Exosomal transfer of miR-501 confers doxorubicin resistance and tumorigenesis via targeting of BLID in gastric cancer
Authors: Ying Lu
Lianhong Li
Yunchao Xu
Hongwei Guan
Jinyao Zhao
Bo Song
Xu Liu
Bo Wang
Sizhu Hou
Shujun Fan
Shilin Xia
Li Hou
Yue Du
Jinli Huang
Jingfang Ju
Bo Huang
Zijie Ding
Jianwu Tang
Zhiyue Li
Xiaotang Yu
Shuo An
Journal: Cancer Letters (2019)
Discipline: CLINICAL MEDICINE
Keywords: Chemoresistance; Doxorubicin; Exosome; Gastric cancer; microRNA-501-5p.
Affiliations: Department of Pathology and Forensics, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China., Teaching Laboratory of Morphology, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China., Institute of Cancer Stem Cells, Second Affiliated Hospital Collaborative Innovation Center of Oncology, Dalian Medical University, Dalian, 116044, China., Clinical Laboratory of Integrative Medicine, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China., Department of Clinical Medicine, Grade 2016, Dalian Medical University, Dalian, 116044, China., Department of Clinical Medicine, Grade 2017, Dalian Medical University, Dalian, 116044, China., Department of Pathology, Liaoning Cancer Hospital & Institute, Shenyang, 110042, China., Translational Research Laboratory, Department of Pathology, Stony Brook University, Stony Brook, NY, 11794, USA. Electronic address: ., Department of Pathology, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China. Electronic address: ., Department of Pathology and Forensics, College of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China. Electronic address: .

Abstract:  Exosomal transfer of oncogenic miRNAs can enhance recipient cell growth, metastasis and chemoresistance. Currently we found that microRNA-501-5p (miR-501) was overexpressed in doxorubicin-resistant gastric cancer (GC) SGC7901/ADR cell-secreted exosomes (ADR Exo) than that in SGC7901 cell-secreted exosomes (7901 Exo). ADR Exo was internalized by SGC7901, and a Cy3-miR-501 mimic was transferred from SGC7901/ADR to SGC7901 via exosomes. ADR Exo conferred doxorubicin resistance, proliferation, migration and invasion abilities to negative control miRNA inhibitor-expressing GC cells, whereas it inhibited apoptosis. MiR-501 knockdown or BH3-like motif-containing protein, cell death inducer (BLID) overexpression could reverse the effects of ADR Exo on recipient cells. SGC7901 cells cocultured with SGC7901/ADR prior to treatment with GW4869 or transfection of a miR-501 inhibitor were sensitive to doxorubicin and exhibited attenuated proliferation, migration and invasion and increased apoptosis. The intratumoral injection of ADR Exo into negative control miRNA inhibitor-expressing SGC7901 cells induced rapid subcutaneous tumor growth and resistance to doxorubicin compared to that of miR-501 knockdown or BLID-overexpressing cells. This effect is possibly achieved by exosomal miR-501-induced downregulation of BLID, subsequent inactivation of caspase-9/-3 and phosphorylation of Akt. Exosomal miR-501 might be a therapeutic target for GC. 

Retracted: No

PubPeer comments:
 Figure 5 C and F Potential overlap between the Invasion of 7901NCi (Fig. 5C) and Invasion of ADR 501i+siBLID (Fig 5F). ![] , 
 #1 Two panels of 5B overlap after a 90-deg turn and rescaling. ![file] , 
 5C: Two panels show the same image apart from a 40-deg rotation. ![file] , 
 5E: ![file] ,