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Now published in The Lancet

A miR-567-PIK3AP1- PI3K/AKT-c-Myc Feedback Loop Regulates Tumor Growth and Chemoresistance in Gastric Cancer

38 Pages Posted: 31 Mar 2019

See all articles by Feifei Zhang

Feifei Zhang

Southern Medical University, Nanfang Hospital, Department of Pathology

Kaitao Li

Southern Medical University - Nanfang Hospital

Xueqing Yao

Guangdong Academy of Medical Sciences - Guangdong General Hospital

Hui Wang

Guangzhou Medical University

Weidong Li

Guangzhou Medical University

Juan Wu

Guangzhou Medical University

Mingyi Li

Guangzhou Medical University

Rui Zhou

Southern Medical University - Department of Pathology

Lijun Xu

Southern Medical University, School of Basic Medical Sciences, Department of Pathology

Liang Zhao

Southern Medical University, Nanfang Hospital, Department of Pathology; Southern Medical University, School of Basic Medical Sciences, Department of Pathology

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Abstract

BACKGROUND: Gastric cancer (GC) ranks the fifth most common cancer and third for cancer death, chemotherapy is one of the most common treatments for GC. However, chemoresistance limits the effectiveness of chemotherapy and leads to treatment failure. This study aims to investigate the biological effect of miR-567 on gastric cancer and to reveal the possible mechanism.

METHODS: We measured the expression of miR-567 in 37 paired normal and stomach tumor specimens, as well as GC cell lines by Real-time PCR. The functional effects of miR-567 were validated using in vitro and in vivo assays. Dual-luciferase report assays and Chromatin immunoprecipitation (ChIP) assay were conducted for target evaluation, western blot assay was used to confirm the relationships.  

FINDINGS:  Our data showed that miR-567 was downregulated in gastric tissues and gastric cancer cells compared with normal tissues and gastric epithelial cells. In vitro, Gain- and lose-of-function assays showed miR-567 not only weakened cells proliferative ability, but also sensitized GC cells to 5-FU and oxaliplatin. In vivo, miR-567 overexpression significantly repressed the tumorigenesis of GC cells compared with the vector control. Mechanistic analyses showed that PIK3AP1 activated AKT phosphorylation in GC, miR-567 directly targeted PIK3AP1 to inactivate PI3K/AKT/c-Myc and regulated its own expression. This feedback loop further inhibited cells proliferation via PI3K/AKT pathway.  

INTERPRETATION:  Our studies revealed that as a tumor suppressor, miR-567 repressed tumor growth, cells proliferation and increased drug sensitivity via a miR-567-PIK3AP1- PI3K/AKT-c-Myc feedback loop. These results suggest that miR-567 may serve as a target for chemoresistance and a potential prognostic biomarker for gastric cancer.

FUNDING STATEMENT: This work was supported by the National Natural Science Foundation of China (Nos. 81572813, 81773082, 81702903, 81872423), Guangdong Natural Science Foundation (2017A030310038, 2018B030311036), Fork Ying Tung Education Foundation (161035), Higher Education Fund Project of Guangzhou (2012C070) and Special Funds for the Cultivation of Guangdong College Students' Scientific and Technological Innovation. (“Climbing Program” Special Funds) (pdjhb0102).

DECLARATION OF INTERESTS: The authors have declared that no conflict of interest exists.

ETHICS APPROVAL STATEMENT: All experiments performed are endorsed by the Ethics Committee of Southern Medical University and complied with the Declaration of Helsinki. No informed consent was required because data were going to be analyzed anonymously.

All animal experiments were carried out with the approval of the Southern Medical University Animal Care and Use Committee in accordance with the guidelines for the ethical treatment of animals.

Keywords: microRNA-567; gastric cancer; chemoresistance; tumor growth; prognostic biomarker

Suggested Citation

Zhang, Feifei and Li, Kaitao and Yao, Xueqing and Wang, Hui and Li, Weidong and Wu, Juan and Li, Mingyi and Zhou, Rui and Xu, Lijun and Zhao, Liang, A miR-567-PIK3AP1- PI3K/AKT-c-Myc Feedback Loop Regulates Tumor Growth and Chemoresistance in Gastric Cancer (March 28, 2019). Available at SSRN: https://ssrn.com/abstract=3362441 or http://dx.doi.org/10.2139/ssrn.3362441

Feifei Zhang (Contact Author)

Southern Medical University, Nanfang Hospital, Department of Pathology ( email )

Guangzhou, Guangdong Province
China

Kaitao Li

Southern Medical University - Nanfang Hospital ( email )

Xueqing Yao

Guangdong Academy of Medical Sciences - Guangdong General Hospital ( email )

Daxuecheng Outer Ring E Rd,
Panyu Qu
Guangzhou Shi, Guangdong Sheng
China

Hui Wang

Guangzhou Medical University ( email )

195 Dongfeng W Rd
Yuexiu Qu
Guangzhou Shi, Guangdong Sheng 510080
China

Weidong Li

Guangzhou Medical University ( email )

195 Dongfeng W Rd
Yuexiu Qu
Guangzhou Shi, Guangdong Sheng 510080
China

Juan Wu

Guangzhou Medical University ( email )

195 Dongfeng W Rd
Yuexiu Qu
Guangzhou Shi, Guangdong Sheng 510080
China

Mingyi Li

Guangzhou Medical University ( email )

195 Dongfeng W Rd
Yuexiu Qu
Guangzhou Shi, Guangdong Sheng 510080
China

Rui Zhou

Southern Medical University - Department of Pathology ( email )

Guangzhou
China

Lijun Xu

Southern Medical University, School of Basic Medical Sciences, Department of Pathology ( email )

Guangzhou
China

Liang Zhao

Southern Medical University, Nanfang Hospital, Department of Pathology ( email )

Guangzhou, Guangdong Province
China

Southern Medical University, School of Basic Medical Sciences, Department of Pathology ( email )

Guangzhou
China

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