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Theranostics 2022; 12(7):3217-3236. doi:10.7150/thno.73226 This issue Cite

Research Paper

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

Hyeongi Kim^1,2, Javeria Zaheer^1,3, Eui-Ju Choi², Jin Su Kim^1,3✉

1. Division of RI Application, Korea Institute Radiological and Medical Sciences, Seoul 01812, Republic of Korea.
2. Department of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.
3. Radiological and Medico-Oncological Sciences, University of Science and Technology (UST), Seoul 01812, Republic of Korea.

✉ Corresponding author: Jin Su Kim, PhD, Division of RI Application, Korea Institute Radiological and Medical Sciences, 75 Nowon-Gil, Gongneung-Dong, Nowon-Gu, Seoul 01812, Korea. Radiological and Medico-Oncological Sciences, University of Science and Technology (UST), Seoul 01812, Republic of Korea. Tel: 82-2-970-1661, Fax: 82-2-970-2416, E-mail: kjsre.kr. More

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.

Keywords: Microplastics, gastric cancer, cancer hallmarks, polystyrene, ASGR2

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