Enhanced ASGR2 by microplastic exposure leads to resistance to therapy in gastric cancer

Hyeongi Kim, Javeria Zaheer, Eui Ju Choi, Jin Su Kim

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

Background: Microplastics (MPs) are a new global environmental threat. Previously, we showed the biodistribution of MPs using [64Cu] polystyrene (PS) and PET in mice. Here, we aimed to identify whether PS exposure has malignant effects on the stomach and induces resistance to therapy. Methods: BALB/c nude mice were fed 1.72 × 104 particles/mL of MP. We investigated PS accumulation in the stomach using radioisotope-labeled and fluorescent-conjugated PS. Further, we evaluated whether PS exposure induced cancer stemness and multidrug resistance, and whether it affected tumor development, tumor growth, and survival rate in vivo using a 4-week PS-exposed NCI-N87 mouse model. Using RNA-Seq analysis, we analyzed whether PS exposure induced gene expression changes in gastric tissues of mice. Results: PET imaging results showed that a single dose of [64Cu]-PS remained for 24 h in the mice stomach. The 4-week daily repetitive dose of fluorescent conjugated PS was deposited in the gastric tissues of mice. When PS was exposed, a 2.9-fold increase in migration rate was observed for NCI-N87 cells. Immunocytochemistry results showed decreased E-cadherin and increased N-cadherin expression, and flow cytometry, qPCR, and western blot analysis indicated a 1.9-fold increase in N-cadherin expression after PS exposure. Further, PS-induced multidrug resistance to bortezomib, paclitaxel, gefitinib, lapatinib, and trastuzumab was observed in the NCI-N87 mouse model due to upregulated CD44 expression. RNA-seq results identified increased asialoglycoprotein receptor 2 (ASGR2) expression after PS exposure, and ASGR2 knockdown decreased cell proliferation, migration, invasion, and drug resistance. Conclusion: We demonstrated that ASGR2 enhanced cancer hallmarks on PS exposure and induced resistance to chemo- and monoclonal antibody-therapy. Our preclinical findings may provide an incentive for further epidemiological studies on the role of MP exposure and its association with gastric cancer.

Original languageEnglish
Pages (from-to)3217-3236
Number of pages20
JournalTheranostics
Volume12
Issue number7
DOIs
Publication statusPublished - 2022

Bibliographical note

Funding Information:
This study was funded by the Ministry of Science and ICT (MSIT), Republic of Korea (NRF-2020R1F1A1061476, NRF-2021M2E8A1039980, 50536-2022, 50461-2022).

Funding Information:
This study was funded by the Ministry of Science and ICT (MSIT), Republic of Korea

Publisher Copyright:
© The author(s)

Keywords

  • ASGR2
  • Microplastics
  • cancer hallmarks
  • gastric cancer
  • polystyrene

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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