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Journal of Traditional Chinese Medicine >

2025 , Vol. 45 >Issue 4: 896 - 908

DOI: https://doi.org/10.19852/j.cnki.jtcm.2025.04.020

Original Articles

Reversal of amino acid metabolism patterns between circulating blood and tumors as a new biomarker for the Zhengxu Xieshi syndrome in patients with esophageal squamous cell carcinoma

  • Siliang WANG ,
  • Yushui MA ,
  • Lei LIU ,
  • Pei WANG ,
  • Jia WU ,
  • Xing JIN ,
  • Qiang JIN ,
  • Congcong WANG ,
  • Chentai QIN ,
  • Miaomiao ZHENG ,
  • Xi YANG ,
  • Jun PAN ,
  • Hanchen XU ,
  • Changsheng DONG ,
  • Wenlian CHEN
Expand
  • 1 Cancer Institute, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
    2 Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, Shanghai 200032, China
    3 Department of Thoracic Surgery, the Affiliated Tumor Hospital of Nantong University, Nantong 226300, China
    4 Traditional Chinese Medicine department, the Affiliated Tumor Hospital of Nantong University, Nantong 226300, China
    5 Department of Oncology, Shanxi Provincial Hospital of Traditional Chinese Medicine, Shanxi 030001, China
    6 Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
    7 Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
CHEN Wenlian, Cancer Institute, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China and Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, Shanghai 200032, China. chenwl8412@shutcm.edu.cn，Telephone: +86-17756177005
DONG Changsheng, Cancer Institute, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China and Shanghai Frontiers Science Center of Disease and Syndrome Biology of Inflammatory Cancer Transformation, Shanghai 200032, China. csdong@shutcm.edu.cn;

Received date: 2024-04-12

  Accepted date: 2024-11-18

  Online published: 2025-07-25

Supported by

Natural Science Foundation-funded Project: Establishment of Syndrome-Disease Warning System and Investigation of the Clinical Features and Evolution Patterns of Traditional Chinese Medicine Syndromes in Esophageal Cancer under Modern Medical Diagnosis and Treatment(2023YFC3503200);Natural Science Foundation-funded Project: Establishment of Syndrome-Disease Warning System and Investigation of the Clinical Features and Evolution Patterns of Traditional Chinese Medicine Syndromes in Esophageal Cancer under Modern Medical Diagnosis and Treatment(2023YFC3503201);Biological Basis of the Pathogenesis of Cancer Toxin in Traditional Chinese Medicine(2022YFC3500200);Biological Basis of the Pathogenesis of Cancer Toxin in Traditional Chinese Medicine(2022YFC3500202);Natural Science Foundation-funded Project: Mechanistic Study of the Nucleolar Methyltransferase Fibrillarin to Promote Neoplastic Growth of Esophageal Squamous Cell Carcinoma via Activating Nucleoside Synthesis(32170778);Mechanistic Study of Renal Cancer Neoplastic Growth Driven by Glucose Transporter 5-Mediated Fructose Metabolism Reprogramming(31970708);Mechanistic Study of Methionine Cycle Modulating the Growth of Esophageal Squamous Cell Carcinoma through "DNA Methylation-DNA Stability-p53/p21-cell Cycle" Pathway(82002953);Antitumor Mechanism of Oleanolic Acid via Autophagy by Regulating Adenosine Monophosphate-Activated Protein Kinase-Mammalian Target of Rapamycin- Unc51 Like Kinase 1 Pathway and Inhibiting Purine Salvage Pathway(82004177);USP14 Cooperates with Ubiquitin C-Terminal Hydrolase L5 to Regulate Constitutive Photomorphogenic 9 Signalosome-mediated Programmed Death-Ligand 1 Deubiquitination and Promote Immune Evasion in Hepatocellular Carcinoma(81972214);National Scientific and Technological Major Special Project of China: Shuang Huang Sheng Bai Oral Liquid: Efficacy and Safety Evaluation of Traditional Chinese Medicine Compound Based on Systems Biology Approaches(2019ZX09201004-002-013);A special clinical research initiative for the health business sponsored by the Shanghai Municipal Health Commission(202040155);Shanghai Municipal Science and Technology Commissions Special Biomedical Technology Support Plan(20S31904100);Shanghai "Science and Technology Innovation Action Plan" Medical Innovation Research Project--Shanghai Clinical Research Center of Traditional Chinese Medicine Oncology(21MC1930500);Shanghai 13th Five-Year Plan Key Specialty of Traditional Chinese Medicine Oncology(shslczdzk03701);Tracking Programme for Eastern Scholar at Shanghai Institutions of Higher Learning, Shanghai High-level Talent Leadership Programme of Traditional Chinese Medicine(ZY(2021-2023)-0403);Scientific Research Project of Industry Development Center of Shanghai University of Traditional Chinese Medicine(602076D)

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Abstract

OBJECTIVE: To uncover the biological foundation of the prevailing TCM syndrome in individuals with Esophageal squamous cell carcinoma (ESCC), Zhengxu Xieshi (ZXXS), which is characterized by a deficiency in vital Qi and an excess in evil Qi.

METHODS: We investigated shifts in vital Qi by quantifying systemic metabolic changes in the peripheral blood. Serum metabolomic profiling was conducted on the ESCC cohort 1 along with a matched healthy control cohort. Additionally, we assessed changes in evil Qi by examining metabolic perturbations in ESCC tissues. This analysis involved metabolomic and proteomic surveys of ESCC tissues and paired normal adjacent tissues as controls in an independent ESCC cohort 2.

RESULTS: Serum metabolomic profiling highlighted the prevalent downregulation of differentially expressed metabolites in patient sera, in contrast to the upregulation observed in ESCC tissues, compared to their respective controls. Remarkably, the group of differential metabolites in the ESCC tissues was predominantly composed of amino acids. Thus, we focused on amino acid metabolism. Our integrative analysis showed the downregulation of a significant majority of disturbed amino acids in patient sera relative to the upregulation of an overwhelming proportion of perturbed amino acids within ESCC tissues. Enrichment analysis of these amino acids revealed seven metabolic pathways that contribute to the metabolism of antioxidants, energy intermediates, and biosynthetic precursors. Interestingly, these pathways displayed attenuation in patient sera but augmentation in ESCC tissues. Similarly, the proteomic data confirmed the activation of these pathways in ESCC tissues.

CONCLUSION: This study presents a new perspective on the prevalence of ZXXS syndrome in patients with ESCC, contextualized within the realm of metabolic reprogramming. Specifically, diminished amino acid metabolism in the circulating blood corresponds to a deficiency in vital Qi. Conversely, hyperactive amino acid metabolism in ESCC tissues signifies an augmentation of local evil Qi. These findings hold potential to enrich the current medical framework and offer a deeper understanding of ESCC management by integrating the principles of ZXXS syndrome.

Key words： esophageal squamous cell carcinoma; metabolic reprogramming; amino acid metabolism; Zhengxu Xieshi syndrome; vital Qi; evil Qi

Cite this article

Siliang WANG , Yushui MA , Lei LIU , Pei WANG , Jia WU , Xing JIN , Qiang JIN , Congcong WANG , Chentai QIN , Miaomiao ZHENG , Xi YANG , Jun PAN , Hanchen XU , Changsheng DONG , Wenlian CHEN . Reversal of amino acid metabolism patterns between circulating blood and tumors as a new biomarker for the Zhengxu Xieshi syndrome in patients with esophageal squamous cell carcinoma[J]. Journal of Traditional Chinese Medicine, 2025 , 45(4) : 896 -908 . DOI: 10.19852/j.cnki.jtcm.2025.04.020

References

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Jemal ISA, Bray F. Global Cancer Statistics 2020: globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71: 209-49.
2. Liang H, Fan JH, Qiao YL. Epidemiology, etiology, and prevention of esophageal squamous cell carcinoma in China. Cancer Biol Med 2017; 14: 33-41.
3. Lagergren J, Smyth E, Cunningham D, Lagergren P. Oesophageal cancer. Lancet 2017; 390: 2383-96.
4. Wang ZX, Cui C, Yao J, et al. Toripalimab plus chemotherapy in treatment-naive, advanced esophageal squamous cell carcinoma (JUPITER-06): a multi-center phase 3 trial. Cancer Cell 2022; 40: 277-88.
5. Wu HX, Pan YQ, He Y, Wang ZX, Guan WL, Chen YX, et al. Clinical benefit of first-line programmed death-1 antibody plus chemotherapy in low programmed cell death ligand 1-expressing esophageal squamous cell carcinoma: a post hoc analysis of jupiter-06 and Meta-analysis. J Clin Oncol 2022: JCO2201490.
6. Tang JL, Liu BY, Ma KW. Traditional Chinese Medicine. Lancet 2008; 372: 1938-40.
7. Liu S, Zhu JJ, Li JC. The interpretation of human body in Traditional Chinese Medicine and its influence on the characteristics of TCM theory. Anat Rec (Hoboken) 2021; 304: 2559-65.
8. Ji Q, Luo YQ, Wang WH, Liu X, Li Q, Su SB. Research advances in Traditional Chinese Medicine syndromes in cancer patients. J Integr Med 2016; 14: 12-21.
9. Bower H, Bjorkholm M, Dickman PW, Hoglund M, Lambert PC, Andersson TM. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol 2016; 34: 2851-7.
10. Hu J, Liu YF, Wu CF, et al. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA 2009; 106: 3342-7.
11. Liu J, Wang S, Zhang Y, Fan HT, Lin HS. Traditional Chinese medicine and cancer: history, present situation, and development. Thorac Cancer 2015; 6: 561-9.
12. Cao L, Wang X, Zhu G, et al. Traditional Chinese Medicine therapy for esophageal cancer: a literature review. Integr Cancer Ther 2021; 20: 1-11.
13. Lopez-Otin C, Kroemer G. Hallmarks of health. Cell 2021; 184: 33-63.
14. Chen WL, Wang JH, Zhao AH, et al. A distinct glucose metabolism signature of acute myeloid leukemia with prognostic value. Blood 2014; 124: 1645-54.
15. Chen T, Xie G, Wang X, et al. Serum and urine metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma. Mol Cell Proteomics 2011; 10: M110.004945.
16. Liu L, Wu J, Shi M, et al. New metabolic alterations and a predictive marker pipecolic acid in sera for esophageal squamous cell carcinoma. Genomics Proteomics Bioinformatics 2022; 20: 670-87.
17. Schild T, Low V, Blenis J, Gomes AP. Unique metabolic adaptations dictate distal organ-specific metastatic colonization. Cancer cell 2018; 33: 347-54.
18. Brand A, Singer K, Koehl GE, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 2016; 24: 657-71.
19. Vander Heiden MG, DeBerardinis RJ. Understanding the Intersections between metabolism and cancer biology. Cell 2017; 168: 657-69.
20. Chen WL, Jin X, Wang M, et al. GLUT5-mediated fructose utilization drives lung cancer growth by stimulating fatty acid synthesis and AMPK/mTORC 1 signaling. JCI Insight 2020; 5: e131596.
21. Jin X, Liang Y, Liu D, et al. An essential role for GLUT5-mediated fructose utilization in exacerbating the malignancy of clear cell renal cell carcinoma. Cell Biol Toxicol 2019; 35: 471-83.
22. Jin X, Liu L, Wu J, et al. A multi-omics study delineates new molecular features and therapeutic targets for esophageal squamous cell carcinoma. Clin Transl Med 2021; 11: e538.
23. Amin MB, Greene FL, Edge SB, et al. The eighth edition AJCC cancer staging manual: continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. CA Cancer J Clin 2017; 67: 93-9.
24. National Health Commission of The People's Republic of China. Chinese guidelines for diagnosis and treatment of esophageal carcinoma 2018 (English version). Chin J Cancer Res 2019; 31: 223-58.
25. Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics 2016; 32: 2847-9.
26. Gu Z, Gu L, Eils R, Schlesner M, Brors B. Circlize implements and enhances circular visualization in R. Bioinformatics 2014; 30: 2811-2.
27. Rohart F, Gautier B, Singh A, Lê Cao KA. MixOmics: an R package for 'omics feature selection and multiple data integration. PLoS Comput Biol 2017; 13: e1005752.
28. Hakimi AA, Reznik E, Lee CH, et al. An integrated metabolic atlas of clear cell renal cell carcinoma. Cancer Cell 2016; 29: 104-16.
29. Zhou G, Pang Z, Lu Y, Ewald J, Xia J. OmicsNet 2.0: a web-based platform for multi-omics integration and network visual analytics. Nucleic Acids Res 2022; 50: 527-33.
30. Wen Y, Chen H, Zhang L, et al. Glycyrrhetinic acid induces oxidative/nitrative stress and drives ferroptosis through activating NADPH oxidases and iNOS, and depriving glutathione in triple-negative breast cancer cells. Free Radic Biol Med 2021; 173: 41-51.
31. Qian CJ, Tong YY, Wang YC, Teng XS, Yao J. Circ_ 0001093 promotes glutamine metabolism and cancer progression of esophageal squamous cell carcinoma by targeting miR-579-3p/glutaminase axis. J Bioenerg Biomembr 2022; 54: 119-34.
32. Liang Z, Zhao B, Hou J, Zheng J, Xin G. CircRNA circ-OGDH (hsa_circ_0003340) acts as a cerna to regulate glutamine metabolism and esophageal squamous cell carcinoma progression by the mir-615-5p/pdx1 axis. Cancer Manag Res 2021; 13: 3041-53.
33. Bansal A, Simon MC. Glutathione metabolism in cancer progression and treatment resistance. J Cell Biol 2018; 217: 2291-8.
34. Nunes SC, Ramos C, Lopes-Coelho F, et al. Cysteine allows ovarian cancer cells to adapt to hypoxia and to escape from carboplatin cytotoxicity. Sci Rep 2018; 8: 9513.
35. Bonifácio VDB, Pereira SA, Serpa J, Vicente JB. Cysteine metabolic circuitries: druggable targets in cancer. Br J Cancer 2021; 124: 862-79.
36. Li AM, Ye J. Reprogramming of serine, glycine and one-carbon metabolism in cancer. Biochim Biophys Acta Mol Basis Dis 2020; 1866: 165841.
37. Dobrzyn P. CoA in Health and Disease. Int J Mol Sci 2022; 23: 4317.
38. Lind DS. Arginine and cancer. J Nutr 2004; 134: 2837S-41S.
39. Dolce V, Cappello AR, Capobianco L. Mitochondrial tricarboxylate and dicarboxylate-tricarboxylate carriers: from animals to plants. IUBMB Life 2014; 66: 462-71.
40. Guertin DA, Wellen KE. Acetyl-CoA metabolism in cancer. Nat Rev Cancer 2023; 23: 156-72.
41. Hirschhaeuser F, Sattler UG, Mueller-Klieser W. Lactate: a metabolic key player in cancer. Cancer Res 2011; 71: 6921-5.
42. Knott SRV, Wagenblast E, Khan S, et al. Asparagine bioavailability governs metastasis in a model of breast cancer. Nature 2018; 554: 378-81.
43. Brosnan ME, Brosnan JT. Histidine metabolism and function. J Nutr 2020; 150: 2570s-5s.
44. Peng H, Wang Y, Luo W. Multifaceted role of branched-chain amino acid metabolism in cancer. Oncogene 2020; 39: 6747-56.
45. Xutian S, Cao D, Wozniak J, Junion J, Boisvert J. Comprehension of the unique characteristics of Traditional Chinese Medicine. Am J Chin Med 2012; 40: 231-44.
46. Hu X, Guo F. Amino acid sensing in metabolic homeostasis and health. Endocr Rev 2021; 42: 56-76.
47. Harris IS, Treloar AE, Inoue S, et al. Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 2015; 27: 211-22.
48. Wang W, Wu Z, Dai Z, Yang Y, Wang J, Wu G. Glycine metabolism in animals and humans: implications for nutrition and health. Amino Acids 2013; 45: 463-77.
49. Naquet P, Kerr EW, Vickers SD, Leonardi R. Regulation of coenzyme a levels by degradation: the 'Ins and Outs'. Prog Lipid Res 2020; 78: 101028.
50. Sun C, Wang A, Zhou Y, et al. Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer. Nat Commun 2023; 14: 2692.
51. Liu D, Huang J, Gao S, Jin H, He J. A temporo-spatial pharmacometabolomics method to characterize pharmacokinetics and pharmacodynamics in the brain microregions by using ambient mass spectrometry imaging. Acta Pharm Sin B 2022; 12: 3341-53.
52. Morris SM Jr. Arginine metabolism revisited. J Nutr 2016; 146: 2579S-86S.
53. Eagle H, Barban S, Levy M, Schulze HO. The utilization of carbohydrates by human cell cultures. J Biol Chem 1958; 233: 551-8.
54. Djukic T, Simic T, Pljesa-Ercegovac M, et al. Upregulated glutathione transferase omega-1 correlates with progression of urinary bladder carcinoma. Redox Rep 2017; 22: 486-92.
55. Manupati K, Debnath S, Goswami K, et al. Glutathione S-transferase omega 1 inhibition activates JNK-mediated apoptotic response in breast cancer stem cells. FEBS J 2019; 286: 2167-92.
56. Wang K, Zhang FL, Jia W. Glutathione S-transferase omega 1 promotes the proliferation, migration and invasion, and inhibits the apoptosis of non-small cell lung cancer cells, via the JAK/STAT3 signaling pathway. Mol Med Rep 2021; 23:71.
57. Locasale JW, Grassian AR, Melman T, et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 2011; 43: 869-74.
58. Pataskar A, Champagne J, Nagel R, et al. Tryptophan depletion results in tryptophan-to-phenylalanine substitutants. Nature 2022; 603: 721-7.
59. Liu X, Olszewski K, Zhang Y, et al. Cystine transporter regulation of pentose phosphate pathway dependency and disulfide stress exposes a targetable metabolic vulnerability in cancer. Nat Cell Biol 2020; 22: 476-86.
60. Gueta I, Perach Ovadia Y, Markovits N, Schacham YN, Epsztein A, Loebstein R. Is pyroglutamic acid a prognostic factor among patients with suspected infection? A prospective cohort study. Sci Rep 2020; 10: 10128.
61. Sanderson SM, Gao X, Dai Z, Locasale JW. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat Rev Cancer 2019; 19: 625-37.
62. Fernstrom JD, Fernstrom MH. Tyrosine, phenylalanine, and catecholamine synthesis and function in the brain. J Nutr 2007; 137: 1539S-47 S; discussion 48S.
63. Hoy AJ, Nagarajan SR, Butler LM. Tumour fatty acid metabolism in the context of therapy resistance and obesity. Nat Rev Cancer 2021; 21: 753-66.
64. Chen WL, Wang YY, Zhao A, et al. Enhanced fructose utilization mediated by SLC2A5 is a unique metabolic feature of acute myeloid leukemia with therapeutic potential. Cancer Cell 2016; 30: 779-91.
65. Goncalves MD, Lu C, Tutnauer J, et al. High-fructose corn syrup enhances intestinal tumor growth in mice. Science 2019; 363: 1345-9.
66. Hwang JJ, Jiang L, Hamza M, et al. The human brain produces fructose from glucose. JCI Insight 2017; 2: e90508.
67. Lane AN, Fan TW. Regulation of mammalian nucleotide metabolism and biosynthesis. Nucleic Acids Res 2015; 43: 2466-85.
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