CN103063850A - Application of Shp2 protein in preparation of liver cancer prognosis evaluation kit - Google Patents
Application of Shp2 protein in preparation of liver cancer prognosis evaluation kit Download PDFInfo
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Abstract
The invention belongs to the biotech field, relates to an application of an Shp2 protein, and concretely relates to an application of the Shp2 protein in preparation of a liver cancer prognosis evaluation kit. The relative Shp2 protein expression level of a tumor tissue to a tissue adjacent to the tumor is determined through utilizing an immunohistochemical technology, microscope shooting and computer image processing software, and postoperative follow-up information is combined to determine that the relative Shp2 protein expression level is related with the hepatocellular carcinoma patient prognosis after the operation, so the Shp2 protein can be used for preparing a protein molecule maker for determining the liver cancer patient, and is of great guiding significance to the postoperative monitoring and sequential treatment of hepatocellular carcinoma patients.
Description
Technical field
The invention belongs to biological technical field, relate to a kind of application of Shp2 albumen, specifically, relate to the application of Shp2 albumen in preparation prognosis in hcc assessment kit.
Background technology
Liver cancer is a kind of serious harm human diseases.China is Liver Cancer country, and M ﹠ M is all in rising trend, and the rejuvenation of age of onset formation, and the annual expenditure that is used for liver cancer treatment increases greatly, and liver cancer is serious harm China people life property safety, affects socio-economic development.Statistical data shows that high transfer and relapse rate behind the Liver Cancer Operation (recurrence rate reached 70% in 5 years, and small liver cancer also reaches 50%) has become the bottleneck of further raising late result, also is the important key of capturing liver cancer.The mechanism of relapse and metastasis is not clear to be the clinical main cause that lacks prognosis in hcc judge index and effective treatment means.
Hepatoma Metastasis is a multifactor participation and interactional complex process, relates to the interaction of all microenvironments of cancer cell itself, cancer cell and cancer and host immune state; The many factors of these aspects has participated in the transfer process of liver cancer unusually.It is relevant with the genesis of liver cancer to have at least at present more than 20 kind gene unconventionality expressions to be determined, but fixed liver cancer related gene unconventionality expression rate in liver cancer is not high, and the susceptibility of these indexs and specificity still are difficult to satisfy the dlinial prediction requirement.Liver cancer occurs, the concrete mechanism of development is not illustrated yet.
Therefore, it is imperative to the liver cancer fundamental research to strengthen, and this area is in the urgent need to related gene and/or the albumen of the searching energy predicting liver cancer state of an illness and prognosis, and liver cancer is correlated with and is transformed the important topic of medical research at present, the significant and value to clinical treatment.
Shp2 albumen is by gene PTPN11 coded (GeneID:5781), it has been a kind of non-transmembrane Protein-tyrosine-phosphatase (the English full name: protein tyrosine phosphatase of dephosphorylation, non-receptor type11), its N end contains 2 identical SH2 domains, Shp2 passes through the SH2 domain in conjunction with phosphotyrosine, tyrosine phosphatase (PTP enzyme) in himself structure is activated, other signaling molecules in the cell are brought into play dephosphorylized effect (referring to document: A.Alonso, J.Sasin, N.Bottini, I.Friedberg, A.Osterman, A.Godzik, T.Hunter, J.Dixon and T.Mustelin, Protein tyrosine phosphatases in the human genome, Cell117 (2004), pp.699-711.).In general protein kinase promotes the signal transmission, and the phosphoprotein phosphatase Inhibitory signal transmits, and the special character of Shp2 just is being that not only its dephosphorylation effect does not suppress but also promotes the signal transmission, and then plays an important role in the multi-signal transduction process of regulating cell biological and control cytoactive.
Experimental studies have found that more in recent years the substantial connection that has of Shp2 molecule and mutant thereof and multiple malignant disease, bibliographical information
[2-6]Shp2 is unusual distribution and overexpression in Hematopoietic Malignancies, this process is considered to Shp2 and participates in signal such as the IL-3(interleukin-13 that the transducer cell outgrowth factor produces), PDGF (platelet-derived growth factor), GM-CSF (colony stimulating factor) etc., and forward is regulated the Ras/Erk relevant with cell proliferation, the signal transduction pathway such as PI3K/Akt and Jak/STAT is (referring to document: A.Ostman, C.Hellbergt and F.D.Bohmer, Protein-tyrosine phosphatases and cancer, Nat Rev Cancer6 (2006), pp.307 – 320.; ] M.L.Loh, S.Vattikuti, S.Schubbert, M.G.Reynolds, E.Carlson, K.H.Lieuw, J.W.Cheng, C.M.Lee, D.Stokoe and J.M.Bonifas et al., Mutations in PTPN11implicate the SHP-2phosphatase in leukemogenesis, Blood103 (2004), pp.2325 – 2331.; M.Scherr, A.Chaturvedi, K.Battmer, I.Dallmann, B.Schultheis, A.Ganser and M.Eder, Enhanced sensitivity to inhibition of SHP2, STAT5and Gab2expression in chronic myelogenous leukemia (CML), Blood107 (2006), pp.3279 – 3287.; J.Chen, W.-M.Yu, H.Daino, H.E.Broxmeyer, B.J.Druker and C.-K.Qu, SHP-2phosphatase is required for hematopoietic cell transformation by Bcr-Abl, Blood109 (2007), pp.778-785.; W.M.Yu, H.Daino, J.Chen, K.D.Bunting and C.-K.Qu, Effects of a leukemia-associated gain-of-function mutation of SHP-2phosphatase on interleukin-3signaling, J Biol Chem281 (2006), pp.5426 – 5434.).
Also be considered to bring into play vital role (referring to document: M Golam Mohi at gastric epithelial cell Shp2 and its in the process of cancerous cell transformation in conjunction with Protein G ab2, Benjamin G Neel, The role of Shp2 (PTPN11) in cancer, Current Opinion in Genetics﹠amp; Development17 (2007), pp.23-30.).
Research shows that also Shp2 and Gab2 participate in abnormal activation galactophore epithelial cell HER2/Neu path, cause galactophore epithelial cell to transform with canceration (referring to document: M.Bentntires-Alj, S.G.Gii, R.Chan, Z.C.Wang, N.Imanaka, L.Harris, A.Richardson, B.G.Neel and H.Gu, Casual role of the scaffolding adapter Gab2in breast cancer, Nat Med12 (2006), pp.114-121.).
In the research of liver diseases, Shp2 is in the news by hepatocellular regeneration after the paths such as adjusting Erk, Akt and the IL-6/STAT3 promotion hepatic injuries.Produce and utilize this molecule can regulate IF-1 as target spot, for the immune correlated diseases such as effective treatment virus hepatitis have been opened up new way (referring to document: Emilie A.Bard-Chapeau, Jing Yuan, Nathalie Droin, Shinong Long, Eric E.Zhang, and Gen-Sheng Feng, Concerted Functions of Gab1and Shp2in Liver Regeneration and Hepatoprotection, Molecular and Cellular Biology26 (2006), pp.4664-4674.).
Liver cancer is as human health is threatened one of maximum tumour, the molecular mechanism of so far its generation is still unclear, treatment to it also lacks specific molecular target, and Shp2 there is no at present bibliographical information Shp2 albumen and judges that prognosis in hcc or hepatoma Metastasis are relevant as very important tumour oncogene.
Summary of the invention
The object of the present invention is to provide the new application of Shp2 albumen, particularly the application in preparation prognosis in hcc assessment kit.
The inventor finds first through extensive and deep research, adopts ImmunohistochemistryMethods Methods to detect the relative expression quantity of Shp2 albumen in liver cancer tissue, can judge that risk and the post-operative conditions of DISTANT METASTASES IN appear in liver cancer patient.Based on the relative expression quantity of Shp2 albumen and this correlativity of hepatocellular carcinoma, its expression is detected the prognosis judgement that can be used for instructing liver cancer with this albumen as molecular labeling.
The invention provides the application of Shp2 albumen in preparation prognosis in hcc assessment kit, this application refers to Shp2 albumen as molecular labeling, utilize Shp2 monoclonal antibody or polyclonal antibody, binding immunoassay group experiment reagent detects the relative expression quantity of Shp2 albumen in liver cancer tissue.
The antibody of the anti-Shp2 albumen of specificity comprises monoclonal antibody and polyclonal antibody, and for the preparation of preparation or the kit of determining the operation of liver cancer prognosis, this it will be apparent to those skilled in the art that.
Described Shp2 polyclonal antibody utilize for inventor waits prepare behind the Shp2 recombinant protein immune rabbit (referring to document Yokoyama, W.M., Christensen, M., Santos, G.D.and Miller, D.2006.Production of Monoclonal Antibodies.Current Protocols in Immunology.74:2.5.1 – 2.5.25.).
The present invention also provides and has used the mentioned reagent box to be used for vitro detection Shp2 albumen in the method for the expression of liver cancer tissue, and the method may further comprise the steps:
(a) utilize immunohistochemical experiment reagent (dimethylbenzene, ethanol, 3%H in this kit
2O
2Methanol solution, 1%BSA confining liquid, DAB chromogenic reagent, haematoxylin and horseradish peroxidase) the mark goat anti-rabbit igg carries out immunohistochemical staining with the liver cancer tissue section;
(b) utilize microscope and imaging device to take and be digital photograph;
(c) utilize biometric image process software analysis tumour and knurl side to organize positive signal intensity, provide scoring;
(d) according to Shp2 protein molecular expression in the score calculation tumor tissues.
Described the method concrete steps are as follows:
(1) preparation liver cancer tissue paraffin section, 60 ℃ of baking boxs spend the night;
(2) section is taken off cured to water;
Dimethylbenzene 10min → dimethylbenzene 10min → dimethylbenzene 10min → 100% ethanol 5min → 95% ethanol 5min → 85% ethanol 5min → 75% ethanol 5min → distilled water 5min((3) 3%H
2O
2Methanol solution, room temperature is placed 20min;
(4) distilled water is washed three times, each 5min;
(5) antigen retrieval: section is put into 0.01M citrate buffer (pH6.0) and is boiled 5min, and truce 10min boils 5min again;
(6) naturally cool to room temperature, distilled water is washed three times, each 5min;
(7) 1%BSA sealing 30min, 37 ℃;
(8) get rid of deblocking liquid, do not wash, directly add primary antibodie, described primary antibodie is rabbit Shp2 polyclonal antibody (can identify Shp2 albumen in the mammals such as people, mouse), available from U.S. CST company, and dilution ratio 1:75; Insert 30min in the wet box, 37 ℃, then 4 ℃ of refrigerator overnight are 16 hours;
(9) 4 ℃ of taking-ups, room temperature rewarming 15min, then 0.01M PBS washes four times, each 5min;
(10) drip two anti-ly, described two anti-ly are the horseradish peroxidase-labeled goat anti-rabbit igg, and available from Denmark DAKO company, instant need not dilution, 45min, 37 ℃;
(11) 0.01M PBS washes four times, each 5min, the DAB 2-10min that develops the color, Microscopic observation;
(12) distilled water color development stopping, haematoxylin were redyed 10 seconds;
(13) tap water returns indigo plant, distilled water immersion after the differentiation;
(14) dehydration is transparent, and cover glass covers;
(15) microscopically is observed positive staining, respectively chooses at random 3 visuals field respectively at liver cancer tissue and cancer beside organism, takes pictures;
(16) employing Image Scope(Aperio company) software scans tissue samples, adopt Algorithms (the Positive Pixel Count) program of this software that each sample is carried out " positive Pixel " calculating after the scanning, obtain computational data such as following table:
The group score calculation method of each tissue is Log10[255/Iavg], Iavg=(Iwp+Ip+Isp)/(Nwp+Np+Nsp) wherein, i.e. positive mean intensity, computing method:
Positive mean intensity=(weak positive pixel total intensity+positive pixel total intensity+strong positive pixel total intensity)/(weak positive pixel number+positive pixel number+strong positive pixel number) is the SABC scoring of this tissue, is used for subsequent analysis.
Shp2 just expresses standard Shp2 in the 301 routine liver cancer tissues and expresses the median (0.36) of scoring as the boundary.
Be found to be existence or the death predicted behind hepatocellular carcinoma DISTANT METASTASES IN risk and the operation in patients of Shp2 albumen of the present invention and liver cancer correlativity provide a brand-new approach, to judging that the patients with hepatocellular carcinoma prognosis has vital role, also has important directive significance for the monitoring of hepatocellular carcinoma patient postoperative and sequential therapy.When the scoring of cancerous tissue Shp2 SABC was higher than 0.36, hepatocellular carcinoma was prone to recurrence or DISTANT METASTASES IN, and the liver cancer patient postoperative is easily dead.
By above test findings as can be known, detect existence or death after Shp2 protein molecular relative expression quantity can be predicted hepatocellular carcinoma DISTANT METASTASES IN risk and operation in patients by the method that adopts SABC.When the scoring of cancerous tissue Shp2 SABC was higher than 0.36, hepatocellular carcinoma was prone to DISTANT METASTASES IN, and the liver cancer patient postoperative is easily dead.Obviously, Shp2 albumen and hepatocellular carcinoma have correlativity, therefore, as protein molecular marker its expression are detected events such as can predicting the transfer of hepatocellular carcinoma recurrence after operation and judging prognosis with Shp2 albumen.
The present invention utilizes immunohistochemistry technique, microscope to take pictures and measures Shp2 albumen relative expression quantity in the other tissue of the relative knurl of tumor tissues with Computer Image Processing software, and in conjunction with Follow-up After information, determine that there is correlativity in the rear patients with hepatocellular carcinoma prognosis of Shp2 albumen relative expression quantity and operation, Shp2 albumen can for the preparation of the protein molecular marker of judging the liver cancer patient prognosis, also have important directive significance for the monitoring of hepatocellular carcinoma patient postoperative and sequential therapy.
Description of drawings
Fig. 1 is the high expressed of Shp2 in hepatocellular carcinoma and cancer beside organism and low immunohistochemical staining picture of expressing;
Fig. 2 be Shp2 in the hepatocellular carcinoma sample of 301 examples, cancerous tissue is than presenting high expressed (p＜0.05) in the cancer beside organism;
Fig. 3 is Shp2 high expressed case liver cancer tissue section immunohistochemical staining result, and visible Shp2 strong positive is painted in the tumor tissues;
Fig. 4 is Shp2 high expressed case liver cancer tissue section immunohistochemical staining result, and the visible Shp2 positive is painted in the tumor tissues;
Fig. 5 expresses height with the overall survivorship curve figure of liver cancer patient grouping according to Shp2;
Fig. 6 be according to Shp2 express height with the liver cancer patient grouping without knurl survivorship curve figure.
Embodiment
Below in conjunction with embodiments of the invention enforcement of the present invention is elaborated; following examples are to implement under take technical solution of the present invention as prerequisite; provided detailed embodiment and concrete operating process, but protection scope of the present invention is not limited to following embodiment.
In following examples, the tumor tissue section of liver cancer patient clearly is hepatocellular carcinoma all from east hospital of liver and gall surgical department by 2 Pathologis.
Embodiment 1:
The present invention adopts ImmunohistochemistryMethods Methods to detect the relative expression quantity of Shp2 albumen in liver cancer tissue, and concrete steps are:
(1) preparation liver cancer tissue paraffin section, 60 ℃ of baking boxs spend the night;
(2) section is taken off cured to water;
(dimethylbenzene 10min → dimethylbenzene 10min → dimethylbenzene 10min → 100% ethanol 5min → 95% ethanol 5min → 85% ethanol 5min → 75% ethanol 5min → distilled water 5min)
(3) 3%H
2O
2Methanol solution, room temperature is placed 20min;
(4) distilled water is washed three times, each 5min;
(5) antigen retrieval: section is put into 0.01M citrate buffer (pH6.0) and is boiled 5min, and truce 10min boils 5min again;
(6) naturally cool to room temperature, distilled water is washed three times, each 5min;
(7) 1%BSA sealing 30min, 37 ℃;
(8) get rid of deblocking liquid, do not wash, directly add primary antibodie (1:75).Insert 30min in the wet box, 37 ℃, then 4 ℃ of refrigerator overnight are 16 hours;
(9) 4 ℃ of taking-ups, room temperature rewarming 15min, then 0.01M PBS washes four times, each 5min;
(10) drip DAKO two and resist 45min, 37 ℃;
(11) 0.01M PBS washes four times, each 5min, the DAB 2-10min that develops the color, Microscopic observation;
(12) distilled water color development stopping, haematoxylin were redyed 10 seconds;
(13) tap water returns indigo plant, distilled water immersion after the differentiation;
(14) dehydration is transparent, and cover glass covers;
(15) microscopically is observed positive staining, respectively chooses at random 3 visuals field respectively at liver cancer tissue and cancer beside organism, takes pictures;
(16) utilize biometric image process software Image-Pro plus (Media Cybernetics, Inc.) analysis tumour and knurl side to organize positive signal intensity, provide scoring; Concrete grammar is, employing Image Scope(Aperio company) software scans tissue samples, adopt Algorithms (the Positive Pixel Count) program of this software that each sample is carried out " positive Pixel " calculating after the scanning, obtain computational data such as following table:
The group score calculation method of each tissue samples is Log10[255/Iavg], Iavg=(Iwp+Ip+Isp)/(Nwp+Np+Nsp) wherein, i.e. positive mean intensity, computing method:
Positive mean intensity=(weak positive pixel total intensity+positive pixel total intensity+strong positive pixel total intensity)/(weak positive pixel number+positive pixel number+strong positive pixel number) is the SABC scoring of this tissue, is used for subsequent analysis.Shp2 just expresses standard Shp2 in the 301 routine liver cancer tissues and expresses the median (0.36) of scoring as the boundary;
As shown in Figure 1, be respectively the high expressed of Shp2 in hepatocellular carcinoma and cancer beside organism and low immunohistochemical staining picture of expressing, through the experimental verification of many groups, as shown in Figure 2, Shp2 is in the hepatocellular carcinoma sample of 301 examples, and cancerous tissue is than presenting high expressed (p＜0.05) in the cancer beside organism.
Embodiment 2:
Sample: the histotomy of certain hepatoma carcinoma cell cancer patient tumors, adopt the test procedure of above ImmunohistochemistryMethods Methods to detect the relative expression quantity of Shp2 albumen in liver cancer tissue.The displaing micro picture of liver cancer tissue as shown in Figure 3.As calculated, the scoring of its cancerous tissue Shp2 SABC is 0.46.
Know that through Follow-up After death in 6 months behind this operation in patients is without only 3 months life cycle of knurl.
Embodiment 3:
Sample: the histotomy of certain hepatoma carcinoma cell cancer patient tumors, adopt the test procedure of above ImmunohistochemistryMethods Methods to detect the relative expression quantity of Shp2 albumen in liver cancer tissue.The displaing micro picture of liver cancer tissue as shown in Figure 4.As calculated, the scoring of cancerous tissue Shp2 SABC is 0.21.
Know through Follow-up After, alive behind this operation in patients, without recurrence.
Embodiment 4:
Get at random liver cancer patient excision hepatic tissue, the histotomy of preparation hepatoma carcinoma cell cancer patient tumors adopts the test procedure of above ImmunohistochemistryMethods Methods to detect the relative expression quantity of Shp2 albumen in liver cancer tissue.Express height (scoring of cancerous tissue Shp2 SABC is higher than 0.36 and is high expressed, is lower than 0.36 and expresses for low) with the liver cancer patient grouping according to Shp2, draw overall survivorship curve figure (Fig. 5) and without knurl survivorship curve figure (Fig. 6).The result shows that Shp2 in the tumour is behind the corrective surgery of high expressed overall life cycle and is significantly shorter than low expresser life cycle without knurl.
By above test findings as can be known, detect existence or death after Shp2 protein molecular relative expression quantity can be predicted hepatocellular carcinoma DISTANT METASTASES IN risk and operation in patients by the method that adopts SABC.When the scoring of cancerous tissue Shp2 SABC was higher than 0.36, hepatocellular carcinoma was prone to DISTANT METASTASES IN, and the liver cancer patient postoperative is easily dead.Obviously, Shp2 albumen and hepatocellular carcinoma have correlativity, therefore, as protein molecular marker its expression are detected events such as can predicting the transfer of hepatocellular carcinoma recurrence after operation and judging prognosis with Shp2 albumen.Accordingly, the antibody of the anti-Shp2 albumen of specificity comprises monoclonal antibody and polyclonal antibody, can be for the preparation of preparation or the kit of determining the operation of liver cancer prognosis, and this it will be apparent to those skilled in the art that.
More than show and described ultimate principle of the present invention, principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; that describes in above-described embodiment and the instructions just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.The claimed scope of the present invention is defined by appending claims and equivalent thereof.
Claims (4)
1.Shp2 the application of albumen in preparation prognosis in hcc assessment kit, it is characterized in that this application refers to Shp2 albumen to utilize Shp2 monoclonal antibody or polyclonal antibody as molecular labeling, binding immunoassay group experiment reagent detects the relative expression quantity of Shp2 albumen in liver cancer tissue.
2. the application of Shp2 albumen according to claim 1 in preparation prognosis in hcc assessment kit is characterized in that Shp2 polyclonal antibody wherein prepares after utilizing Shp2 recombinant protein immune rabbit.
3. the application of Shp2 albumen according to claim 1 in preparation prognosis in hcc assessment kit is characterized in that immunohistochemical experiment reagent wherein refers to dimethylbenzene, ethanol, 3%H
2O
2Methanol solution, 1%BSA confining liquid, DAB chromogenic reagent, haematoxylin and horseradish peroxidase.
4. the application of Shp2 albumen according to claim 1 in preparation prognosis in hcc assessment kit, it is characterized in that, this application is to use described kit at the expression of vitro detection Shp2 albumen in liver cancer tissue, and its detection method may further comprise the steps:
(a) utilize dimethylbenzene in this kit, ethanol, 3%H
2O
2Methanol solution, the 1%BSA confining liquid, the DAB chromogenic reagent, haematoxylin and horseradish peroxidase-labeled goat anti-rabbit igg carry out immunohistochemical staining with the liver cancer tissue section;
(b) utilize microscope and imaging device to take and be digital photograph;
(c) utilize biometric image process software analysis tumour and knurl side to organize positive signal intensity, provide scoring;
(d) according to Shp2 protein molecular expression in the score calculation tumor tissues.
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Cited By (2)
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| CN103525916A (en) * | 2013-09-24 | 2014-01-22 | 浙江大学医学院附属义乌医院 | Kit for evaluating HCC (hepatocellular carcinoma) prognosis and application of RFFL (E3 ubiquitin-protein ligase rififylin) |
| CN109870576A (en) * | 2017-12-05 | 2019-06-11 | 中国科学院大连化学物理研究所 | Application of the quantitative detection of USP10 albumen in primary carcinoma of liver Index for diagnosis kit |
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| CN106645723A (en) * | 2016-11-04 | 2017-05-10 | 中国人民解放军第二军医大学 | Application of Shp2 protein in preparation of kit for evaluating therapeutic effect of sorafenib on liver cancer |
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| CN103525916A (en) * | 2013-09-24 | 2014-01-22 | 浙江大学医学院附属义乌医院 | Kit for evaluating HCC (hepatocellular carcinoma) prognosis and application of RFFL (E3 ubiquitin-protein ligase rififylin) |
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