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

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Abstract

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.

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Most cited references 18

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Origins and Mechanisms of miRNAs and siRNAs.

Richard W. Carthew, Erik J. Sontheimer (2009)

Over the last decade, approximately 20-30 nucleotide RNA molecules have emerged as critical regulators in the expression and function of eukaryotic genomes. Two primary categories of these small RNAs--short interfering RNAs (siRNAs) and microRNAs (miRNAs)--act in both somatic and germline lineages in a broad range of eukaryotic species to regulate endogenous genes and to defend the genome from invasive nucleic acids. Recent advances have revealed unexpected diversity in their biogenesis pathways and the regulatory mechanisms that they access. Our understanding of siRNA- and miRNA-based regulation has direct implications for fundamental biology as well as disease etiology and treatment.

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Targeting mTOR for cancer therapy

Hui Hua, Qingbin Kong, Hongying Zhang … (2019)

Mechanistic target of rapamycin (mTOR) is a protein kinase regulating cell growth, survival, metabolism, and immunity. mTOR is usually assembled into several complexes such as mTOR complex 1/2 (mTORC1/2). In cooperation with raptor, rictor, LST8, and mSin1, key components in mTORC1 or mTORC2, mTOR catalyzes the phosphorylation of multiple targets such as ribosomal protein S6 kinase β-1 (S6K1), eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), Akt, protein kinase C (PKC), and type-I insulin-like growth factor receptor (IGF-IR), thereby regulating protein synthesis, nutrients metabolism, growth factor signaling, cell growth, and migration. Activation of mTOR promotes tumor growth and metastasis. Many mTOR inhibitors have been developed to treat cancer. While some of the mTOR inhibitors have been approved to treat human cancer, more mTOR inhibitors are being evaluated in clinical trials. Here, we update recent advances in exploring mTOR signaling and the development of mTOR inhibitors for cancer therapy. In addition, we discuss the mechanisms underlying the resistance to mTOR inhibitors in cancer cells.

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MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells.

Francesca Fornari, Maddalena Milazzo, Pasquale Chieco … (2010)

MicroRNAs (miRNA) have rapidly emerged as modulators of gene expression in cancer in which they may have great diagnostic and therapeutic import. MicroRNA-199a-3p (miR-199a-3p) is downregulated in several human malignancies including hepatocellular carcinoma (HCC). Here, we show that miR-199a-3p targets mammalian target of rapamycin (mTOR) and c-Met in HCC cells. Restoring attenuated levels of miR-199a-3p in HCC cells led to G(1)-phase cell cycle arrest, reduced invasive capability, enhanced susceptibility to hypoxia, and increased sensitivity to doxorubicin-induced apoptosis. These in vitro findings were confirmed by an analysis of human HCC tissues, which revealed an inverse correlation linking miR-199a-3p and mTOR as well as a shorter time to recurrence after HCC resection in patients with lower miR-199a-3p expression. These results suggest that tactics to regulate mTOR and c-Met by elevating levels of miR-199a-3p may have therapeutic benefits in highly lethal cancers such as HCC.

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Author and article information

Contributors

Min Zheng: minzheng@zju.edu.cn

Yanning Liu: liuyanning@zju.edu.cn

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 2 January 2020

Publication date PMC-release: 2 January 2020

Publication date Collection: 2020

Volume: 39

Electronic Location Identifier: 4

Affiliations

[1 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, , Zhejiang University, ; 79# Qingchun Road, 6A-17, Hangzhou, 310003 China

[2 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Thyroid Disease Diagnosis and Treatment Center, the First Affiliated Hospital, School of Medicine, , Zhejiang University, ; Hangzhou, China

[3 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Department of Infectious Diseases, Affiliated Hangzhou First People’s Hospital, , Zhejiang University School of Medicine, ; Hangzhou, China

[4 ]ISNI 0000 0004 1759 700X, GRID grid.13402.34, Department of Infectious Disease, the Second Affiliated Hospital, , Zhejiang University School of Medicine, ; Hangzhou, China

Article

Publisher ID: 1512

DOI: 10.1186/s13046-019-1512-5

PMC ID: 6941283

PubMed ID: 31898515

SO-VID: 31a5ce55-9fcd-48d2-b31e-43982d7a4b51

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 12 October 2019

Date accepted : 18 December 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;

Award ID: 81870428

Award Recipient : Guohua Lou

Funded by: Key R & D Projects of Zhejiang Province

Award ID: 2018C03019

Award Recipient : Yanning Liu

Funded by: State S&T Project of 13th Five Years

Award ID: 2018ZX10302206

Award Recipient : Min Zheng

Funded by: FundRef http://dx.doi.org/10.13039/501100008867, Department of Education of Zhejiang Province;

Award ID: Y201738069

Award Recipient : Liying Zhao

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: mesenchymal stem cell,exosome,mir-199a-3p,hepatocellular carcinoma,chemosensitivity

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: mesenchymal stem cell, exosome, mir-199a-3p, hepatocellular carcinoma, chemosensitivity

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

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Abstract

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Methods

Results

Conclusions

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Karger: Oncology

Most cited references 18

Origins and Mechanisms of miRNAs and siRNAs.

Targeting mTOR for cancer therapy

MiR-199a-3p regulates mTOR and c-Met to influence the doxorubicin sensitivity of human hepatocarcinoma cells.

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