MiR-199a-modified exosomes from adipose tissue-derived mesenchymal stem cells improve hepatocellular carcinoma chemosensitivity through mTOR pathway

被引：274

作者：

Lou, Guohua ^{[1
]}

Chen, Liang ^{[2
]}

Xia, Caixia ^{[3
]}

Wang, Weina ^{[1
]}

Qi, Jinjin ^{[1
]}

Li, Aichun ^{[1
]}

Zhao, Liying ^{[4
]}

Chen, Zhi ^{[1
]}

Zheng, Min ^{[1
,4
]}

Liu, Yanning ^{[1
,4
]}

机构：

[1] Zhejiang Univ, Collaborat Innovat Ctr Diag & Treatment Infect Di, State Key Lab Diag & Treatment Infect Dis, Natl Clin Res Ctr Infect Dis,Affiliated Hosp 1,Co, 79 Qingchun Rd,6A-17, Hangzhou 310003, Peoples R China

[2] Zhejiang Univ, Affiliated Hosp 1, Thyroid Dis Diag & Treatment Ctr, Sch Med, Hangzhou, Peoples R China

[3] Zhejiang Univ, Affiliated Hangzhou Peoples Hosp 1, Dept Infect Dis, Sch Med, Hangzhou, Peoples R China

[4] Zhejiang Univ, Affiliated Hosp 2, Dept Infect Dis, Sch Med, Hangzhou, Peoples R China

来源：

JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH | 2020年 / 39卷 / 01期

基金：

中国国家自然科学基金;

关键词：

Mesenchymal stem cell; Exosome; miR-199a-3p; Hepatocellular carcinoma; Chemosensitivity; THERAPY; GROWTH; PROLIFERATION; SENSITIVITY; METASTASIS;

D O I：

10.1186/s13046-019-1512-5

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background MiR-199a-3p (miR-199a) can enhance the chemosensitivity of hepatocellular carcinoma (HCC). Because of the easy degradation of miRNA by direct infusion, effective vehicle-mediated delivery of miR-199a may represent a new strategy for improving HCC chemotherapy. Considering mesenchymal stem cell (MSC)-derived exosomes as promising natural nanovectors for drug and molecule delivery, we aimed to determine whether exosomes from adipose tissue-derived MSCs (AMSCs) could be used to deliver miR-199a and improve HCC chemosensitivity. Methods MiR-199a-modified AMSCs (AMSC-199a) were constructed by miR-199a lentivirus infection and puromycin selection. MiR-199-modified exosomes (AMSC-Exo-199a) were isolated from the supernatant of AMSC-199a and were assessed by transmission electron microscopy, nanoparticle tracking analysis, and flow cytometry analysis. The expression levels of miR-199a in HCC samples, AMSCs, exosomes, and HCC cells were quantified by real-time PCR. The effects of AMSC-Exo-199a on HCC chemosensitivity were determined by cell proliferation and apoptosis assays and by i.v. injection into orthotopic HCC mouse models with doxorubicin treatment. MTOR, p-4EBP1 and p-70S6K levels in HCC cells and tissues were quantified by Western blot. Results AMSC-Exo-199a had the classic characteristics of exosomes and could effectively mediate miR-199a delivery to HCC cells. Additionally, AMSC-Exo-199a significantly sensitized HCC cells to doxorubicin by targeting mTOR and subsequently inhibiting the mTOR pathway. Moreover, i.v.-injected AMSC-Exo-199a could distribute to tumor tissue and markedly increased the effect of Dox against HCC in vivo. Conclusions AMSC-Exo-199a can be an effective vehicle for miR-199a delivery, and they effectively sensitized HCC to chemotherapeutic agents by targeting mTOR pathway. AMSC-Exo-199a administration may provide a new strategy for improving HCC chemosensitivity.

引用

页数：9

共 34 条

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