjuan, differential expression proteins in serum samples between platinum drug-resistant groups and platinum sensitive groups are screened by a quantitative proteomics technology, 32 proteins are expressed up-regulated, and 30 proteins are expressed down-regulated, wherein the up-regulated proteins comprise ApoA1, and the ApoA1 is related to the drug resistance of platinum chemotherapy. Cruz and the like find 189 differential proteins in platinum-resistant ovarian cancer cells and tissues by utilizing a proteomic technology, find related proteins aiming at a proteasome ubiquitination drug-resistant signal pathway, and confirm that ApoA1 is significantly up-regulated in the platinum-chemotherapeutic drug-resistant related differential proteins through tissue sample verification, so that the protein can be used as a platinum-chemotherapeutic drug-resistant prediction marker for ovarian cancer. However, no predictive target point and therapeutic target point exist for the drug resistance of the cervical cancer at present, and the mechanism of the ApoA1 participating in the drug resistance of the platinum chemotherapy of the cervical cancer is not clear.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a new application of apolipoprotein ApoA1, namely an application of apolipoprotein ApoA1 in the detection of the platinum chemotherapy drug resistance of cervical cancer. Through the research of the invention, the apolipoprotein ApoA1 can be used as a platinum chemotherapy drug resistance marker for the cervical cancer, can promote cell proliferation and enables the chemotherapy drug resistance of the platinum drugs.
In order to solve the technical problems, the invention provides the application of apolipoprotein ApoA1 in the detection of the drug resistance of cervical cancer to platinum chemotherapy.
Further, apolipoprotein ApoA1 is used as a platinum chemotherapy drug resistance marker of cervical cancer.
Further, the detection is the immunohistochemistry of the cervical cancer tissue by detecting the apolipoprotein ApoA1 of the subject. As a result, the ApoA1 positive expression rate of the cervical cancer patients resistant to the platinum chemotherapy is higher than that of the cervical cancer patients sensitive to the platinum chemotherapy.
Further, apolipoprotein ApoA1 promotes cell proliferation, making platinum drugs resistant to chemotherapy.
Further, apolipoprotein ApoA1 promotes cell proliferation by regulating MAPK signaling pathway through STAT1, making platinum drugs resistant to chemotherapy.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a new application of apolipoprotein ApoA1, and particularly relates to the application of apolipoprotein ApoA1 in the detection of the drug resistance of platinum chemotherapy for cervical cancer, which confirms that apolipoprotein ApoA1 can be used as a drug resistance marker of platinum chemotherapy for cervical cancer through research, and promotes the cell proliferation to cause the drug resistance of platinum chemotherapy by regulating an MAPK signal channel through STAT 1.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a graph of the corresponding IC50 values for the OE group in SiHa cells of the invention;
FIG. 2 is a graph of the corresponding IC50 values for the NC group in SiHa cells of the invention;
FIG. 3 is a schematic view of a nude mouse graft tumor according to the present invention;
FIG. 4 is a growth curve of a nude mouse graft tumor according to the present invention;
FIG. 5 is a comparison of the weight of transplanted tumors in groups of nude mice according to the present invention;
FIG. 6 is a graph showing the effect of over-expressing ApoA1 of the present invention on the clonality of Caski cells;
FIG. 7 is a graph showing the effect of overexpression of ApoA1 on SiHa cell clonogenic capacity;
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
Example 1
Screening platinum chemotherapy drug resistance differential protein from cervical squamous carcinoma cells:
the cervical squamous carcinoma SiHa cells are cultured in a platinum chemotherapeutic drug for 14 days, a SiHa cell line resistant to the platinum chemotherapeutic drug is cultured, proteins are extracted, the total protein number is identified to be 7139 through iTRAQ reagent marking and LC-MS/MS, a biomarker screening result in a low molecular weight range (1000-. 85 different proteins with statistical significance, namely carboplatin group/Mock group, 70 up-regulated proteins and 15 expressed down-regulated proteins are screened out by GO classification and KEGG annotation assistance. The test results are shown in table 1:
TABLE 1 Calplatin group and MOCK group differentially expressed proteins (15 upregulated proteins)
Example 2
Verification of over-expression of ApoA1 platinum chemotherapy drug-resistant protein:
according to domestic and foreign documents and GO and KEGG analysis results, ApoA1 with up-regulated expression is selected as a target protein for gene overexpression. An ApoA1 overexpressing lentivirus (no fluorescence) was constructed and co-cultured with SiHa cells. The expression of the over-expressed ApoA1 in SiHa cells is detected by Real-PCR, and the expression abundance of the ApoA1 gene in an over-expression (OE) group is 355.459 times that of an NC group. CCK-8 was used to test the effect of ApoA1 overexpression on the concentration of chemotherapeutic drugs (carboplatin). After the carboplatin group over-expresses ApoA1, the concentration of IC50 corresponding to 86.31ug/ml is higher than that of IC50 corresponding to 51.88ug/ml in the NC group (as shown in figure 1-2), which proves that ApoA1 is related to SiHa cell (squamous cell carcinoma) platinum drug resistance.
Example 3
Expression of ApoA1 in cervical cancer-resistant tissues:
in 10 cases of cancer focus tissues of patients with locally advanced cervical squamous carcinoma, all patients receive NACT treatment of CBP combined with paclitaxel before the first operation, and the patients are classified into Complete Remission (CR), Partial Remission (PR), Stable Disease (SD), and disease Progression (PD) according to WHO solid tumor curative effect evaluation standard (RECIST) by taking 21-28 days after the chemotherapy treatment as a time standard, wherein SD + PD is chemotherapy resistant drug group, CR is chemotherapy sensitive group, and each group has 5 specimens. ApoA1 protein expression was determined by IHC. The results show that: ApoA1 is highly expressed in 40% (2/5) of squamous cell carcinoma tissues in the chemotherapy-resistant group, while only 20% (1/5) of ApoA1 is highly expressed in the chemotherapy-sensitive group. The average staining intensity scores of the chemotherapy resistant drug group and the chemotherapy sensitive group are both 6 +/-1.67, and the test results are shown in table 2:
table 2IHC assay for expression of ApoA1 in cervical cancer tissue
Example 4
ApoA1 was shown to be associated with platinum chemotherapy resistance to cervical cancer in nude mice:
siha cells are selected to carry out nude mouse tumorigenesis experiments and chemotherapy, and the experiments are divided into an NC group, an OE group, an NC + CBP group and an OE + CBP group. Siha cells over-expressing ApoA1 are inoculated to the subcutaneous surface of a nude mouse, platinum (CBP) chemotherapy is given when the diameter of a tumor body is 7mm, the length and the short diameter of the transplanted tumor are measured once every 3 days, the tumor volume is calculated, and a tumor growth curve is drawn. The solid pattern of the transplanted tumor of the nude mice at the end of the experiment is shown in fig. 3, after 14 days of CBP intervention, compared with the NC group, the tumor volume of the OE group is significantly reduced, and the difference has statistical significance (P <0.01), which indicates that the over-expression of ApoA1 can inhibit the tumor growth; compared with the NC group, the NC + CBP group has obviously reduced tumor volume, and the difference has statistical significance (P is less than 0.05), which indicates that CBP chemotherapy can inhibit tumor growth; whereas the difference in tumor volume between the OE and OE + CBP groups was not statistically significant (P > 0.05), indicating that Siha cells were less sensitive to CBP chemotherapy after overexpression of ApoA1 (as shown in FIGS. 3-4).
The subcutaneous transplanted tumors of nude mice were exfoliated and weighed 14 days after CBP chemotherapy administration, and the results showed: compared with the NC group, the OE group has obviously reduced tumor weight, and the difference has statistical significance (P <0.01), which indicates that the over-expression of ApoA1 can inhibit tumor growth; compared with the NC group, the tumor weight of the NC + CBP group is obviously reduced, and the difference has statistical significance (P is less than 0.01), which indicates that the CBP chemotherapy can inhibit the tumor growth; whereas the difference in tumor body weight between the OE group and the OE + CBP group was not statistically significant (P > 0.05), indicating a decreased sensitivity of SiHa cells to CBP chemotherapy after ApoA1 overexpression (as shown in fig. 5).
Example 5
The mechanism of the over-expression of ApoA1 in the SiHa cell of cervical cancer to influence the drug resistance of platinum chemotherapy is as follows:
cell function tests are carried out on C-33A, Caski and SiHa cervical squamous carcinoma cell line,
(1) cell cloning experiments
Plate cloning experiments were used to observe that overexpression of ApoA1 detected clonogenic capacity in C-33A, Caski and SiHa cells, which were cultured for 12 days before counting cell clones. The results show that: in Caski and SiHa cells, the cell clone number of the OE + CBP group is obviously increased compared with that of the NC + CBP group, and the difference has statistical significance. The clone number did not increase significantly in C-33A (as shown in FIGS. 6-7, wherein (A) NC group, (B) NC + CBP, (C) OE, (D) OE + CBP (P < 0.05)).
(2) Cell proliferation, apoptosis and cell transfer assays
The influence of over-expression of ApoA1 on the proliferation of cervical cancer cells is researched, C-33A, Caski and SiHa cells are cultured in carboplatin for 48 hours, and NC group and OE group are cultured for 1 day, 2 days, 3 days, 4 days and 5 days respectively, and MTT detection is carried out, so that compared with NC + CBP, the proliferation of cells in the OE + CBP group has no obvious change.
The influence of over-expressed ApoA1 on apoptosis of CBP chemotherapeutic cells in C-33A, Caski and SiHa cells is researched, and apoptosis detection is carried out on cells of an NC group and an OE group by a Tunel method after the cells of the NC group and the OE group are treated by CBP for 48 hours, and the results show that: the apoptosis difference of NC group and OE group has no statistical significance (P > 0.05).
The influence of over-expressing ApoA1 on the migration of CBP chemotherapeutic cells in C-33A, Caski and SiHa cells is researched, and cell migration detection is carried out by a Transwell method after NC group cells and OE group cells are treated by CBP for 48 hours, and the results show that: the cell migration differences of the NC group and the OE group have no statistical significance (P > 0.05).
Example 6
Protein polypeptide mass spectrometry (TMT) detects differential proteins downstream of the overexpressed APOA1 and performs PRM validation:
the over-expressed APOA1 is subjected to TMT labeling, downstream differential expression proteins of over-expressed APOA1 are searched through GO and KEGG bioinformatics analysis, 29 downstream differential expression proteins are searched through IPA associated word analysis (chemotherapy resistance, tumor metastasis, recurrence and signal path), the PRM identification is carried out, the differences have statistical significance (P <0.05) test, and the test results are shown in Table 3. In combination with literature reports, the participation of APOA1 in MAPK signaling pathway through the regulation of downstream STAT1 enhances the resistance to platinum chemotherapy.
TABLE 3PRM validation of TMT-screened APOA1 downstream protein
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and such modifications or alterations do not depart from the essence of the corresponding technical solution.
Claims (5)
1. The apolipoprotein ApoA1 is used for detecting the drug resistance of cervical cancer to platinum chemotherapy.
2. The use according to claim 1, characterized in that apolipoprotein ApoA1 is used as a platinum-based chemotherapy resistance marker for cervical cancer.
3. The use of claim 2, wherein said detection is immunohistochemistry of cervical cancer tissue by detecting apolipoprotein ApoA1 in a subject.
4. The use of claim 1 wherein the apolipoprotein ApoA1 promotes cell proliferation and renders the platinum group drug resistant to chemotherapy.
5. The use according to claim 4, characterized in that apolipoprotein ApoA1 promotes cell proliferation by STAT1 modulating the MAPK signaling pathway, rendering the platinum group drugs resistant to chemotherapy.
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| WO2012019300A1 (en) * | 2010-08-10 | 2012-02-16 | Siu K W Michael | Endometrial cancer biomarkers and methods of identifying and using same |
| CN103570826A (en) * | 2013-08-30 | 2014-02-12 | 新疆医科大学 | New generation of cervical cancer specific early-warning plasma protein |
| CN110058024A (en) * | 2019-04-19 | 2019-07-26 | 山西医科大学第二医院 | The purposes of c-IAP1, MCM2 and P-gP before preparing cervical carcinoma NACT in sensitivity assessment reagent |
| CN111249465A (en) * | 2020-01-16 | 2020-06-09 | 山东大学齐鲁医院 | Application of TOPK as cervical cancer cisplatin resistance treatment target |
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