KIRAMS / 김현기, 김진수*
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.
(A) 미세플라스틱 노출에 의한 위암세포의 변화 요약
(B) Cu-64 표지 폴리스틸렌 PET/CT 영상의 대표적 그림
(C) 마우스 위 조직에 형광 폴리스틸렌 입자 확인의 대표적 그림
(D) 폴리스틸렌유발 위암세포주의 Migration / Invasion 증가 확인의 대표적 그림
(E) 폴리스틸렌유발 암 줄기세포 유전자 CD44의 증가 확인의 대표적 그림
(F) 폴리스틸렌유발 면역 회피 유전자 PD-L1 증가 확인의 대표적 그림
Affiliations
Hyeongi Kim1,2, Javeria Zaheer1,3, Eui-Ju Choi2, and Jin Su Kim1,3
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: kjs@kirams.re.kr.