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

• Published in: Theranostics 2022, Vol.12 (7), p.3217-3236
• Main Authors: Kim, Hyeongi, Zaheer, Javeria, Choi, Eui-Ju, Kim, Jin Su
• Format: Article
• Language: English
• Subjects: Animals; Asialoglycoprotein Receptor; Cadherins - metabolism; Cell Line, Tumor; Cytotoxicity; Drug dosages; Drug resistance; Flow cytometry; Food; Gastric cancer; Gene expression; Mice; Mice, Nude; Microplastics; Plastics - metabolism; Plastics - therapeutic use; Polymerase chain reaction; Research Paper; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Student's t-test; Tissue Distribution
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.73226

Microplastics (MPs) are a new global environmental threat. Previously, we showed the biodistribution of MPs using [ Cu] 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. BALB/c nude mice were fed 1.72 × 10 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 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. PET imaging results showed that a single dose of [ Cu]-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 ( ) expression after PS exposure, and knockdown decreased cell proliferation, migration, invasion, and drug resistance. We demonstrated that 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.