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Exosome-Delivered c-Met siRNA Could Reverse Chemoresistance to Cisplatin in Gastric Cancer

Int J Nanomedicine. 2020 Apr 1:15:2323-2335. doi: 10.2147/IJN.S231214. eCollection 2020.

Abstract

Background: Drug resistance often occurs in the treatment of gastric cancer, which is the main cause of poor prognosis of chemotherapy. c-Met is overexpressed in a variety of tumors including gastric cancer, often leads to poor prognosis of gastric cancer, therefore regarded as a key target for the treatment of gastric cancer. This study aims to determine whether exosomes with si-c-Met could inhibit the resistance to cisplatin in gastric cancer (GC).

Methods: The protein expression levels of c-Met in tumor tissues and normal tissues of patients were evaluated by Western blot (WB) and immunohistochemistry (IHC), HEK293T cells were transfected with si-c-Met, exosomes were isolated, then co-cultured with gastric cancer cell lines and confirmed that it was incorporated into the cells by transmitted electron microscopy. Functional experiments were performed to examine the inhibitory effect of exo-si-c-Met on gastric cancer cell resistance in vitro, and xenograft models were used to reveal that exo-si-c-Met can enhance the sensitivity of tumors to cisplatin in vivo.

Results: High expression of c-Met is associated with poor prognosis of GC patients. si-c-Met significantly inhibited migration, invasion and promoted apoptosis in vitro, which indicated that si-c-Met sensitizes the response of gastric cancer cells to cisplatin. Exo-si-c-Met sharply reduced c-Met expression in gastric cancer cells and reverse the resistance to cisplatin in vitro and in vivo.

Conclusion: Our results indicate that exo-si-c-Met can inhibit the invasion and migration of gastric cancer cells and promote apoptosis in vitro and inhibit tumor growth in vivo, reversing the resistance to cisplatin in gastric cancer.

Keywords: c-Met; chemoresistance; exosomes; gastric cancer; siRNA.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line
  • Cell Proliferation / drug effects
  • Cisplatin / pharmacology*
  • Drug Delivery Systems / methods*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics*
  • Exosomes / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mice, Nude
  • RNA, Small Interfering / administration & dosage*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Stomach Neoplasms / drug therapy*
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / mortality
  • Stomach Neoplasms / pathology
  • Xenograft Model Antitumor Assays
  • c-Mer Tyrosine Kinase / genetics*
  • c-Mer Tyrosine Kinase / metabolism

Substances

  • RNA, Small Interfering
  • MERTK protein, human
  • c-Mer Tyrosine Kinase
  • Cisplatin

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81772629, 81602158, 81602156, 81702275, 81802363, 81702431, 81702437, 81772843) and the Demonstrative Research Platform of Clinical Evaluation Technology for New Anticancer Drugs (No. 2018ZX09201015). This work was also supported by the Tianjin Science Foundation (Nos. 18JCQNJC81900, 18JCYBJC92000, 18JCYBJC25400, 16PTSYJC00170) and the Science & Technology Development Fund of the Tianjin Education Commission for Higher Education (2018KJ046, 2017KJ227, 2017KJ204). The funders had no role in the study design, the data collection and analysis, the interpretation of the data, the writing of the report, and the decision to submit this article for publication.