c-Myc shuttled by tumour-derived extracellular vesicles promotes lung bronchial cell proliferation through miR-19b and miR-92a

Cristina Borzi, Linda Calzolari, Anna M. Ferretti, Laura Caleca, Ugo Pastorino, Gabriella Sozzi, Orazio Fortunato

Research output: Contribution to journalArticle

Abstract

Lung cancer causes approximately one fifth of all cancer deaths. Tumour cells actively communicate with the surrounding microenvironment to support malignant progression. Extracellular vesicles (EVs) play a pivotal role in intercellular communication and modulate recipient cells by delivering their contents, including proteins and nucleic acids such as microRNAs (miRNAs). We isolated EVs from the conditioned medium (CM) of human lung cancer cell lines and plasma of lung cancer patients and cancer-free smokers using an ultracentrifugation method. A significant increase in bronchial HBEC-KRASV12high cell proliferation, confirmed by cell cycle analysis, was observed after treatment with cancer-derived EVs. Lung cancer-derived EVs induced transcription of the pri-miR-92a gene, resulting in the overexpression of mature miR-19b and miR-92a in recipient bronchial cells. Modulation of these two miRNAs using miRNA mimics or inhibitors confirmed their ability to promote proliferation. In silico analysis and experimental validation showed that miR-19b and miR-92a impaired the TGF-beta (TGFB) pathway and identified TGFBRI and TGFBRII as target genes involved in EV-mediated bronchial cell proliferation. Interestingly, the oncoprotein c-Myc, a well-known miR-17-92 cluster activator, was detected only in the EVs derived from lung cancer patients and cell lines and was able to modulate the proliferation of HBEC-KRASV12high recipient cells. These data support the role of c-Myc shuttling in lung cancer-derived EVs in inducing the upregulation of onco-miR-19b and miR-92a expression with concomitant impairment of the TGFB signalling pathway in recipient cells.

Original languageEnglish
Article number759
JournalCell Death and Disease
Volume10
Issue number10
DOIs
Publication statusPublished - Oct 1 2019

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Cell Proliferation
Lung Neoplasms
Lung
MicroRNAs
Neoplasms
Transforming Growth Factor beta
Cell Line
Oncogene Proteins
Ultracentrifugation
Conditioned Culture Medium
Extracellular Vesicles
Computer Simulation
Nucleic Acids
Genes
Cell Cycle
Up-Regulation
Proteins
Therapeutics

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

c-Myc shuttled by tumour-derived extracellular vesicles promotes lung bronchial cell proliferation through miR-19b and miR-92a. / Borzi, Cristina; Calzolari, Linda; Ferretti, Anna M.; Caleca, Laura; Pastorino, Ugo; Sozzi, Gabriella; Fortunato, Orazio.

In: Cell Death and Disease, Vol. 10, No. 10, 759, 01.10.2019.

Research output: Contribution to journalArticle

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