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OBJECTIVE To investigate the levels of tricarboxylic acid cycle (TCA)-related metabolites in human epidermal growth factor receptor 2 (HER2)-positive breast cancer trastuzumab-resistant and trastuzumab-sensitive cells, as well as to screen potential biomarkers of trastuzumab resistance. METHODS Targeted metabolomics was adopted to detect TCA-related metabolite levels including citrate, cis-aconitate, isocitrate, alpha-ketoglutarate, succinic acid,fumaric acid,malic acid and oxaloacetic acid based on ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) in trastuzumab-resistant and trastuzumab-sensitive cells. The linearity, accuracy and precision of the method were validated. Then, orthogonal partial least-squares discrimination analysis (OPLS-DA) was used to compare the relative differential expression in trastuzumab-resistant and trastuzumab-sensitive cells. Differentially expressed metabolites were screened according to P<0.05, fold change (FC)>1.5 or FC<0.67. Finally, a multivariable model based on SVM and receiver operating characteristic (ROC) curve analysis was used to assess the classification accuracy of each metabolite. RESULTS For all TCA-related metabolites, the standard curves were linear, the correlation coefficients (r) were greater than 0.994, the established method accuracy was 94%-105% and the precision coefficient of variation (CV, %) was less than 15%. Trastuzumab-resistant and trastuzumab-sensitive cells were clearly separated from each other in the OPLS-DA model. Malic acid, succinic acid and fumaric acid were significantly upregulated in trastuzumab-resistant cells (P<0.05) compared to trastuzumab-sensitive cells. The areas under the curves (AUCs) of malic acid, succinic acid and fumaric acid were greater than 0.9 and the SVM model yielded the highest AUC of 1.000. CONCLUSION TCA-related metabolites are differentially expressed in trastuzumab-resistant and trastuzumab-sensitive cells. Succinic acid, fumaric acid and malic acid can serve as biomarkers that may provide potential value for the diagnosis of trastuzumab resistance in HER2-positive breast cancer.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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