CN113755602A - Gene marker for identifying lung adenocarcinoma tumor stem cells and application thereof - Google Patents
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Abstract
The invention relates to a gene marker for identifying lung adenocarcinoma tumor stem cells and application thereof, belonging to the technical field of biological medicines. The gene marker is selected from the group consisting of genes RPS4X, FTH1, CYBA, POMP, SLC25A5, RPL35A, BST2, SEC61G, HMGB1, COMMD6, CLIC1, COX6B1, NDUFB4, TPI1, COX8A, SAP18, HMGN1 and XIST. The lung adenocarcinoma tumor stem cell marker obtained based on single-cell transcriptome sequencing can accurately identify lung adenocarcinoma stem cells in lung adenocarcinoma, is not limited to dry genes on the cell surface, and provides a new molecular target for further research on the lung adenocarcinoma stem cells and treatment aiming at the lung adenocarcinoma stem cells.
Description
Technical Field
The invention relates to a gene marker for identifying lung adenocarcinoma tumor stem cells and application thereof, belonging to the technical field of biological medicines.
Background
The incidence and mortality of lung cancer is ranked in the prostate among all tumors, with the most prominent lung cancer subtype being lung adenocarcinoma. At present, although clinical treatment means aiming at the lung adenocarcinoma are diversified, the overall survival rate of patients is still poor, so that it is necessary to further improve the effectiveness of the current treatment means for the lung adenocarcinoma. The lung adenocarcinoma tumor stem cells are a small group of cell types with self-renewal and differentiation potential in lung adenocarcinoma tissues, and play an important role in the proliferation, metastasis and chemoradiotherapy drug resistance of lung adenocarcinoma. Further and deeply researching the lung adenocarcinoma stem cells has important significance for overcoming the lung adenocarcinoma. However, in the past, researchers usually defined the dryness of cells by a flow method, i.e., by the dryness gene on the cell surface, which has fewer selectable marker genes on one hand and more complicated operations on the other hand. Therefore, it is necessary to develop a gene marker for identifying tumor stem cells in lung adenocarcinoma. Therefore, a convenient and accurate gene combination with higher sensitivity, specificity and application value can still exist, and the gene combination can be applied to distinguishing lung adenocarcinoma stem cells from common lung adenocarcinoma cells.
The advent of single cell transcriptome sequencing in recent years has enabled researchers to detect cell expression at the single cell level. Stem cells in lung adenocarcinoma can be studied at the level of single cells by single-cell transcriptome sequencing, thereby obtaining a specific expression profile (i.e. lung adenocarcinoma stem cell gene marker combination) for identifying lung adenocarcinoma stem cells. This will help researchers to more accurately distinguish tumor stem cells in lung adenocarcinoma.
Disclosure of Invention
The invention aims to solve the technical problems of obtaining a gene marker for identifying lung adenocarcinoma tumor stem cells and application thereof.
In order to solve the above problems, the present invention provides a genetic marker for identifying lung adenocarcinoma tumor stem cells, wherein the genetic marker comprises at least one of genes RPS4X, FTH1, CYBA, POMP, SLC25a5, RPL35A, BST2, SEC61G, HMGB1, COMMD6, CLIC1, COX6B1, NDUFB4, TPI1, COX8A, SAP18, HMGN1, and XIST.
The invention provides an application of a gene marker for identifying lung adenocarcinoma tumor stem cells in preparing a diagnostic kit for detecting the lung adenocarcinoma tumor stem cells.
The invention provides application of a gene marker for identifying lung adenocarcinoma tumor stem cells in preparation of a diagnostic kit for lung adenocarcinoma prognosis.
The invention provides application of a gene marker for identifying lung adenocarcinoma tumor stem cells in preparation of a medicament for treating lung adenocarcinoma.
The invention provides application of a gene marker for identifying lung adenocarcinoma tumor stem cells in a non-diagnosis method and a non-treatment method.
Compared with the prior art, the invention has the following beneficial effects:
1. the lung adenocarcinoma tumor stem cell marker obtained based on single-cell transcriptome sequencing can accurately identify lung adenocarcinoma stem cells in lung adenocarcinoma, is not limited to dry genes on the cell surface, and provides a new molecular target for further research on the lung adenocarcinoma stem cells and treatment aiming at the lung adenocarcinoma stem cells.
2. The risk assessment model can be established based on a machine learning method, and has the advantages of quantitative analysis, high accuracy and good sensitivity and specificity.
Drawings
FIG. 1 is a graph showing the clustering results of tumor stem cells and non-tumor stem cells of lung adenocarcinoma;
FIG. 2 is a ROC graph of 18 genes such as RPS4X in differentiating tumor stem cells and non-tumor stem cells of lung adenocarcinoma;
wherein the abscissa represents specificity and the ordinate represents sensitivity;
FIG. 3 is a ROC plot of a risk assessment model constructed based on 18 genes, such as RPS 4X;
wherein the abscissa represents specificity and the ordinate represents sensitivity;
FIG. 4 is a graph showing the results of RT-qPCR method to detect the difference of 18 gene mRNA expression such as RPS4X in tumor stem cells and non-tumor stem cells in lung adenocarcinoma;
where the ordinate represents the fold difference in mRNA expression.
Detailed Description
In order to make the invention more comprehensible, preferred embodiments are described in detail below with reference to the accompanying drawings:
the invention provides a gene marker for identifying lung adenocarcinoma tumor stem cells, which comprises at least one of genes RPS4X, FTH1, CYBA, POMP, SLC25A5, RPL35A, BST2, SEC61G, HMGB1, COMMD6, CLIC1, COX6B1, NDUFB4, TPI1, COX8A, SAP18, HMGN1 and XIST.
The invention provides an application of a gene marker for identifying lung adenocarcinoma tumor stem cells in preparing a diagnostic kit for detecting the lung adenocarcinoma tumor stem cells.
The invention provides application of a gene marker for identifying lung adenocarcinoma tumor stem cells in preparation of a diagnostic kit for lung adenocarcinoma prognosis.
The invention provides application of a gene marker for identifying lung adenocarcinoma tumor stem cells in preparation of a medicament for treating lung adenocarcinoma.
The invention provides application of a gene marker for identifying lung adenocarcinoma tumor stem cells in a non-diagnosis method and a non-treatment method.
Example 1
Screening of the gene set:
analyzing a single cell sequencing result of lung adenocarcinoma tissues;
tumor tissue samples of 10 lung adenocarcinoma samples were first obtained and dissociated to prepare single cell suspensions. The lung adenocarcinoma tumor stem cells were then initially sorted by flow sorting based on the currently recognized tumor stem cell marker genes (CD133 and ALDH1) and tumor marker gene (EPCAM). These sorted tumor stem cells were then subjected to single cell transcriptome sequencing with the remaining common tumor cells and off-line data was obtained. Based on this sequencing, a total of 46106 single cell gene expression data were obtained.
And (4) completing dimension reduction and cluster analysis of the single cell data by using a Seurat packet through an R language. Subsequently 6955 lung adenocarcinoma tumor stem cells were identified based on putative cell markers (fig. 1). After the cell identification was completed, the transcriptome differential analysis of tumor stem cells and common lung adenocarcinoma cells in lung adenocarcinoma was completed using the "FindMakrers" function (± 0.5 is log2FC cutoff), resulting in 230 genes up-regulated in tumor stem cells in lung adenocarcinoma and 152 genes down-regulated in tumor stem cells in lung adenocarcinoma.
After the screening of the differential genes is completed, the marker genes capable of better distinguishing the lung adenocarcinoma tumor stem cells from the non-tumor stem cells are screened by the pROC package in the R language, and 55 genes with the area under the ROC curve (AUC) value of more than 0.87 are included and enter the next Lasso regression analysis.
After the primary screening of the lung adenocarcinoma tumor stem cell marker genes is completed, the marker genes are further screened by a method of Lasso regression, and eighteen genes are obtained: RPS4X, FTH1, CYBA, POMP, SLC25A5, RPL35A, BST2, SEC61G, HMGB1, COMMD6, CLIC1, COX6B1, NDUFB4, TPI1, COX8A, SAP18, HMGN1, XIST. The AUC values, sensitivity and specificity values of the 18 genes are shown in table 1 and fig. 2:
TABLE 1 AUC, sensitivity and idiosyncratic values of genes for constructing a lung adenocarcinoma tumor stem cell risk assessment model
| Gene | AUC | Sensitivity of the composition | Specificity of |
| RPS4X | 0.924269 | 0.862246 | 0.845866 |
| FTH1 | 0.901666 | 0.838529 | 0.809346 |
| CYBA | 0.905836 | 0.821226 | 0.86197 |
| POMP | 0.918887 | 0.877163 | 0.833789 |
| SLC25A5 | 0.899039 | 0.866423 | 0.790079 |
| RPL35A | 0.90888 | 0.833234 | 0.837958 |
| BST2 | 0.874737 | 0.831817 | 0.81711 |
| SEC61G | 0.89172 | 0.810263 | 0.819986 |
| HMGB1 | 0.92438 | 0.876492 | 0.824874 |
| COMMD6 | 0.893396 | 0.849717 | 0.803019 |
| CLIC1 | 0.87347 | 0.818243 | 0.788641 |
| COX6B1 | 0.881678 | 0.849567 | 0.756147 |
| NDUFB4 | 0.883504 | 0.830474 | 0.796262 |
| TPI1 | 0.881813 | 0.878505 | 0.734292 |
| COX8A | 0.872772 | 0.780579 | 0.816966 |
| SAP18 | 0.899207 | 0.857921 | 0.800719 |
| HMGN1 | 0.894659 | 0.857249 | 0.775988 |
| XIST | 0.871428 | 0.783189 | 0.921783 |
A scoring model was constructed by Logistic regression:
Score＝0.252*RPS4X+0.609*FTH1+0.287*CYBA+0.358*POMP+0.477*SLC25A5+0.586*RPL35A+0.197*BST2+0.444*SEC61G+0.420*HMGB1+0.351*COMMD6+0.626*CLIC1+0.512*COX6B1+0.426*NDUFB4+0.379*TPI1+0.850*COX8A+0.480*SAP18+0.498*HMGN1-1.373*XIST；
the Logistic regression risk model was then validated for its effect using the single cell transcriptome data in example 1. According to the model, the normalized expression value (unit: TPM) of the corresponding gene is substituted into a scoring model, and the result shows that the specificity and the sensitivity of the risk model are improved to a certain extent compared with a single-gene model, and the AUC value is close to 0.95, which shows that the prediction model can more accurately distinguish lung adenocarcinoma tumor stem cells and non-lung adenocarcinoma tumor stem cells (figure 3). The cutoff value for Score in this model was 8.5. According to the model, when the value obtained by the Score calculation formula is more than 8.5, the cell is judged as the lung adenocarcinoma tumor stem cell; when the value obtained by the Score calculation formula is less than 8.5, the cell is judged as a common lung adenocarcinoma cell.
Example 2 effect verification:
flow cytometry sorting lung adenocarcinoma tumor stem cells and non-tumor stem cells to verify gene expression:
the fold difference of mRNA expression of the 18 genes was detected in the selected lung adenocarcinoma tumor stem cells and common lung adenocarcinoma cells by RT-qPCR method, and the result is shown in FIG. 4. From the results in fig. 4, it is known that 18 genes of RPS4X, FTH1, CYBA, POMP, SLC25a5, RPL35A, BST2, SEC61G, HMGB1, COMMD6, CLIC1, COX6B1, NDUFB4, TPI1, COX8A, SAP18, HMGN1, and XIST are generally expressed in higher amounts in lung adenocarcinoma tumor stem cells than in non-tumor stem cells. Therefore, 18 genes such as RPS4X can be used for distinguishing lung adenocarcinoma tumor stem cells from non-tumor stem cells.
While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention. Those skilled in the art can make various changes, modifications and equivalent arrangements, which are equivalent to the embodiments of the present invention, without departing from the spirit and scope of the present invention, and which may be made by utilizing the techniques disclosed above; meanwhile, any changes, modifications and variations of the above-described embodiments, which are equivalent to those of the technical spirit of the present invention, are within the scope of the technical solution of the present invention.
Claims (5)
1. A genetic marker for identifying lung adenocarcinoma tumor stem cells, wherein the genetic marker comprises at least one of genes RPS4X, FTH1, CYBA, POMP, SLC25a5, RPL35A, BST2, SEC61G, HMGB1, COMMD6, CLIC1, COX6B1, NDUFB4, TPI1, COX8A, SAP18, HMGN1, and XIST.
2. The use of the genetic marker for identifying lung adenocarcinoma tumor stem cells as claimed in claim 1 in the preparation of a diagnostic kit for detecting lung adenocarcinoma tumor stem cells.
3. The use of the gene marker for identifying lung adenocarcinoma tumor stem cells according to claim 1 in the preparation of a diagnostic kit for lung adenocarcinoma prognosis.
4. The use of the gene marker for identifying lung adenocarcinoma tumor stem cells according to claim 1 in the preparation of a medicament for treating lung adenocarcinoma.
5. The use of the genetic marker of claim 1 for identifying lung adenocarcinoma tumor stem cells in non-diagnostic and non-therapeutic methods.
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| US20090062144A1 (en) * | 2007-04-03 | 2009-03-05 | Nancy Lan Guo | Gene signature for prognosis and diagnosis of lung cancer |
| CN113151460A (en) * | 2021-01-29 | 2021-07-23 | 复旦大学附属中山医院 | Gene marker for identifying lung adenocarcinoma tumor cells and application thereof |
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| US20090062144A1 (en) * | 2007-04-03 | 2009-03-05 | Nancy Lan Guo | Gene signature for prognosis and diagnosis of lung cancer |
| CN113151460A (en) * | 2021-01-29 | 2021-07-23 | 复旦大学附属中山医院 | Gene marker for identifying lung adenocarcinoma tumor cells and application thereof |
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| 张洪彬;张满娥;: "干细胞标志物Nanog基因检测在肺癌诊断中的临床意义", 中国实验诊断学, no. 12, pages 2155 - 2157 * |
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