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Functional metabolome profiling may improve individual outcomes in colorectal cancer management implementing concepts of predictive, preventive, and personalized medical approach

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Abstract

Objectives

Colorectal cancer (CRC) is one of the most common solid tumors worldwide, but its diagnosis and treatment are limited. The objectives of our study were to compare the metabolic differences between CRC patients and healthy controls (HC), and to identify potential biomarkers in the serum that can be used for early diagnosis and as effective therapeutic targets. The aim was to provide a new direction for CRC predictive, preventive, and personalized medicine (PPPM).

Methods

In this study, CRC patients (n = 30) and HC (n = 30) were recruited. Serum metabolites were assayed using an ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) technology. Subsequently, CRC cell lines (HCT116 and HCT8) were treated with metabolites to verify their function. Key targets were identified by molecular docking, thermal shift assay, and protein overexpression/inhibition experiments. The inhibitory effect of celastrol on tumor growth was also assessed, which included IC50 analysis, nude mice xenografting, molecular docking, protein overexpression/inhibition experiments, and network pharmacology technology.

Results

In the CRC group, 15 serum metabolites were significantly different in comparison with the HC group. The level of glycodeoxycholic acid (GDCA) was positively correlated with CRC and showed high sensitivity and specificity for the clinical diagnostic reference (AUC = 0.825). In vitro findings showed that GDCA promoted the proliferation and migration of CRC cell lines (HCT116 and HCT8), and Poly(ADP-ribose) polymerase-1 (PARP-1) was identified as one of the key targets of GDCA. The IC50 of celastrol in HCT116 cells was 121.1 nM, and the anticancer effect of celastrol was supported by in vivo experiments. Based on the potential of GDCA in PPPM, PARP-1 was found to be significantly correlated with the anticancer functions of celastrol.

Conclusion

These findings suggest that GDCA is an abnormally produced metabolite of CRC, which may provide an innovative molecular biomarker for the predictive identification and targeted prevention of CRC. In addition, PARP-1 was found to be an important target of GDCA that promotes CRC; therefore, celastrol may be a potential targeted therapy for CRC via its effects on PARP-1. Taken together, the pathophysiology and progress of tumor molecules mediated by changes in metabolite content provide a new perspective for predictive, preventive, and personalized medical of clinical cancer patients based on the target of metabolites in vivo.

Clinical trials registration number: ChiCTR2000039410.

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Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

All software applications used are included in this article.

Abbreviations

PPPM:

Predictive, preventive, and personalized medicine

CRC:

Colorectal cancer

GDCA:

Glycodeoxycholic acid

PARP-1:

Protein poly (ADP-ribose) polymerase-1

PCA:

Principal component analysis

OPLS-DA:

Orthogonal partial least squares discriminant analysis

ROC:

Receiver operating characteristic

KEGG:

Kyoto Encyclopedia of Genes and Genomes

GO:

Gene Ontology

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Funding

This work was supported by the National Natural Science Foundation of China (81573825, 81902826, 81672781 and 81973356) and Tianjin Development Program for Innovation and Entrepreneurship (20190617), the Fundamental Research Funds for the Central Universities, Nankai University (3206054, 91923101, 63213082 and 92122017), and the National Key R&D Program of China (No. 2018YFC2002000).

National Natural Science Foundation of China,81573825,Yubo Li,81902826,Shuai Zhang,81672781,Shuai Zhang,81973356,Shuai Zhang,Tianjin Development Program for Innovation and Entrepreneurship,20190617,Yubo Li,Fundamental Research Funds for the Central Universities,3206054,Changliang Shan,91923101,Changliang Shan,63213082,Changliang Shan,92122017,Changliang Shan,National Key R&D Program of China,2018YFC2002000,Changliang Shan

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Author notes

  1. Yu Yuan and Chenxin Yang contributed equally to this work

Authors and Affiliations

  1. Tianjin State Key Laboratory of Modern Chinese Medicine, School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China

    Yu Yuan, Chenghao Bi, Sitong Sun & Yubo Li

  2. School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China

    Chenxin Yang, Lingling Li & Shuai Zhang

  3. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300350, China

    Yingzhi Wang, Mingming Sun & Changliang Shan

  4. Department of Kidney Disease and Blood Purification, Second Hospital of Tianjin Medical University, Tianjin, 300211, China

    Guijiang Sun

  5. Department of Anorectal Surgery, Second Hospital of Tianjin Medical University, Tianjin, 300211, China

    Jingpeng Hao

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  1. Yu Yuan
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Contributions

SZ and YL conceived the study and designed the experiments. YY and CY performed most experiments and analyzed the data. YY, CY, YW, SS and LL assisted with cells culture. GS and JH collected clinical samples. YY, SS, and CB assisted with UPLC-Q-TOF/MS analysis. YM and MS performed animal experiments. CS, SZ, and YL performed writing. The author(s) read and approved the final manuscript.

Corresponding authors

Correspondence to Shuai Zhang or Yubo Li.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Ethics Committee of the Second Hospital of Tianjin Medical University (Ethical approval number: KY2019K144) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Supplementary file 1 Figure 1:

The base peak intensity (BPI) chromatogram of serum in the QC sample. (ai 481 KB)

Supplementary file 2 Figure 2:

Effect of GDCA on the activity of FHC cell line. Cell viability was measured with MTT assay in FHC cells. (ai 175 KB)

Supplementary file 3 Figure 3:

Anticancer effect of celastrol on CRC. A: The docking results of PARP-1 protein (PDB:5DS3) with celastro (2D). B: Weight changes of xenograft mice. (ai 200 KB)

Supplementary file 4

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Supplementary file 5

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Yuan, Y., Yang, C., Wang, Y. et al. Functional metabolome profiling may improve individual outcomes in colorectal cancer management implementing concepts of predictive, preventive, and personalized medical approach. EPMA Journal 13, 39–55 (2022). https://doi.org/10.1007/s13167-021-00269-8

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  • DOI: https://doi.org/10.1007/s13167-021-00269-8

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