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CircSETD3 Contributes to Acquired Resistance to gefitinib in Non-Small Cell Lung Cancer by Targeting miR-520h/ABCG2 Pathway

37 Pages Posted: 18 Jun 2019

See all articles by Yi Dai

Yi Dai

Chongqing Medical University - Institute of Life Sciences

Yutang Huang

Chongqing Medical University - Institute of Life Sciences

Chunjie Wen

Chongqing Medical University - Institute of Life Sciences

Shuai He

Chongqing Medical University - Institute of Life Sciences

Jingjing Shi

Chongqing Medical University - Institute of Life Sciences

Lanxiang Wu

Chongqing Medical University - Institute of Life Sciences

Honghao Zhou

Central South University - Pharmacogenetics Research Institute

More...

Abstract

Background: Gefitinib is approved for first-line treatment of advanced non-small cell lung cancer (NSCLC), but acquired resistance is a major obstacle to its therapeutic efficacy, and the underlying mechanisms are not fully elucidated. Recent studies have indicated that circular RNAs play a crucial role in chemoresistance, but their expression and function in NSCLC cells with acquired resistance to gefitinib are still unknown.

Methods: CircSETD3 expression was anaylzed in gefitinib-sensitive and -resistant NSCLC cell lines and in the plasma of gefitinib-sensitive and -resistant NSCLC patients. The influence of circSETD3 on gefitinib sensitivity was elucidated in vitro and in nude mice xenografts. The regulatory actions of circSETD3 on the miR-520h and ATP-binding cassette subfamily G member 2 (ABCG2) were assessed. Furthermore, the molecular mechanism of circSETD3 upregulation was also investigated.

Findings: circSETD3 was significantly upregulated in gefitinib-resistant NSCLC cell lines and in the plasma of gefitinib-resistant NSCLC patients, and it decreased the gefitinib sensitivity both in vitro and in nude mice xenografts. CircSETD3 could directly bind to miR-520h and lead to the upregulation of ABCG2, an efflux transporter of gefitinib, resulting in reduced intracellular gefitinib concentration. The downregulation of serine/arginine splicing factor 1 (SRSF1) contributed to the aberrantly expression of circSETD3 in NSCLC cells with acquired resistance to gefitinib.

Interpretation: circSETD3 decreases the gefitinib sensitivity through targeting the miR-520h/ABCG2 pathway, and may serve as a prognostic biomarker and a potential therapeutic target for acquired resistance to gefitinib in NSCLC.

Trial Registration: Registered with the Chinese Clinical Trial Registry (No. ChiCTR1800014660).

Funding Statement: The National Scientific Foundation of China (No. 81473284, 81603201).

Declaration of Interests: The authors declare no conflict of interest.

Ethics Approval Statement: This study was approved by the Ethics Committee Board of Chongqing Medical University (No. 2017009).

All animal experiments were approved by the Animal Ethics and Experimental Committee of the Chongqing Medical University, and performed according to the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Keywords: circSETD3; NSCLC; acquired resistance; gefitinib; miR-520h; ABCG2

Suggested Citation

Dai, Yi and Huang, Yutang and Wen, Chunjie and He, Shuai and Shi, Jingjing and Wu, Lanxiang and Zhou, Honghao, CircSETD3 Contributes to Acquired Resistance to gefitinib in Non-Small Cell Lung Cancer by Targeting miR-520h/ABCG2 Pathway (June 17, 2019). Available at SSRN: https://ssrn.com/abstract=3405549 or http://dx.doi.org/10.2139/ssrn.3405549

Yi Dai

Chongqing Medical University - Institute of Life Sciences

Chongqing
China

Yutang Huang

Chongqing Medical University - Institute of Life Sciences

Chongqing
China

Chunjie Wen

Chongqing Medical University - Institute of Life Sciences

Chongqing
China

Shuai He

Chongqing Medical University - Institute of Life Sciences

Chongqing
China

Jingjing Shi

Chongqing Medical University - Institute of Life Sciences

Chongqing
China

Lanxiang Wu (Contact Author)

Chongqing Medical University - Institute of Life Sciences ( email )

Chongqing
China

Honghao Zhou

Central South University - Pharmacogenetics Research Institute

Changsha
China

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