CN104004830A - Use of Kin17 gene or protein in preparation of cervical cancer diagnosis and treatment medicaments - Google Patents

Use of Kin17 gene or protein in preparation of cervical cancer diagnosis and treatment medicaments Download PDF

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CN104004830A
CN104004830A CN201410188539.4A CN201410188539A CN104004830A CN 104004830 A CN104004830 A CN 104004830A CN 201410188539 A CN201410188539 A CN 201410188539A CN 104004830 A CN104004830 A CN 104004830A
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kin17
cervical cancer
protein
gene
cervical
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CN104004830B (en
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曾涛
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Southern Hospital Southern Medical University
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Abstract

The invention discloses a use of a Kin17 gene or protein in preparation of cervical cancer diagnosis and treatment medicaments. The inventor discoveries that an expression level of the Kin17 protein in normal cervical epithelial tissue and cervical benign lesion tissue cells is low but the expression level is high in cervical cancer tissue and thus the Kin17 protein keeps rapid proliferation activity of cervical cancer cells, is closely related to pathological parameters, chemotherapeutic effects and disease progress and has an important effect in cervical cancer generation and development. Through silencing of Kin17 expression in cervical cancer cells, cancer cell proliferation activity is inhibited and cervical cancer cell sensitivity to chemotherapeutic drugs is improved. The Kin17 gene or protein can be used as a novel cervical cancer diagnosis marker and medicament target. The Kin17 gene or protein can be used for cervical cancer early-identification diagnosis, patient prognosis evaluation and clinical treatment.

Description

The application in the diagnosis of preparation cervical cancer and healing potion of Kin17 gene or albumen
Technical field
The present invention relates to diagnostic markers and drug targets that cervical cancer is new, be specifically related to Kin17 gene or albumen and prepare the application in cervical cancer diagnosis, prognosis evaluation and healing potion.
Background technology
Cervical cancer is one of modal malignant tumour of women.The sickness rate of China's cervical cancer in 2012 is 12.96/10 ten thousand, accounts for 5.12% of whole female tumors formations, and China women's life and health in serious threat.Under cervical intraepithelial neoplasia change and mirror, early invasive carcinoma is generally asymptomatic, and Patients with Cervical Cancer is occurring after classical symptom, has been generally infiltrating carcinoma.And after effective treatment of the means such as underwent operative and chemotherapy, 80% I phase and II phase cervical cancer patient can obtain obvious curative effect.Early screening is most important with prognosis and the curative effect of diagnosis and treatment early to Patients with Cervical Cancer.At present still undesirable for clinical methods for screening and diagnosis index.General Chemotherapy of Cervical Cancer medicine lacks tumour-specific, strong toxicity, and side effect is large.It is good that molecular targeted therapy method has specificity, and pair is rented little feature, in the patient for the treatment of Patients with Cervical Cancer, particularly late period, has unique advantage.Cervical cancer targeted drug is also in early stage development at present, and in clinical trial, occur unstable, the individual Different therapeutical effect of curative effect large, with conventional chemotherapy medicine synergy not good etc. some need the clinical problem of solution badly, there is not yet the molecular targeted agents evident in efficacy clinical treatment for Patients with Cervical Cancer.
Cervical cancer cell has vigorous proliferative ability, lasting DNA replication dna potential and the DNA damage of accumulating.Kin17 albumen is a protein very conservative in spore process, and it is mainly relevant with DNA replication dna, DNA reparation and the cell proliferation function of cell, expresses generally lower in the each histoorgan of human body.At present, also appear in the newspapers at end about Kin17 gene or new diagnostic markers and the drug targets of albumen cervical cancer.
Summary of the invention
The object of the present invention is to provide the application in the diagnosis of preparation cervical cancer, prognosis evaluation and healing potion of Kin17 gene or albumen.
Contriver finds, Kin17 gene or albumen can be used as diagnostic markers and the drug targets that cervical cancer is new, Kin17 albumen is expressed lower in normal-sub uterine neck epithelium and uterine cervix benign disease tissues, and obviously abnormal rising of its expression in cervical cancer tissue; And Kin17 maintained the fast breeding activity of cervical cancer cell, in the developing of cervical cancer, play a significant role.Therefore, Kin17 gene (nucleotide sequence is shown in SEQ ID NO:1) or albumen (aminoacid sequence is shown in SEQ ID NO:2) can be used as diagnostic markers and drug targets that cervical cancer is new, and Kin17 gene or albumen can be used for the Early Identification diagnosis of cervical cancer, prognosis evaluation analysis and the clinical treatment of tumour patient.
Brief description of the drawings
The expression of Fig. 1: Kin17 in the epithelium of uterine cervix benign lesion sample and the cancer nests tissue of cervical cancer sample;
Fig. 2: insert in recombinant plasmid pET32a-KIN17 kIN17the part sequencer map of gene;
The SDS-PAGE electrophorogram of Fig. 3: IPTG induction Kin17 albumen prokaryotic expression in intestinal bacteria;
Fig. 4: the SDS-PAGE electrophorogram (left side) of the His label Kin17 albumen after purifying and Western-blot qualification figure (right side);
Fig. 5: lower Kin17 with siRNA_Kin17 and express (left side), suppressed the growing multiplication activity (right side) of carcinoma canalis cervicis HeLa cell;
Fig. 6: pick and fall Kin17 with siRNA_Kin17, can strengthen the restraining effect of taxol antithetical phrase proliferation of cervical cancer HeLa cell.
Embodiment
naming and sequence of Kin17 gene or albumen
The gene of encoded K in17 albumen is named as " KIN17 gene ", and the albumen of KIN17 genes encoding is named as " Kin17 albumen ", and the accession number of KIN17 gene is: NM_012311.
The nucleotide sequence of KIN17 gene is as shown in SEQ ID NO:1.
The aminoacid sequence of Kin17 albumen is as shown in SEQ ID NO:2.
Below in conjunction with concrete experiment, the present invention is further illustrated, but be not limited to this.
kin17 gene or albumen are applied to cervical cancer diagnosis:
There is pernicious variation by uterine cervix normal epithelium cell and breed uncontrollably and form in cervical cancer tissue.Inventor's immunohistochemical method, detect the expression of Kin17 in 129 example uterine neck biopsy specimens, wherein comprised 27 routine cervical benign lesion samples (becoming sample etc. containing chronic cervicitis, epithelium of cervix uteri atypical hyperplasia and cervical intraepithelial neoplasia) and 102 example cervical cancer samples (containing 82 routine SCC, 15 routine adenocarcinoma of the uterine cervix and 5 routine uterine neck adenosquamous carcinomas).
The step that immunohistochemical methods detects:
1) tissue slice dewaxes to water, is placed in 0.01M citrate buffer (pH6.0), and 100 DEG C of microwave antigen retrieval are processed 20min, naturally cool to room temperature;
2), after distilled water flushing, drip 3%H 2o 2hatch 15min; Then use 0.01M phosphate buffered saline buffer (PBS, pH7.4) to rinse 3 times, each 3min;
3) drip the Kin17 antibody (purchased from Santa cruz) diluting at 1: 150, hatch after 60min for 37 DEG C, with PBS flushing 3 times, each 3min;
4) then drip the EnVision of horseradish peroxidase (HRP) mark tMtwo anti-reagent (purchased from Dako company), hatch after 30min for 37 DEG C, with PBS flushing 3 times, and each 3min.Finally use 3,3 '-diaminobenzidine (DAB) colour developing 3min, Mayer Hematorylin is redyed 3min;
5) gradient alcohol dehydration, transparent, sealing.
dyeing scoring:give a mark with percentage (0-100) % of positive cell with regard to the staining power of every section (, ±, 1+, 2+, 3+, 4+) respectively.Calculating dyeing score=staining power (0,0.5,1,2,3,4) × (0-100).Such as, the staining power of certain slide is 2+, and the percentage of positive cell is 65%, and that score equals 2 × 60=130.Score≤100 are defined as low expression, and score > 100 is defined as high expression level.All section is by the independently marking in the situation that not knowing organizational diagnosis's character of two Pathologis.
According to dyeing appraisal result, data are carried out to statistical study.Found that, Kin17 expresses lower in uterine cervix healthy tissues and cervical dysplasia tissue, and obviously abnormal rising of expression in cervical cancer tissue ( p< 0.01, Fig. 1).The expression of Kin17 along with the process of disease by cervical epithelial cells from normal or atypical hyperplasia, develop into cervical cancer and raise.The tissue site that tumor cell proliferation is more vigorous, the expression of Kin17 is stronger.Therefore, adopt the methods such as immunohistochemical methods, immunofluorescence and real-time quantitative PCR to detect the Kin17 expression level in patient's cervical lesions tissue, contribute to the Cervical benign lesion of differential diagnosis and cervical cancer.
the preparation of Kin17 albumen
Purifying Kin17 albumen is the important materials of preparation Kin17 antibody and relevant diagnostic reagent.In order to research and develop the pulmonary cancer diagnosis reagent of expressing based on Kin17, adopt and prepare with the following method Kin17 albumen.
1) first use primer P1(5'-CG gGATCCaTGGGGAAGTCGGATTTTCT-3', SEQ ID NO:3) and P2(5' – CGT aAGCTTtCAGGCAAGTTTAGAAATGTCTTC-3', SEQ ID NO:4) pcr amplification from cell kIN17gene open reading frame total length, through using restriction endonuclease bamhI and hind carries out respectively after double digestion reaction, is inserted in pET32a-c (+) carrier, and sequencing analysis (Fig. 2) proves successfully to build pET32a-KIN17 recombinant plasmid;
2) recombinant plasmid transformed is entered in escherichia coli expression bacterium BL21, then carry the Kin17 albumen of His label with IPTG abduction delivering, after SDS-PAGE electrophoretic separation and coomassie brilliant blue staining, find better (Fig. 3) of expression of target protein;
3) then utilize Ni-NTA His-Bind post to carry out affinity chromatography and carry out purifying Kin17 albumen.
Purifying end product is through SDS-PAGE electrophoretic analysis demonstration, and one very high with His label Kin17 albumen protein band purity of the same size, reaches on more than 95% (as Fig. 4 left side); This main band is accredited as Kin17 target protein (Fig. 4 right side) through Western blot method.
kin17 gene or albumen are applied to the scheme of the prognosis judgement of Patients with Cervical Cancer:
Collect the data message of the pathological parameter of cervical cancer patient and tumor tissues, the dependency of Kin17 expression and these parameters in statistical study pathological tissue.Result shows, Kin17 expression level height in specimens (scoring > 100 or≤100) and patient P53 sudden change situation ( p=0.035, χ 2inspection), Ki-67 express ( p=0.028, χ 2inspection) and to chemotherapy drug susceptibility ( p=0.046, χ 2inspection) etc. parameter closely related; Follow-up investigation by patient is found, occurs in the tissue of Patients with Cervical Cancer of distant metastasis, that the Patients with Cervical Cancer that the expression ratio of Kin17 does not occur to shift is wanted is high ( p=0.042, χ 2inspection).Therefore, the detection of Kin17 gene or albumen is contributed to disease progression situation, anticancer therapy effect and the prognosis situation of assessment and expection Patients with Cervical Cancer.
kin17 gene or albumen are applied to the scheme of the clinical treatment of cervical cancer:
Carry out RNA interference test according to following steps: cervical cancer HeLa cell is after serum starvation 2h, with liposome Lipofectamine 2000 transfection Kin17 specific siRNA(siRNA_Kin17) with corresponding contrast siRNA(siRNA_NC) in cell; After 48h, collect two groups of cells and carry out Western blot analysis and cell growth curve comparison, find in the HeLa cell of transfection siRNA_Kin17 that Kin17 expresses obviously to be lowered, and its speed of growth obviously slow down ( p< 0.05, Fig. 5).Therefore, in silencer cervical cancer cell, Kin17 expresses, the proliferation activity that inhibition can tumour cell.
Transfection siRNA_Kin17 and siRNA_NC, after HeLa cell 48h, respectively add cervical cancer Common Chemotherapy medicine taxol in two groups of cells, and then relatively the survival rate of two groups of cells changes; Result demonstration, the HeLa cell survival rate of transfection siRNA_Kin17 declines sooner than control group.Now, a lot of chemotherapeutic are to utilize to suppress DNA replication dna and the degree that increases DNA damage in cell, reach the effect of inhibition tumor cell growth.Therefore, in silencer cervical cancer cell to DNA replication dna, repair relevant Kin17 and express, can strengthen its susceptibility (Fig. 6) to chemotherapeutic taxol.
Therefore, Kin17 can be used as the target spot of cervical cancer treatment, adopts specific si_RNA, sh_RNA, the specific antibody of Kin17 or small-molecule drug, reticent or reduce the expression of the Kin17 in tumor tissues, can be used for the clinical treatment of cervical cancer.
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The application in the diagnosis of preparation cervical cancer and healing potion of <120> Kin17 gene or albumen
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<150> CN201310164136.1
<151> 2013-05-07
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Claims (6)

1. the application in the reagent of the diagnosis of preparation cervical cancer or prognosis evaluation for detection of the method for Kin17 gene.
2. the application of the method for detection Kin17 protein expression level in the reagent of the diagnosis of preparation cervical cancer or prognosis evaluation.
3. suppress the preparation of Kin17 protein expression in the application of preparing in the medicine for the treatment of cervical cancer or improving the Patients with Cervical Cancer state of an illness.
4. application according to claim 3, is characterized in that: the preparation that suppresses Kin17 protein expression is selected from Kin17 gene promoter inhibitor, transcription inhibitor and Kin17 protein synthesis inhibitor.
5. make the preparation of Kin17 protein-specific inactivation in the application of preparing in the medicine for the treatment of cervical cancer or improving the Patients with Cervical Cancer state of an illness.
6. application according to claim 5, is characterized in that: make the preparation of Kin17 protein-specific inactivation be selected from Kin17 protein antibodies.
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Cited By (3)

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CN106501516A (en) * 2016-12-16 2017-03-15 南方医科大学南方医院 A kind of reagent that assesses for postoperative gastric cancer prognosis and chemosensitivity and system
CN113238045A (en) * 2021-04-27 2021-08-10 南方医科大学南方医院 Applications of CRMP2 and anti-CRMP 2 antibody
CN114395625A (en) * 2021-12-29 2022-04-26 广东省人民医院 Application of COPA in preparation of cervical cancer diagnosis biomarker and/or cervical cancer drug development

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106501516A (en) * 2016-12-16 2017-03-15 南方医科大学南方医院 A kind of reagent that assesses for postoperative gastric cancer prognosis and chemosensitivity and system
CN106501516B (en) * 2016-12-16 2018-08-17 南方医科大学南方医院 A kind of reagent and system for postoperative gastric cancer prognosis and chemosensitivity assessment
CN113238045A (en) * 2021-04-27 2021-08-10 南方医科大学南方医院 Applications of CRMP2 and anti-CRMP 2 antibody
CN113238045B (en) * 2021-04-27 2021-12-28 南方医科大学南方医院 Applications of CRMP2 and anti-CRMP 2 antibody
CN114395625A (en) * 2021-12-29 2022-04-26 广东省人民医院 Application of COPA in preparation of cervical cancer diagnosis biomarker and/or cervical cancer drug development
CN114395625B (en) * 2021-12-29 2023-08-04 广东省人民医院 Application of COPA in preparation of cervical cancer diagnosis biomarker and/or development of cervical cancer drug

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