| Objective: Esophageal cancer(EC)is one of the most commonmAlignancies with poor prognosis.Metabolomics has been shown to be a powerful approach to discover the potential biomarkers for cancer diagnosis and prognosis.The goal of this study is to investigate the metabolic characteristics of esophageal squamous cell carcinoma(ESCC)serum and tissue samples of Kazakh ethnic group in Xinjiang,to find ESCC related biomarkers,tomAp the metabolic network and to find potential ESCC metabolic key enzymes.The results will provide new ideas for re-understanding the metabolic characteristics of ESCC,and provide new way for early diagnosis and targeted therapy of ESCC.Methods: 1)ESCC serum metabolomics was conducted between tumor serum samples and normal controls using liquid chromatography-mass spectrometry(LC-MS)platform.The potential biomarkers of ESCC serum were screened by univariate data analysis and multivariate data analysis,and the biomarker's trend in different clinicopathological samples were analyzed.2)ESCC tissue metabolomics was carried out on the base of serum metabolomics.Univariate and multivariate data were used to find biomarkers associated with esophageal cancer metabolism.The differences and changes of metabolites in the tissue samples of patients with different clinicopathological features were analyzed.3)Comprehensive analysis were performed for ESCC tissue and serum metabolomics research;Then to explore ESCC metabolic key enzymes based on metabolomics results and metabolic networkmAp.The key enzymes were detected by immunohistochemical technique,and compared with normal esophageal cancer tissue.Results: 1)The first part: 41 ESCC serum samples and 25 control serum samples were analyzed by LC-MS platform.Using univariate data analysis and multivariate data analysis,23 metabolites were selected for distinguish cancer patients and healthy.Furthmore,seven metabolites(pyroglutamic acid,lactic acid,methylglyoxal,glutamate,aspartic acid,choline and taurine)were screened as the final ESCC related biomarkers.These metabolites directly or indirectly involved in the energy metabolism of the tumor,and can distinguish ESCC serum and normal serum well;2)The second part: Using LC-MS platform,40 pairs ESCC tissues and normal control tissues were analyzed.The results showed that there were significant metabolic differences between the two groups,and 20 metabolites associated with esophageal cancer were identified.These metabolites were involved in amino acid metabolism,glutaminolysis,lipid metabolism,purine pyrimidine metabolism;Combined the result with clinical and pathological information,the 20 metabolites were further analyzed.The result showed that nine metabolites changed along with certain pathological changes(such as tumor invasion depth,lymph node metastasis and postoperative survival,and so on).Glutamate was correlated with local invasion of tumor,and oleic acid,LysoPC(15: 0),uracil,inosine and choline were closely related with the lymphatic metastasis,while glutamine,kynurenine,serine and uracil were related with postoperative survival time.So the nine metabolites were identified as the final biomarkers associated with esophageal cancer.The combination of these ninemArkers could distinguish ESCC and normal tissues well.The combined analysis of ESCC serum and tissue metabolism,as well as an ESCC urinary metabolomics study performed by our team previously,showed that glutamate was the most stablemArker of all ESCC-related biomarkers found in our study.Combined with the relevant metabolic network,it is inferred that theremAy be significant glutaminolysis disorders in ESCC.3)The third part: glutaminase 1(GLS1,key enzymes for glutaminolysis)and solute carrier family 1 member 5(SLC1A5,transporter of glutamine)were detected by immunohistochemical technique.The expression of GLS1 in ESCC tissues was higher than that in normal esophageal tissues,and it was related to different TNM stages,lymph node metastasis states and differentiation degrees.And the expression of SLC1A5 in cancer tissues was significantly higher than that in normal controls,and it was related to the degree of tumor differentiation.SLC1A5 was highly expressed in the poorly and moderately differentiation samples.Conclusion: There are obvious metabolic disorders in esophageal squamous cell carcinoma of Kazakh.ESCC related metabolicmArkers can be used to distinguish ESCC samples from normal controls.Glutaminolysis enhancement is one of the significant metabolic features of ESCC.The expression of GLS1 and SLC1A5 in ESCC tissuesmAy play an important role in the development of tumor,whichmAy provide new evidence for future ESCC screening and individualized targeted therapy. |
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