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

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.

• Authors: Hyeongi Kim, Javeria Zaheer, Eui-Ju Choi, Jin Su Kim
• Journal: Theranostics (Theranostics) Vol. 12 Issue 7 Pg. 3217-3236 ( 2022) ISSN: 1838-7640 [Electronic] Australia
• PMID: 35547772 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• Asialoglycoprotein Receptor
• Cadherins
• Microplastics
• Plastics

Topics

• Animals
• Asialoglycoprotein Receptor
• Cadherins (metabolism)
• Cell Line, Tumor
• Mice
• Mice, Nude
• Microplastics
• Plastics (metabolism, therapeutic use)
• Stomach Neoplasms (drug therapy, genetics, metabolism)
• Tissue Distribution