CN110904232B - Molecular marker for evaluating curative effect of sorafenib and detection kit thereof - Google Patents
Molecular marker for evaluating curative effect of sorafenib and detection kit thereof Download PDFInfo
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Abstract
The invention discloses a molecular marker for evaluating the curative effect of sorafenib and a detection kit thereof, wherein the molecular marker for evaluating the curative effect of sorafenib comprises one or more of POU5F1 mutant gene, OCT4 protein and OCT4 mutant protein; a kit for evaluating the curative effect of sorafenib comprises a PCR primer designed according to a POU5F1 mutant gene; another kit for evaluating the curative effect of sorafenib comprises a monoclonal/polyclonal antibody of OCT4 protein or a monoclonal/polyclonal antibody of OCT4 mutant protein, an immunohistochemical experimental reagent; the invention provides a molecular marker capable of being used for evaluating the curative effect of sorafenib and a kit thereof.
Description
Technical Field
The invention relates to the technical field of medical biological detection, in particular to a mutant gene for evaluating the curative effect of sorafenib and a detection kit thereof.
Background
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver, with annual diagnostic rates ranked fifth among cancers worldwide and the third leading cause of cancer-related death. Nearly 70 million new cases occur every year, and China accounts for more than 50% of the new HCC diagnoses worldwide. Because hepatitis B carriers are in large population (more than 1.2 hundred million) in China, chronic hepatitis, liver cirrhosis and liver cancer caused by hepatitis B are main pathogenic factors of liver cancer occurrence in China. Sorafenib is the only clinical drug approved by FDA to treat late-stage liver cancer, and can inhibit the proliferation and angiogenesis of tumor cells and promote the apoptosis of the tumor cells. It is an oral multi-kinase inhibitor, and can block tumor cell proliferation by inhibiting Raf-1 and B-Raf in Ras/Raf/MEK/ERK signal pathway; furthermore, sorafenib inhibits angiogenesis by targeting the hepatocyte cytokine receptor (c-Kit), Fms-like tyrosine kinase (FLT-3), Vascular Endothelial Growth Factor Receptor (VEGFR) -2, VEGFR-3, platelet-derived growth factor receptor (PDGFR- β) and other tyrosine kinases, and thus has dual anti-tumor effects. Although the overall survival time of patients with advanced liver cancer can be prolonged more remarkably, some patients have inherent drug resistance to sorafenib due to the genetic heterogeneity of HCC. Therefore, identification of biomarkers of sorafenib resistance is helpful in assessing the efficacy of sorafenib.
The OCT4 gene belongs to the POU transcription factor family, and is an important transcription factor for regulating the characteristics of Embryonic stem cells (ES), and it has been found that OCT 4is involved in the regulation of the processes of Cancer Stem Cells (CSCs) and Epithelial-mesenchymal transition (EMT) of tumor cells. In recent years, OCT 4is reported to be expressed in various human malignant tumors and is closely related to biological behaviors such as tumor proliferation, apoptosis, metastasis, epithelial-mesenchymal cell transformation and the like, and research on Samardzijia and the like (Samardzijac, Luworrb, QuinnMA, et al. correlation of OCT4A and beta 1 integrating tumors in vitro Cancer in ovarian Cancer [ J ]. BMC Cancer,2016,16:432.) shows that OCT4 plays an important role in the metastasis process of ovarian Cancer; yin et al (YinX, ZhangBH, Zhengss, et al. expression of gene OCT4 and nanog initiates step cell characterization in hepatocellular carcinoma and promoter epi-mesenchymal transition through activation of Stat3/Snail signaling [ J ]. J Hematol Oncol,2015,8:23.) found that OCT4 could initiate the epithelial-mesenchymal transition process of hepatocellular carcinoma by activating the Stat3/Snail signaling pathway. Researchers (Hu T, Liu S, Breiter DR, Wang F, Tang Y, Sun S. Octamer 4small interfering RNA results in cancer stem cell-like apoptosis. cancer Res 2008; 68: 6533-. Researches on Wen ([13] Wen K, Fu Z, Wu X, Feng J, Chen W, Qian J. Oct-4is required for an anti-cancer latent extractor of cancer cells expressed for cancer cells, efffects associated with STAT3/survivin cancer Lett 2013, 333:56-65.) and the like suggest that OCT4 can regulate and control the expression of surface marker molecules CD133 and CD44 and the like, and OCT 4is presumed to control the transcription of tumor stem cells and maintain the activity of the tumor stem cells, so that the occurrence and development of colon cancer can be participated.
Currently, there is no reliable evidence that a single chemotherapeutic agent can improve survival in advanced liver cancer patients, as does a combination of chemotherapeutic agents. Chemotherapeutic drugs commonly used in clinic include cisplatin, doxorubicin, 5-fluorouracil and the like, wherein doxorubicin is a hot spot of recent research. In recent years, the OCT4 expression is found to be higher than that of normal tissues in liver cancer tissues and paracarcinoma tissues. However, no research on the evaluation of the therapeutic effect of sorafenib on hepatocellular carcinoma by OCT4 gene mutation is available.
Disclosure of Invention
Aiming at the technical problems, the invention provides a molecular marker for evaluating the curative effect of sorafenib and a detection kit thereof.
In a first aspect of the invention, a molecular marker for evaluating the curative effect of sorafenib is provided, and the molecular marker comprises one or more of a POU5F1 mutant gene, an OCT4 protein and an OCT4 mutant protein.
Wherein the encoding gene of the OCT4 protein is POU5F1 gene, which has the sequence shown in SEQ ID NO: 5 in the sequence listing.
Preferably, the mutation site of the POU5F1 mutant gene is c.G52C (the 52 th base guanine of the gene is mutated into cytosine).
Preferably, the POU5F1 mutant gene has the amino acid sequence as shown in SEQ ID NO: 1, or a nucleotide sequence represented by the formula (I).
SEQ ID NO：1
ATGGCGGGACACCTGGCTTCGGATTTCGCCTTCTCGCCCCCTCCAGGTGGTCGAGGTGATGGGCCAGGGGGGCCGGAGCCGGGCTGGGTTGATCCTCGGACCTGGCTAAGCTTCCAAGGCCCTCCTGGAGGGCCAGGAATCGGGCCGGGGGTTGGGCCAGGCTCTGAGGTGTGGGGGATTCCCCCATGCCCCCCGCCGTATGAGTTCTGTGGGGGGATGGCGTACTGTGGGCCCCAGGTTGGAGTGGGGCTAGTGCCCCAAGGCGGCTTGGAGACCTCTCAGCCTGAGGGCGAAGCAGGAGTCGGGGTGGAGAGCAACTCCGATGGGGCCTCCCCGGAGCCCTGCACCGTCACCCCTGGTGCCGTGAAGCTGGAGAAGGAGAAGCTGGAGCAAAACCCGGAGGAGTCCCAGGACATCAAAGCTCTGCAGAAAGAACTCGAGCAATTTGCCAAGCTCCTGAAGCAGAAGAGGATCACCCTGGGATATACACAGGCCGATGTGGGGCTCACCCTGGGGGTTCTATTTGGGAAGGTATTCAGCCAAACGACCATCTGCCGCTTTGAGGCTCTGCAGCTTAGCTTCAAGAACATGTGTAAGCTGCGGCCCTTGCTGCAGAAGTGGGTGGAGGAAGCTGACAACAATGAAAATCTTCAGGAGATATGCAAAGCAGAAACCCTCGTGCAGGCCCGAAAGAGAAAGCGAACCAGTATCGAGAACCGAGTGAGAGGCAACCTGGAGAATTTGTTCCTGCAGTGCCCGAAACCCACACTGCAGCAGATCAGCCACATCGCCCAGCAGCTTGGGCTCGAGAAGGATGTGGTCCGAGTGTGGTTCTGTAACCGGCGCCAGAAGGGCAAGCGATCAAGCAGCGACTATGCACAACGAGAGGATTTTGAGGCTGCTGGGTCTCCTTTCTCAGGGGGACCAGTGTCCTTTCCTCTGGCCCCAGGGCCCCATTTTGGTACCCCAGGCTATGGGAGCCCTCACTTCACTGCACTGTACTCCTCGGTCCCTTTCCCTGAGGGGGAAGCCTTTCCCCCTGTCTCCGTCACCACTCTGGGCTCTCCCATGCATTCAAACTGA
Preferably, the OCT4 mutant protein is a protein encoded by the POU5F1 mutant gene; further preferably, the OCT4 has the sequence as set forth in SEQ ID NO: 2, or a pharmaceutically acceptable salt thereof.
SEQ ID NO：2
MetAlaGlyHisLeuAlaSerAspPheAlaPheSerProProProGlyGlyArgGlyAspGlyProGlyGlyProGluProGlyTrpValAspProArgThrTrpLeuSerPheGlnGlyProProGlyGlyProGlyIleGlyProGlyValGlyProGlySerGluValTrpGlyIleProProCysProProProTyrGluPheCysGlyGlyMetAlaTyrCysGlyProGlnValGlyValGlyLeuValProGlnGlyGlyLeuGluThrSerGlnProGluGlyGluAlaGlyValGlyValGluSerAsnSerAspGlyAlaSerProGluProCysThrValThrProGlyAlaValLysLeuGluLysGluLysLeuGluGlnAsnProGluGluSerGlnAspIleLysAlaLeuGlnLysGluLeuGluGlnPheAlaLysLeuLeuLysGlnLysArgIleThrLeuGlyTyrThrGlnAlaAspValGlyLeuThrLeuGlyValLeuPheGlyLysValPheSerGlnThrThrIleCysArgPheGluAlaLeuGlnLeuSerPheLysAsnMetCysLysLeuArgProLeuLeuGlnLysTrpValGluGluAlaAspAsnAsnGluAsnLeuGlnGluIleCysLysAlaGluThrLeuValGlnAlaArgLysArgLysArgThrSerIleGluAsnArgValArgGlyAsnLeuGluAsnLeuPheLeuGlnCysProLysProThrLeuGlnGlnIleSerHisIleAlaGlnGlnLeuGlyLeuGluLysAspValValArgValTrpPheCysAsnArgArgGlnLysGlyLysArgSerSerSerAspTyrAlaGlnArgGluAspPheGluAlaAlaGlySerProPheSerGlyGlyProValSerPheProLeuAlaProGlyProHisPheGlyThrProGlyTyrGlySerProHisPheThrAlaLeuTyrSerSerValProPheProGluGlyGluAlaPheProProValSerValThrThrLeuGlySerProMetHisSerAsn
In a second aspect of the invention, a kit for evaluating the efficacy of sorafenib is provided, the kit comprising PCR primers designed according to the POU5F1 mutant gene.
Preferably, the PCR primer has the sequence as shown in SEQ ID NO: 3. SEQ ID NO: 4, or a nucleotide sequence represented by (4).
SEQ ID NO：3
GGGACACCTGGCTTCGGATT
SEQ ID NO：4
aacccccggcccgattcctg
In a third aspect of the invention, another kit for evaluating the curative effect of sorafenib is provided, which comprises a monoclonal/polyclonal antibody of OCT4 protein or a monoclonal/polyclonal antibody of OCT4 mutant protein, and an immunohistochemical experimental reagent.
Preferably, the immunohistochemical experimental reagent comprises xylene, ethanol and H2O23% by volume of H2O2Methanol solution, 1% BSA blocking solution, DAB chromogenic reagent, hematoxylin and horseradish peroxidase.
In a fourth aspect of the invention, the invention provides application of the molecular marker in preparation of a reagent or a detection device for evaluating the curative effect of sorafenib.
Preferably, the sorafenib therapeutic effect comprises an effect of sorafenib on treating liver cancer.
Preferably, the detection reagent comprises: one or more of primers, probes, antibodies and nucleic acid chips.
Preferably, the detection apparatus comprises: a detection platform containing a gene chip for detecting the POU5F1 mutant gene.
Compared with the prior art, the technical scheme of the invention has the following advantages: the invention provides a molecular marker for evaluating the curative effect of sorafenib, can judge the reactivity of a postoperative liver cancer patient to sorafenib medicaments, and has important guiding significance for clinical medication, postoperative monitoring and sequential treatment of the patient.
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 only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without creative efforts.
FIG. 1 shows the staining condition of typical samples with low, medium and high OCT4 expression levels in hepatocarcinoma tissue;
FIG. 2 shows that 100 liver cancer patients tested by immunohistochemistry method have OCT4 protein expression level and RECIST grouping;
FIG. 3 is a prediction of the prognosis of patients taking Sorafenib in combination with OCT4 expression levels;
FIG. 4is a prediction of prognosis of patients taking sorafenib in combination with AFP expression levels;
FIG. 5 is the correlation between the amount of OCT4 expression and the effect of hepatoma cells on regorafenib treatment;
FIG. 6 shows the response of OCT4 encoding gene mutation in liver cancer tissue and patient to sorafenib;
FIG. 7 shows in vitro experiments to verify the effect of wild-type and mutant OCT4 expression levels in hepatoma cells on sorafenib reactivity.
Detailed Description
The conception, the specific structure and the technical effects of the present invention will be further described with reference to the accompanying drawings to fully understand the objects, the features and the effects of the present invention.
EXAMPLE 1 selection of clinical tissue samples
100 primary hepatocellular carcinoma tissue specimens were randomly obtained from HCC patients who underwent hepatectomy at the Oriental hepatobiliary surgery Hospital of the second military medical university from 1 month to 2013 month in 2009. Written informed consent was obtained prior to surgery. Criteria for inclusion and exclusion: a preoperative physical ability score WHO 0-1; liver function Child-Pugh is classified as class A; ascites can not be seen by naked eyes; no hepatic encephalopathy; before operation, the patient does not receive any radiotherapy and chemotherapy; all are radical excision; all patients demonstrated hepatocellular carcinoma in their postoperative pathology. TNM staging was performed according to international association for cancer (UICC)2002, sixth edition. Of 100 hepatocellular carcinoma patients in this study, 90 were male, 10 were female, and the male-female ratio was 9: 1; the mean age was 49.46 ± 10.2 years, range 29-74 years; the proportion of HBsAg positive patients in the group is 87% (87/100); there were no perioperative death cases.
Example 2
The immunohistochemical method for detecting the OCT4 protein expression level and mRECIST grouping condition of 100 liver cancer patients in example 1 after taking sorafenib after surgery comprises the following steps:
(a) construction of tissue chips
Each donor wax block of 100 patients in example 1 was first sectioned and stained with hematoxylin-eosin (HE). Positioning target tissues to be penetrated under a microscope, respectively selecting 3 sites of representative cancer and tissues beside the cancer, sequentially penetrating tissue cores with the diameter of 1mm from a donor wax block by using a tissue chip making instrument, inserting the tissue cores into a receptor wax block with 240 dot matrixes, and continuously slicing the tissue cores in the thickness of 4 microns, wherein each point of the obtained tissue chip is subjected to pathological diagnosis.
(b) Using immunohistochemical assay reagents (including but not limited to: xylene, ethanol, 3% H2O2Methanol solution, antigen retrieval solution, confining liquid, DAB color reagent, methyl green, hematoxylin-eosin, horseradish peroxidase labeled anti-rabbit IgG antibody and OCT4 antibody), and performing immunohistochemical staining on the sliced liver cancer tissues;
(c) shooting the picture as a digital picture by using a microscope and an imaging device;
(d) and analyzing the positive signal intensity of the whole tissue chip by using biological image processing software to give a score. And calculating the expression quantity of the OCT4 molecule in the tumor tissue according to the score. The entire tissue chip may be scanned using Image Scope (Aperio) software, and after scanning, a "positive Pixel" calculation, defined as an "OCT 4 score", is performed for each chip site using the software's algorithms (positive Pixel count) program.
The results were:
1) mRECIST grouping conditions OCT4 was scored as 0, 1, 2, 3 from low to high depending on the expression level as described in fig. 1.
2) The scoring results are shown in fig. 2, where CR + PR indicates complete/partial remission, SD indicates stable disease, and PD indicates disease progression. The liver cancer tissue chips are divided into the following 2 types by combining with the OCT4 expression level, and the liver cancer tissue chips are obtained by comparing with follow-up results: the first type is: patients with low OCT4 expression had low mortality after taking sorafenib; patients with high OCT4 expression in the second category had high mortality after sorafenib administration. Therefore, patients with high OCT4 expression had a higher proportion of sorafenib resistance (disease progression).
Example 3
The expression levels of OCT4 protein and AFP protein of 100 liver cancer patients in example 1 were tested by the immunohistochemical method in example 2 on 100 patients in example 1 with sorafenib intervention, and the results are as follows:
as shown in fig. 3, in combination with the OCT4 expression level, the prognosis of patients taking sorafenib was predicted, in this cohort, the patients were divided into two groups according to the OCT4 expression level, and the patients with high OCT4 expression level had shorter overall survival and poorer prognosis;
as shown in FIG. 4, combined with the expression level of AFP (the most common marker for liver cancer), the prognosis of patients taking sorafenib was predicted, and in this cohort, the patients were divided into two groups according to the expression level of AFP, and the overall survival time of the patients between the groups was not statistically different;
the above results indicate that OCT4 expression levels can be used to predict the prognosis of patients taking sorafenib, whereas AFP expression levels cannot be used to predict the prognosis of patients taking sorafenib.
Example 4
In vitro experiments of 100 patients in example 1 were performed by intervention of a second-line targeting drug regorafenib for liver cancer, and the immunohistochemistry method in example 2 was used to detect the expression level of OCT4 protein in 100 liver cancer patients, the results are shown in fig. 5, and the in vitro experiments show that the expression level of OCT 4is irrelevant to the curative effect of liver cancer cells on the second-line targeting drug regorafenib for liver cancer.
Example 5 Whole exon sequencing
The results of sequencing the whole exon of the patient taking sorafenib after the liver cancer operation are shown in figure 6, wherein CR + PR shows complete/partial remission, SD shows stable disease, and PD shows disease progression.
The repeated mutation of POU5F1 gene (c.G52C) results in the mutation of 18 th glycine of OCT4 encoded protein to arginine (p.G18R). Wherein the base sequence after POU5F1 gene mutation (c.G52C) is as follows: SEQ ID NO: 1; the amino acid sequence of OCT4 with 18 th glycine mutated into arginine (p.G18R) is as follows: SEQ ID NO: 2.
in the present example, 3 patients with 18 th glycine mutation of OCT4 protein to arginine had a mutation rate of 3.4%, and after sorafenib treatment and mRICIST evaluation, 2 patients had SD and CR, and most of the patients with POU5F1 gene mutation (c.G52C) or OCT4 protein mutation (p.G18R) were in the treatment response group after sorafenib treatment according to clinical mRESIST criteria.
Example 6 in vitro experiments
In vitro experiments verify that the influence of the expression level of 18 th glycine of OCT4 protein encoded by POU5F1 wild type (base sequence: SEQ ID NO: 5) and mutant type (base sequence: SEQ ID NO: 1) OCT4 to sorafenib reactivity is caused by mutation of 18 th glycine of the OCT4 protein.
SEQ ID NO：5
ATGGCGGGACACCTGGCTTCGGATTTCGCCTTCTCGCCCCCTCCAGGTGGTGGAGGTGATGGGCCAGGGGGGCCGGAGCCGGGCTGGGTTGATCCTCGGACCTGGCTAAGCTTCCAAGGCCCTCCTGGAGGGCCAGGAATCGGGCCGGGGGTTGGGCCAGGCTCTGAGGTGTGGGGGATTCCCCCATGCCCCCCGCCGTATGAGTTCTGTGGGGGGATGGCGTACTGTGGGCCCCAGGTTGGAGTGGGGCTAGTGCCCCAAGGCGGCTTGGAGACCTCTCAGCCTGAGGGCGAAGCAGGAGTCGGGGTGGAGAGCAACTCCGATGGGGCCTCCCCGGAGCCCTGCACCGTCACCCCTGGTGCCGTGAAGCTGGAGAAGGAGAAGCTGGAGCAAAACCCGGAGGAGTCCCAGGACATCAAAGCTCTGCAGAAAGAACTCGAGCAATTTGCCAAGCTCCTGAAGCAGAAGAGGATCACCCTGGGATATACACAGGCCGATGTGGGGCTCACCCTGGGGGTTCTATTTGGGAAGGTATTCAGCCAAACGACCATCTGCCGCTTTGAGGCTCTGCAGCTTAGCTTCAAGAACATGTGTAAGCTGCGGCCCTTGCTGCAGAAGTGGGTGGAGGAAGCTGACAACAATGAAAATCTTCAGGAGATATGCAAAGCAGAAACCCTCGTGCAGGCCCGAAAGAGAAAGCGAACCAGTATCGAGAACCGAGTGAGAGGCAACCTGGAGAATTTGTTCCTGCAGTGCCCGAAACCCACACTGCAGCAGATCAGCCACATCGCCCAGCAGCTTGGGCTCGAGAAGGATGTGGTCCGAGTGTGGTTCTGTAACCGGCGCCAGAAGGGCAAGCGATCAAGCAGCGACTATGCACAACGAGAGGATTTTGAGGCTGCTGGGTCTCCTTTCTCAGGGGGACCAGTGTCCTTTCCTCTGGCCCCAGGGCCCCATTTTGGTACCCCAGGCTATGGGAGCCCTCACTTCACTGCACTGTACTCCTCGGTCCCTTTCCCTGAGGGGGAAGCCTTTCCCCCTGTCTCCGTCACCACTCTGGGCTCTCCCATGCATTCAAACTGA
As shown in FIG. 7, the cells were significantly resistant to sorafenib after overexpression of the wild type (POU5F1wt) in liver cancer, while the sensitivity of the cells to sorafenib was not greatly changed by overexpression of the mutant type (POU5F1 mut).
The foregoing detailed description of the preferred embodiments of the invention has been presented. It should be understood that numerous modifications and variations can be devised by those skilled in the art in light of the above teachings. Therefore, the technical solutions available to those skilled in the art through logic analysis, reasoning and limited experiments based on the prior art according to the concept of the present invention should be within the scope of protection defined by the claims.
Claims (5)
1. The application of a reagent for detecting molecular markers in preparation of a reagent or detection equipment for evaluating the curative effect of sorafenib on hepatocellular carcinoma is characterized in that the molecular markers comprise POU5F1 gene and c.G52C mutant gene thereof, or OCT4 protein and p.G18R mutant protein thereof; wherein the nucleotide sequence of the POU5F1 gene is shown as SEQ ID NO: 5, the c.G52C mutation is that the 52 th base guanine of the POU5F1 gene is mutated into cytosine, the p.G18R mutation is that the 18 th glycine of the OCT4 protein coded by the POU5F1 gene is mutated into arginine, and the amino acid sequence of the p.G18R mutein is shown as SEQ ID NO: 2, respectively.
2. Use of the reagent for detecting molecular markers according to claim 1 for the preparation of a reagent or a detection device for evaluating the efficacy of sorafenib treatment on hepatocellular carcinoma, wherein the reagent or the detection device for evaluating the efficacy of sorafenib treatment on hepatocellular carcinoma comprises PCR primers designed according to the POU5F1 gene and its c.g52c mutant gene.
3. The use of the reagent for detecting molecular markers according to claim 2 for the preparation of a reagent or a detection device for evaluating the efficacy of sorafenib treatment on hepatocellular carcinoma, wherein the nucleotide sequence of the PCR primer is as set forth in SEQ ID NO: 3. SEQ ID NO: 4, respectively.
4. The use of a reagent for detecting molecular markers as in claim 1 for the preparation of a reagent or a detection device for evaluating the efficacy of sorafenib treatment on hepatocellular carcinoma, wherein the reagent or the detection device for evaluating the efficacy of sorafenib treatment on hepatocellular carcinoma comprises a monoclonal/polyclonal antibody of the OCT4 protein, a monoclonal/polyclonal antibody of the p.g18r mutein, and an immunohistochemical test reagent.
5. Use of the reagent for detecting molecular markers according to claim 4, in the preparation of a reagent or a detection device for evaluating the efficacy of sorafenib in treating hepatocellular carcinoma, wherein the immunohistochemical test reagent comprises xylene, ethanol, H, and H2O23% by volume of H2O2Methanol solution, 1% BSA blocking solution, DAB chromogenic reagent, hematoxylin and horseradish peroxidase.
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