Full Text | PDF

Theranostics 2022; 12(4):1904-1920. doi:10.7150/thno.66814 This issue Cite

Research Paper

The peroxisome proliferator-activated receptor agonist rosiglitazone specifically represses tumour metastatic potential in chromatin inaccessibility-mediated FABP4-deficient gastric cancer

Qi-Yue Chen^1,2,3*, Xiao-Bo Huang^1,2,3*, Ya-Jun Zhao^4*, Hua-Gen Wang^1,2,3*, Jia-Bin Wang^1,2,3*, Li-Chao Liu^1,2,3, Ling-Qian Wang^1,2,3, Qing Zhong^1,2,3, Jian-Wei Xie^1,2,3, Jian-Xian Lin^1,2,3, Jun Lu^1,2,3, Long-Long Cao^1,2,3, Mi Lin^1,2,3, Ru-Hong Tu^1,2,3, Chao-Hui Zheng^1,2,3✉, Ping Li^1,2,3✉, Chang-Ming Huang^1,2,3✉

1. Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou 350001, Fujian, P. R. China
2. Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
3. Fujian Key Laboratory of Tumor Microbiology, Fujian Medical University, Fuzhou 350001, Fujian, P. R. China
4. The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, Anhui, P. R. China
^*These authors contributed equally to this work.

✉ Corresponding authors: Chang-Ming Huang, Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou 350001, Fujian, P. R. China, E-mail: hcmlr2002com. Ping Li, Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou 350001, Fujian, P. R. China. E-mail: pingli811002com. Chao-Hui Zheng, Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou 350001, Fujian, P. R. China. E-mail: wwkzchcom. Telephone: +86-591-83363366, Fax: +86-591-83320319. More

Abstract

Background: Efforts to prevent recurrence in gastric cancer (GC) patients are limited by current incomplete understanding of the pathological mechanisms. The present study aimed to identify novel tumour metastasis-associated genes and investigate potential value of these genes in clinical diagnosis and therapy.

Methods: RNA sequencing was performed to identify differentially expressed genes related to GC metastasis. The expression and prognostic significance of fatty acid binding protein 4 (FABP4) were evaluated in two independent cohorts of GC patients. Chromatin immunoprecipitation sequencing, diverse mouse models and assays for transposase-accessible chromatin with high-throughput sequencing were used to investigate the roles and mechanisms of action of FABP4.

Results: The results of the present multicentre study confirmed an association between a decrease in the expression of FABP4 and poor outcomes in GC patients. FABP4 inhibited GC metastasis but did not influence tumour growth in vitro and in vivo. Mechanistically, FABP4 binding with peroxisome proliferator-activated receptor γ (PPAR-γ) facilitated the translocation of PPAR-γ to the nucleus. FABP4 depletion suppressed PPAR-γ-mediated transcription of cell adhesion molecule 3 (CADM3), which preferentially governed GC metastasis. Notably, the PPAR-γ agonist rosiglitazone reversed the metastatic properties of FABP4-deficient GC cells in vitro and demonstrated viable therapeutic potential in multiple mouse models. For GC patients with diabetes, low FABP4 portends better prognosis than high FABP4 after receipt of rosiglitazone treatment. Additionally, chromatin inaccessibility induced by HDAC1 reduced FABP4 expression at the epigenetic level.

Conclusions: Our findings suggest that chromatin inaccessibility orchestrates a reduction in FABP4 expression, which inhibits CADM3 transcription via PPAR-γ, thereby resulting in GC metastasis. The antidiabetic drug rosiglitazone restores PPAR-γ/CADM3 activation in FABP4-deficient GC and thus has promising therapeutic potential.

Keywords: Gastric cancer, FABP4, PPAR-γ, CADM3, Rosiglitazone

Citation styles

©2024 Ivyspring International Publisher. Terms of use