2. Academic Validation
  3. Oleanolic acid inhibits hypoxic tumor-derived exosomes-induced premetastatic niche formation in hepatocellular carcinoma by targeting ERK1/2-NFκB signaling

Oleanolic acid inhibits hypoxic tumor-derived exosomes-induced premetastatic niche formation in hepatocellular carcinoma by targeting ERK1/2-NFκB signaling

  • Phytomedicine. 2024 Apr:126:155208. doi: 10.1016/j.phymed.2023.155208.
Wentao Jia 1,  Shufang Liang 2,  Mingming Jin 3,  Shu Li 4,  Jiaying Yuan 5,  Jinbo Zhang 6,  Wanfu Lin 7,  Yuqian Wang 1,  Shuchang Nie 1,  Changquan Ling 8,  Binbin Cheng 9
Affiliations

Affiliations

  • 1 Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China; Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai 200043, China.
  • 2 Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China.
  • 3 Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China.
  • 4 Department of Gastroenterology, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201900, China.
  • 5 Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China.
  • 6 Department of Pharmacy, Tianjin Rehabilitation and Recuperation Center, Joint Logistics Support Force, Tianjin 300000, China.
  • 7 Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai 200043, China.
  • 8 Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China; Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai 200043, China. Electronic address: [email protected].
  • 9 Oncology Department of Traditional Chinese Medicine, the First Affiliated Hospital of Naval Medical University (Second Military Medical University), Shanghai 200433, China; Faculty of Traditional Chinese Medicine, Naval Medical University (Second Military Medical University), Shanghai 200043, China. Electronic address: [email protected].
PMID: 38387275 DOI: 10.1016/j.phymed.2023.155208
Abstract

Background: Pulmonary premetastatic niche (PMN) formation plays a key role in the lung metastasis of hepatocellular carcinoma (HCC). Hypoxia promotes the secretion of tumor-derived exosomes (TDEs) and facilitates the formation of PMN. However, the mechanisms remain unexplored.

Methods: TDEs from normoxic (N-TDEs) or hypoxic (H-TDEs) HCC cells were used to induce fibroblast activation in vitro and PMN formation in vivo. Oleanolic acid (OA) was intragastrically administered to TDEs-preconditioned mice. Bioinformatics analysis and drug affinity responsive target stability (DARTS) assays were performed to identify targets of OA in fibroblasts.

Results: H-TDEs induced activation of pulmonary fibroblasts, promoted formation of pulmonary PMN and subsequently facilitated lung metastasis of HCC. OA inhibited TDEs-induced PMN formation and lung metastasis and suppressed TDEs-mediated fibroblast activation. MAPK1 and MAPK3 (ERK1/2) were the potential targets of OA. Furthermore, H-TDEs enhanced ERK1/2 phosphorylation in fibroblasts in vitro and in vivo, which was suppressed by OA treatment. Blocking ERK1/2 signaling with its inhibitor abated H-TDEs-induced activation of fibroblasts and PMN formation. H-TDEs-induced phosphorylation of ERK1/2 in fibroblasts touched off the activation NF-κB p65, which was mitigated by OA. In addition, the ERK Activator C16-PAF recovered the activation of ERK1/2 and NF-κB p65 in H-TDEs-stimulated MRC5 cells upon OA treatment.

Conclusion: The present study offers insights into the prevention of TDEs-induced PMN, which has been insufficiently investigated. OA suppresses the activation of inflammatory fibroblasts and the development of pulmonary PMN by targeting ERK1/2 and thereby has therapeutic potential in the prevention of lung metastasis of HCC.

Keywords

Hepatocellular carcinoma; Hypoxia; Oleanolic acid; Premetastatic niche; Tumor-derived exosomes.

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