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Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and related clinical significance

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Abstract

Lipid metabolism rewiring in gastric adenocarcinoma (GA) pathogenesis is still not clearly elucidated. This study aimed to describe the role of lipid catabolism in GA patient outcomes and possible therapeutic targets by analyzing the effect of hypoxia-inducible factor-1α (HIF-1α) on fatty acid oxidation (FAO). AGS cell line was cultured in normoxic and hypoxic conditions, and FAO-related genes were analyzed by real-time-PCR and Western-blot. The study group comprised 108 newly diagnosed GA patients and 152 control cases. Serum concentrations of medium and long-chain acyl-CoA dehydrogenases (MCAD and LCAD) proteins were measured using ELISA, and local expression of HIF-1α, carnitine palmitoyl transferase 1 (CPT1A) and peroxisome proliferator-activated receptor γ (PPARγ) was evaluated by immunohistochemistry. In addition, gene expression of PPARγ, CPT1A, LCAD, and MCAD was assessed by real-time-PCR. In vitro findings indicate HIF-1α upregulation and FAO-related genes and proteins reduction in the hypoxic culture of AGS cells. GA patients had significantly lower circulating levels of LCAD compared to controls. Higher protein expression of HIF-1α and downregulated CPT1A and PPARγ were observed in GA tissues versus controls. Gene expression of CPT1A, PPARγ, LCAD, and MCAD were repressed in GA tissues compared to controls. Moreover, reduced expression of CPT1A, PPARγ, and MCAD were correlated with HIF-1α upregulation in GA. Poor patient outcome was associated with lower PPARγ and LCAD expression in GA. HIF-1α upregulation in human GA patients and AGS cells was paralleled by downregulation of lipid catabolism genes potentially via reduced PPARγ-mediated FAO. This metabolic adaptation to hypoxic condition may play a role in GA pathogenesis and might have clinical and therapeutic value in GA patients.

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Data availability

The data are available from the corresponding author upon request.

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Acknowledgements

The authors are grateful to Professor Kh. Adeli and V. Higgins from Toronto University for valuable scientific comments on the manuscript. We thank Dr. Amirtaher Eftekharosadat from Liver and Gastrointestinal Diseases Research Center of Tabriz for evaluating the pathological sections. Our thanks also to the staff on the endoscopy ward from Liver and Gastrointestinal Diseases Research Center of Tabriz for kind cooperation. Great supports from Professor SM. Moazzeni are appreciated.

Funding

This work was supported by Iran National Science Foundation (Grant number: 94016621), Tarbiat Modares University (Grant number: 52D.7928), Liver and Gastrointestinal Diseases Research Center (Grant number: 144.257), and Hematology and Oncology Research Center (Grant number: 95.1).

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Authors and Affiliations

  1. Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Rana Ezzeddini, Mohammad Taghikhani, Nasser Samadi & Ali Esfahani

  2. Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Jalal AleAhmad Highway, Nasr, P.O.Box: 14115-331, Tehran, Iran

    Rana Ezzeddini & Mohammad Taghikhani

  3. Department of Immunology, School of Medicine, Semnan University of Medical Sciences, Semnan, Iran

    Amir Salek Farrokhi

  4. Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

    Mohammad Hossein Somi

  5. Department of Biochemistry, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

    Nasser Samadi

  6. Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Jalal AleAhmad Highway, Nasr, P.O.Box: 14115-331, Tehran, Iran

    Mohammad Javad Rasaee

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  1. Rana Ezzeddini
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  2. Mohammad Taghikhani
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Contributions

Conceived and designed the experiments: R.E.; M.T.;. M.H.S.; N.S. Performed the experiments: R.E.; A.S.F. Analyzed and interpreted the data: R.E.; M.T.; M.J.R.; A.S.F.; A.E. Contributed reagents/materials/analysis tools: R.E.; M.T.;. M.H.S.; A.S.F.; N.S. Wrote the paper: R.E.; A.S.F.; M.J.R; A.E. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Mohammad Taghikhani or Mohammad Javad Rasaee.

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The Human Research Ethics Committees of Tarbiat Modares University (Tehran, Iran) (Ethic code: IR.TMU.REC.1394.184) and Hematology and Oncology Research Center (Tabriz, Iran) (Ethic code: TBZMED.REC.1395.12) approved the study protocols. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.

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Informed consent was obtained from all individual participants included in the study.

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Key points

HIF-1α-mediated metabolic adaptation in human GA is correlated with downregulation of FAO genes via reduced PPARγ.

FAO metabolic repression seems to be involved in GA pathogenesis and is associated with poor patient outcome.

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Ezzeddini, R., Taghikhani, M., Salek Farrokhi, A. et al. Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and related clinical significance. J Physiol Biochem 77, 249–260 (2021). https://doi.org/10.1007/s13105-021-00791-3

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