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AKR1B10 Promotes Brain Metastasis of Lung Cancer Cells in a Multi-Organ Microfluidic Chip Model

27 Pages Posted: 30 Jan 2019 First Look: Accepted

See all articles by Wenwen Liu

Wenwen Liu

Dalian University - Department of Respiratory Medicine

Jing Song

Dalian University - Department of Respiratory Medicine

Xiaohui Du

Dalian University - Department of Scientific Research Center

Yang Zhou

Dalian University - Department of Scientific Research Center

Yang Li

Dalian University of Technology - Key Laboratory for Micro/Nano Technology and System of Liaoning Province

Rui Li

Dalian University - Department of Hepatological Surgery

Li Lyu

Dalian University - Department of Pathology

Yeting He

Dalian University - Department of Neurosurgery

Junxia Hao

Dalian University - Department of Respiratory Medicine

Jing Ben

Dalian University - Department of Respiratory Medicine

Wei Wang

Peking University - Institute of Microelectronics

Haibin Shi

Soochow University - State Key Laboratory of Radiation Medicine and Protection; Soochow University - Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions

Qi Wang

Dalian University - Department of Respiratory Medicine

Abstract

Brain metastasis (BM) is a leading cause of mortality in patients with non-small cell lung cancer (NSCLC). However, the molecular mechanisms underlying BM of NSCLC remain largely unknown because we lack models to accurately investigate such a dynamic and complex process. Here we developed a multi-organ microfluidic chip and provided a new methodological platform to study BM. The chip consisted of two bionic organ units – an upstream “lung” and a downstream “brain” characterized by a functional “blood-brain barrier (BBB)” structure. The chip allowed real-time visual monitoring of the entire BM process, from the growth of primary tumor to its breaking through the BBB, and finally reaching the brain parenchyma. We verified this model using lung cancer cell lines with differing metastatic abilities. We first demonstrated that the protein expression of Aldo-keto reductase family 1 B10 (AKR1B10) was significantly elevated in lung cancer cell lines with higher metastatic ability and clinical brain metastases of lung cancers. Silencing AKR1B10 in brain metastatic tumor cells suppressed their extravasation through the BBB in the in vitro Transwell model and in our ex vivo microfluidic chip, as well as the in vivo model of metastasis to the brain in nude mice. Moreover, AKR1B10 downregulated the expression of matrix metalloproteinase (MMP)-2 and MMP-9 via MEK/ERK signaling in metastatic lung cancers. These data suggest that our multi-organ microfluidic chip is a practical alternative to study BM pathogenesis, and AKR1B10 is a potential diagnostic biomarker and a prospective therapeutic target for NSCLC BM.

Keywords: multi-organ microfluidic chip, lung cancer, brain metastasis, blood-brain barrier, AKR1B10

Suggested Citation

Liu, Wenwen and Song, Jing and Du, Xiaohui and Zhou, Yang and Li, Yang and Li, Rui and Lyu, Li and He, Yeting and Hao, Junxia and Ben, Jing and Wang, Wei and Shi, Haibin and Wang, Qi, AKR1B10 Promotes Brain Metastasis of Lung Cancer Cells in a Multi-Organ Microfluidic Chip Model (January 25, 2019). Available at SSRN: https://ssrn.com/abstract=3321955

Wenwen Liu

Dalian University - Department of Respiratory Medicine

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Jing Song

Dalian University - Department of Respiratory Medicine

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Xiaohui Du

Dalian University - Department of Scientific Research Center

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Yang Zhou

Dalian University - Department of Scientific Research Center

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Yang Li

Dalian University of Technology - Key Laboratory for Micro/Nano Technology and System of Liaoning Province

Huiying Rd
DaLian, LiaoNing, 116024
China

Rui Li

Dalian University - Department of Hepatological Surgery

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Li Lyu

Dalian University - Department of Pathology

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Yeting He

Dalian University - Department of Neurosurgery

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Junxia Hao

Dalian University - Department of Respiratory Medicine

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Jing Ben

Dalian University - Department of Respiratory Medicine

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Wei Wang

Peking University - Institute of Microelectronics ( email )

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Haibin Shi

Soochow University - State Key Laboratory of Radiation Medicine and Protection ( email )

No. 1 Shizi Street
Taipei, Jiangsu 215006
Taiwan

Soochow University - Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions ( email )

No. 1 Shizi Street
Taipei, Jiangsu 215006
Taiwan

Qi Wang (Contact Author)

Dalian University - Department of Respiratory Medicine ( email )

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

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